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Molecular cause of cramps, spasms and strengthening in muscles? (incl. intro to muscle contraction)

Molecular cause of cramps, spasms and strengthening in muscles? (incl. intro to muscle contraction)


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When motor neurons are stimulated to trigger an action potential, this potential propagates down the spine, eventually reaching a neuromuscular junction, causing the release of acetylcholine (ACh).

ACh binds to nicotinic ACh receptors (nAChR) on the muscle fibers, leading to an action potential. The nAChR is a non-selective, ligand-gated ion channel, permeable to sodium-, potassium- and calcium ions. This means sodium ions will flow in, leading to depolarization, but potassium will flow out, working towards hyperpolarization.

If enough of these channels are opened, the post-synaptic membrane potential will be drawn towards $E_{Na}$ enough to reach a threshold, so that voltage-gated sodium channels open on the post-synaptic membrane, causing a post-synaptic action potential.

This action potential travels down inward extrusions of the plasma membrane, called transverse (T) tubules. Is the membrane continuous along these tubules, or does the tubule just end somewhere inside the muscle fiber? Anyway, the action potential comes in contact with the muscle fiber version of an endoplasmic reticulum: The sarcoplasmic reticulum (SR).

Upon contact with the action potential, the calcium ion channels in the SR open, causing calcium ions to flow into the cytosol. Here they bind to troponin complexes on the tropomyosin protein - a regulatory protein, that twists around the thin filaments of the muscle fiber. In short, when calcium ions bind to troponin, it reveals binding sites for myosin on the thin filaments, letting the muscle contraction cycle of the myosin heads proceed, and the muscle contracts!

When the stimulus goes away, calcium ions are transported back into the SR, and myosin has nowhere to bind, thus the cycle is halted, and the muscle relaxes.

When the muscle is twitching… is this neurological of nature, or is it related to a molecular cause in the muscle itself?

When the muscle is cramping… I'm almost certain this arises in the muscle. What causes it? A malfunction with regard to the calcium ions?

Lastly, and on a slightly different subject, what are the microlesions in the muscles that occur during strength training, and what is the overcompensation that happens? The basis of this might not be entirely on the molecular level I feel.


I think a lot of your questions try to split the hair; is this happening at the chemical or the histological level and I do get what you're asking, but you should know that the distinction is often not worth making. Pretty much whenever a neuron's involved, the interesting biology is multi-scale.

Is the membrane continuous along these tubules, or does the tubule just end somewhere inside the muscle fiber?

The membranes are continuous.

When the muscle is twitching… is this neurological of nature, or is it related to a molecular cause in the muscle itself?

Most things you'd call a muscle twitch are at the whole-muscle-group scale, involving the coordinated contraction of many individual motor units, so it's basically neurological.

When the muscle is cramping… I'm almost certain this arises in the muscle. What causes it? A malfunction with regard to the calcium ions?

A muscle cramp is a colloquialism for a couple of things that are quite different from each other. Overall, as with the previous question, if someone's experiencing a muscle cramp that means it's a fairly macroscopic phenomenon and it likely involves a whole group of muscle filaments, so it's neurological. Most spasms and cramps are neurologically mediated.

The connections with electrolyte balances (cramps from low sodium, potassium, magnesium, or calcium) also hint at the neurological basis because neurons act on each other (and on muscles) by forming or dissipating ion gradients. You may know that low dietary calcium can lead to muscle cramps; if this was relevant to the calcium release within the myocyte (from the sarcoplasmic reticulum) then the calcium-starved muscles wouldn't be expected to chronically contract (which requires calcium) but to chronically relax.

That being said, there's a lot of room for feedback mechanisms. So, let's say a person experiences a muscle tear; the tear is small enough that it doesn't compromise the function of the entire muscle group. In this case it's adaptive for the local damage to 'signal' to the rest of the muscle group to initiate spasm so as to stabilize the damaged structures as they're repaired. In this scenario the local damage would 'inform' a neurological (and/or endocrine) response that actually effects the spasm.

Lastly, and on a slightly different subject, what are the microlesions in the muscles that occur during strength training, and what is the overcompensation that happens?

Last time I was updated on this (not my bag), there were some large questions remaining. The tricks used by growing muscle to establish large, regular arrays of contractile machinery, that is organized over many spatial orders of magnitude, are poorly understood. There are structures that monitor the overall organization and that detect any large deformations. Regarding overcompensation, let's play through a generic scenario. A muscle cell is loaded too much and becomes physically damaged. It has to stop taking orders (stop responding to contraction/relaxation signals) and to initiate repairs. The overcompensation results because muscle cell's not really capable of knowing how large it was before the damage, so the safe amount of repairs to do is extra. Probably there are epigenetic processes that let a muscle cell 'count' the number of times its been greatly damaged and to scale-up the response appropriately.

If you just consider two likely sources of damage -- mechanical strain and lactic acidosis -- you can see that there are widely different mechanisms that would be required to detect the damage and to initiate repairs.


Muscle cells work by detecting a flow of electrical impulses from the brain which signals them to contract through the release of calcium by the sarcoplasmic reticulum. Fatigue (reduced ability to generate force) may occur due to the nerve, or within the muscle cells themselves.

Nerves are responsible for controlling the contraction of muscles, determining the number, sequence and force of muscular contraction. Most movements require a force far below what a muscle could potentially generate, and nervous fatigue is seldom an issue. But, during extremely powerful contractions that are close to the upper limit of a muscle's ability to generate force, nervous fatigue (enervation) — in which the nerve signal weakens — can be a limiting factor in untrained individuals.

In novice strength trainers, the muscle's ability to generate force is most strongly limited by nerve’s ability to sustain a high-frequency signal. After a period of maximum contraction, the nerve’s signal reduces in frequency and the force generated by the contraction diminishes. There is no sensation of pain or discomfort, the muscle appears to simply ‘stop listening’ and gradually cease to contract, often going backwards. Often there is insufficient stress on the muscles and tendons to cause delayed onset muscle soreness following the workout.

Part of the process of strength training is increasing the nerve's ability to generate sustained, high frequency signals which allow a muscle to contract with its greatest force. This neural training can cause several weeks of rapid gains in strength, which level off once the nerve is generating maximum contractions and the muscle reaches its physiological limit. Past this point, training effects increase muscular strength through myofibrillar or sarcoplasmic hypertrophy and metabolic fatigue becomes the factor limiting contractile force.

Though not universally used, ‘metabolic fatigue’ is a common term for the reduction in contractile force due to the direct or indirect effects of two main factors:

  1. Shortage of fuel (substrates) within the muscle fiber
  2. Accumulation of substances (metabolites) within the muscle fiber, which interfere either with the release of calcium (Ca 2+ ) or with the ability of calcium to stimulate muscle contraction.

Substrates Edit

Substrates within the muscle serve to power muscular contractions. They include molecules such as adenosine triphosphate (ATP), glycogen and creatine phosphate. ATP binds to the myosin head and causes the ‘ratchetting’ that results in contraction according to the sliding filament model. Creatine phosphate stores energy so ATP can be rapidly regenerated within the muscle cells from adenosine diphosphate (ADP) and inorganic phosphate ions, allowing for sustained powerful contractions that last between 5–7 seconds. Glycogen is the intramuscular storage form of glucose, used to generate energy quickly once intramuscular creatine stores are exhausted, producing lactic acid as a metabolic byproduct.

Substrate shortage is one of the causes of metabolic fatigue. Substrates are depleted during exercise, resulting in a lack of intracellular energy sources to fuel contractions. In essence, the muscle stops contracting because it lacks the energy to do so.

Metabolites Edit

Metabolites are the substances (generally waste products) produced as a result of muscular contraction. They include chloride, potassium, lactic acid, ADP, magnesium (Mg 2+ ), reactive oxygen species, and inorganic phosphate. Accumulation of metabolites can directly or indirectly produce metabolic fatigue within muscle fibers through interference with the release of calcium (Ca 2+ ) from the sarcoplasmic reticulum or reduction of the sensitivity of contractile molecules actin and myosin to calcium.

Chloride Edit

Intracellular chloride partially inhibits the contraction of muscles. Namely, it prevents muscles from contracting due to "false alarms", small stimuli which may cause them to contract (akin to myoclonus).

Potassium Edit

High concentrations of potassium (K + ) also causes the muscle cells to decrease in efficiency, causing cramping and fatigue. Potassium builds up in the t-tubule system and around the muscle fiber as a result of action potentials. The shift in K + changes the membrane potential around the muscle fiber. The change in membrane potential causes a decrease in the release of calcium (Ca 2+ ) from the sarcoplasmic reticulum. [1]

Lactic acid Edit

It was once believed that lactic acid build-up was the cause of muscle fatigue. [2] The assumption was lactic acid had a "pickling" effect on muscles, inhibiting their ability to contract. Though the impact of lactic acid on performance is now uncertain, it may assist or hinder muscle fatigue.

Produced as a by-product of fermentation, lactic acid can increase intracellular acidity of muscles. This can lower the sensitivity of contractile apparatus to Ca 2+ but also has the effect of increasing cytoplasmic Ca 2+ concentration through an inhibition of the chemical pump that actively transports calcium out of the cell. This counters inhibiting effects of potassium on muscular action potentials. Lactic acid also has a negating effect on the chloride ions in the muscles, reducing their inhibition of contraction and leaving potassium ions as the only restricting influence on muscle contractions, though the effects of potassium are much less than if there were no lactic acid to remove the chloride ions. Ultimately, it is uncertain if lactic acid reduces fatigue through increased intracellular calcium or increases fatigue through reduced sensitivity of contractile proteins to Ca 2+ .

Lactic acid is now used as a measure of endurance training effectiveness and VO2 max. [3]

Muscle weakness may be due to problems with the nerve supply, neuromuscular disease (such as myasthenia gravis) or problems with muscle itself. The latter category includes polymyositis and other muscle disorders.

Muscle fatigue may be due to precise molecular changes that occur in vivo with sustained exercise. It has been found that the ryanodine receptor present in skeletal muscle undergoes a conformational change during exercise, resulting in "leaky" channels that are deficient in calcium release. These "leaky" channels may be a contributor to muscle fatigue and decreased exercise capacity. [4]

Fatigue has been found to play a big role in limiting performance in just about every individual in every sport. In research studies, participants were found to show reduced voluntary force production in fatigued muscles (measured with concentric, eccentric, and isometric contractions), vertical jump heights, other field tests of lower body power, reduced throwing velocities, reduced kicking power and velocity, less accuracy in throwing and shooting activities, endurance capacity, anaerobic capacity, anaerobic power, mental concentration, and many other performance parameters when sport specific skills are examined. [5] [6] [7] [8] [9]

Electromyography is a research technique that allows researchers to look at muscle recruitment in various conditions, by quantifying electrical signals sent to muscle fibers through motor neurons. In general, fatigue protocols have shown increases in EMG data over the course of a fatiguing protocol, but reduced recruitment of muscle fibers in tests of power in fatigued individuals. In most studies, this increase in recruitment during exercise correlated with a decrease in performance (as would be expected in a fatiguing individual). [10] [11] [12] [13]

Median power frequency is often used as a way to track fatigue using EMG. Using the median power frequency, raw EMG data is filtered to reduce noise and then relevant time windows are Fourier Transformed. In the case of fatigue in a 30-second isometric contraction, the first window may be the first second, the second window might be at second 15, and the third window could be the last second of contraction (at second 30). Each window of data is analyzed and the median power frequency is found. Generally, the median power frequency decreases over time, demonstrating fatigue. Some reasons why fatigue is found are due to action potentials of motor units having a similar pattern of repolarization, fast motor units activating and then quickly deactivating while slower motor units remain, and conduction velocities of the nervous system decreasing over time. [14] [15] [16] [17]


Muscle Fatigue

Muscle fatigue occurs following a period of sustained activity.

Learning Objectives

Describe the factors involved in metabolic muscle fatigue

Key Takeaways

Key Points

  • Muscle fatigue refers to the decline in muscle force generated over time.
  • Several factors contribute to muscle fatigue, the most important being lactic acid accumulation.
  • With sufficient exercise the onset of muscle fatigue can be delayed.

Key Terms

  • Lactic Acid: A byproduct of anaerobic respiration which strongly contributes to muscle fatigue.

Muscle fatigue refers to the decline in muscle force generated over sustained periods of activity or due to pathological issues. Muscle fatigue has a number of possible causes including impaired blood flow, ion imbalance within the muscle, nervous fatigue, loss of desire to continue, and most importantly, the accumulation of lactic acid in the muscle.

Lactic Acid Accumulation

Long-term muscle use requires the delivery of oxygen and glucose to the muscle fiber to allow aerobic respiration to occur, producing the ATP required for muscle contraction. If the respiratory or circulatory system cannot keep up with demand, then energy will be generated by the much less efficient anaerobic respiration.

In aerobic respiration, pyruvate produced by glycolysis is converted into additional ATP molecules in the mitochondria via the Krebs Cycle. With insufficient oxygen, pyruvate cannot enter the Krebs cycle and instead accumulates in the muscle fiber. Pyruvate is continually processed into lactic acid. With pyruvate accumulation, lactic acid production is also increased. This lactic acid accumulation in the muscle tissue reduces the pH, making it more acidic and producing the stinging feeling in muscles when exercising. This further inhibits anaerobic respiration, inducing fatigue.

Lactic acid can be converted back to pyruvate in well-oxygenated muscle cells however, during exercise the focus in on maintaining muscle activity. Lactic acid is transported to the liver where it can be stored prior to conversion to glucose in the presence of oxygen via the Cori Cycle. The amount of oxygen required to restore the lactic acid balance is often referred to as the oxygen debt.

Ion Imbalance

Contraction of a muscle requires Ca + ions to interact with troponin, exposing the actin binding site to the myosin head. With extensive exercise, the osmotically active molecules outside of the muscle are lost through sweating. This loss changes the osmotic gradient, making it more difficult for the required Ca + ions to be delivered to the muscle fiber. In extreme cases, this can lead to painful, extended maintenance of muscle contraction or cramp.

Nervous Fatigue and Loss of Desire

Nerves are responsible for controlling the contraction of muscles, determining the number, sequence, and force of muscular contractions. Most movements require a force far below what a muscle could potentially generate, and barring disease nervous fatigue is seldom an issue. However, loss of desire to exercise in the face of increasing muscle soreness, respiration, and heart rate can have a powerful negative impact on muscle activity.

Metabolic Fatigue

Depletion of required substrates such as ATP or glycogen within a muscle result in fatigue as the muscle is not able to generate energy to power contractions. Accumulation of metabolites from these reactions other than lactic acid, such as Mg 2+ ions or reactive oxygen species, can also induce fatigue by interfering with the release of Ca + ions from the sarcoplasmic reticulum or through reduction in the sensitivity of troponin to Ca + .

Exercise and Aging

With sufficient training, the metabolic capacity of a muscle can change, delaying the onset of muscle fatigue. Muscle specified for high-intensity anaerobic exercise will synthesise more glycolytic enzymes, whereas muscle for long endurance aerobic exercise will develop more capillaries and mitochondria. Additionally, with exercise, improvements to the circulatory and respiratory systems can facilitate better delivery of oxygen and glucose to the muscle.

With aging, levels of ATP, CTP, and myoglobin begin to decline, reducing the muscle’s ability to function. Muscle fibers shrink or are lost and surrounding connective tissue hardens, making muscle contraction slower and more difficult. Exercise throughout life can help reduce the impact of aging by maintaining a healthy oxygen supply to the muscle.


Preparations

Botox cosmetic ®

Botulinum toxin type A (BOTOX ® Allergan, Irvine, Calif) was the first commercially available type in the United States. Its safety is well established. The drawback is that once the contents of a vial are dissolved, the reconstituted product loses its potency. Therefore, dermatologists tend to schedule the treatments for several patients on the same day so that they can use the entire contents of the vial. This scheduling may be inconvenient for some patients, who may decide not to proceed.

Dysport ® (Ipsen pharmaceuticals) (Botulinum toxin type A)

In Europe, botulinum toxin of the same serotype is marketed by another company (Dysport ® Speywood, United Kingdom). One unit of BOTOX ® has a potency that is approximately equal to 4 unit of Dysport ® .

Xeomin ®

Xeomin ® is the third botulinum toxin type A licensed in the UK. Xeomin ® is an innovative Botulinum type A formulation, in which the complexing proteins have been removed by an extensive purification process from the botulinum toxin complex. In contrast to the other commercially available preparations, Xeomin ® contains the pure 150 kD neurotoxin. Xeomin ® , without the complexing proteins, has the lowest content of bacterial protein of all of the available botulinum toxins and furthermore show that repeated application of Xeomin ® , even in high doses, does not induce the formation of neutralising anti-bodies. Clinical studies have suggested that Xeomin ® has been found similar in its effect to Botox ® in clinical studies. one unit of Xeomin ® is equal to 1 unit of Botox ®

Neurobloc ®

Neurobloc ® (Myobloc) is a registered trademark of Solstice Neurosciences Inc, San Francisco, Calif. It is a Clostridium botulinum type - B neurotoxin complex which became available in the U.K. in 2001.There is limited experience in the use of this type of toxin, and the product does not currently have approval for cosmetic use anywhere in the world. It is marketed as Myobloc ® Injectable Solution (botulinum toxin type B) in the United States and Canada and Neurobloc ® in Europe.

Myobloc (Elan)

Myobloc ® (Elan), Dysport ® when reconstituted, has a shelf life of more than 12 months. This feature is advantageous in terms of patient scheduling. However, larger volumes of Myobloc ® may be needed to obtain effects similar to those of Botox ® . Antibody formation against this product may occur more often because of its higher protein content.

Reconstitution and storage

Botox ® is stored in a freezer at or below 𢄥ଌ. The package insert recommends reconstitution using sterile saline without preservative 0.9% sodium chloride is the preferred diluent. Some investigators suggest that reconstitution with sterile saline solution with preservative (0.9% benzyl alcohol) reduces microbial contamination and provides a weak local anesthetic effect.

Botox ® is denatured easily by bubbling or agitation gently inject the diluent onto the inside wall of the vial and discard the vial if a vacuum does not pull the diluent in. The final dilution of Botox ® is mostly a matter of personal preference 100 units commonly are reconstituted in 1-10 ml of diluent. Theoretically, more concentrated solutions reduce reliability in delivering a specific unit dose, and more dilute solutions lead to greater diffusion of the toxin.

Once reconstituted, Botox ® is kept refrigerated at 2-8ଌ. The reconstituted Botox ® should be used within 4 hours. One study found no loss of activity at 6 hours but a 44% loss after 12 hours and a 70% loss with refreezing at 1-2 weeks.[17] Other authors report no substantial loss of potency in a 10 U/1 ml reconstituted solution kept refrigerated for 1 month.

How botulinum toxin is given

Botulinum toxin is injected into affected muscles or glands using a 30-gauge 1-inch needle. Doses are tailored according to the mode of use and individual patients, and the dose depends on the mass of muscle being injected: The larger the muscle mass the higher the dose required. However, lower doses may be required in patients with preexisting weakness and in females.

Toxin injections are given through hollow teflon coated needles directly into affected/overactive muscles. In localized muscle overactivity, especially, in delicate places such as strabismus, the injections are usually guided by electromyography.

Electromyograph monitoring

Many authors[18] have chosen to administer injections under the guidance of electromyograph (EMG) monitoring. This technique involves using a 27-gauge (1.5 in) polytef-coated EMG needle connected to an EMG recorder by an alligator clip on its shaft. The patient is asked to contract the muscle in question. The injection is placed where the maximal EMG recording can be found within the muscle. This technique ensures that the injection is at the point of the muscle that is contributing most to the hyperfunctional facial line. As these injections have become routine, many centers have obtained satisfactory results without EMG guidance. Many physicians use a readily available 30-gauge insulin syringe instead. However, EMG-guided injections remain a useful adjunct in patients who have residual function after their initial injection.

Precautions after botulinum toxin injection

As a general precaution, one should go home immediately and rest after Botox ® . Do nothing strenuous for one or two days and refrain from laser/IPL treatments, facials and facial massage for one to two weeks after injections. This is to minimize toxins dislodging and traveling (due to increased blood circulation or direct pressure) to the surrounding muscles.

Follow-up monitoring

The weakness induced by injection with botulinum toxin A usually lasts about three months. Hence, further injections at regular intervals are required and the interval varies widely depending on the dose and individual susceptibility. Response after the injections should be assessed both by subjective and by objective measures. Most patients treated with botulinum toxin require repeated injections over many years. Some patients who respond well initially develop tolerance to the injections due to development of neutralizing antibodies to the toxin. Patients who receive higher individual doses or frequent booster injections seem to have a higher risk of developing antibodies. Injections should therefore be given at the lowest effective dose and as infrequently as possible. Several types of antibody assay are available.[4] In clinical trials patients resistant to botulinum A have benefited from injections with other serotypes, including B, C, and F.[19]

Clinical applications

Botulinum toxins now play a very significant role in the management of a wide variety of medical conditions, especially strabismus and focal dystonias, hemifacial spasm, and various spastic movement disorders.[9,20] Besides these, encouraging clinical reports have appeared for other uses such as headaches,[21] hypersalivation,[22] hyperhidrosis,[23] and some chronic conditions that respond only partially to medical treatment. Sometimes it can be used as an alternative to surgical intervention.[24] It seems to be a promising alternative to sphincterotomy in patients with chronic anal fissures[25] and is effective in achalasia.[26] Some autonomic disorders resulting in hypersecretion of glands like ptyalism or gustatory sweating, which often occur after surgery to the parotid gland, respond well to botulinum toxin.[23,27,28] Surprisingly, the response seems to last much longer than in conditions caused by overactivity of striated or smooth muscles.[28] The list of possible new indications is rapidly expanding [ Table 1 ].

Table 1

Indications for botulinum toxin

Established indicationsTried applications
Disorders of neuromuscular overactivityDisorders of neuro-muscular overactivityOther conditions/disorders
Ophthalmic disordersOther neuromuscular disordersOphthalmic disordersOther neuromuscular disordersSpasticityNeuromuscular disordersPainE.N.T. and oroharyngealDisorders of pelvic floorCosmetic and dermatological applications
Concomitant misalignmentIdiopathic focal dystoniasDisorders of ocular motility (nystagmus, oscillopsia)Secondary dystonia,Multiple sclerosisMyokymia,Headache (tension type, migraine, cervicogenic), neck, lower back acheDhtrooling of saliva, Oromandibular disorders (bruxism, Masseter hypertrophy, temporomandibular joint dysfunction)AnismusWrinkles, face rejuvenation
(Primary or secondary esotropia or exotropia)(torticollis, isolated head tremor, blepharospasm, oromandibular dystonia, lingual dystonia, laryngeal dystonia)Thyroid disease (upper eyelid retraction, glabellar furrowing)Tic disorders (simple tics, Tourette's syndrome, dystonic tics)StrokeNeurogenic tibialis anterior hypertrophy with myalgiaMyofascial painPharyngeal disorders (cricopharyngeal dysphagia, closure of larynx in chronic aspiration)VaginismusBrowlift, crow's feet
Nonconcomitant misalignmentOther focal dystonias (writer's cramp, occupational cramps)Therapeutic ptosis for corneal protectionTremor (essential, writing, palatal, cerebellar)Traumatic brain injuryBenign crampfasciculation syndromeTennis elbowAchalasia,Chronic Anal fissuresGlabellar frown
Paralytic strabismus (III, IV, VI nerves palsy, inter-nuclear ophthalmoplegia, skew deviation)Tardive dystonia Painful spinal myoclonusCerebral palsy Laryngeal disorders (vocal fold granuloma, ventricular dysphonia, mutational dysphonia)Detrusorsphincter dyssynergiaFrontalis frown, Bunny nose, Upper lip rhytides Pebbly chin, Naso-labial fold
Duane's syndromeHemifacial spasm/post-facial nerve palsy synkinesis Parkinson's disease (freezing of gait, off period dystonia, severe constipation)Spinal cord injury Stuttering with glottal blocks Platysma, Venus rings (Horizontal neck rhytides)
Restrictive or myogenic strabismus Cephalic tetanus, stiff man syndrome, neuromyotonia Palatal myoclonus oesophageal diverticulosis intrinsic rhinitis Turkey neck (Vertical platysmal bands)
Muscle stiffness, cramps, spasms Hyperhidrosis: Palms, soles and axillae, gustatory sweating

Dermato-cosmetological applications

Cosmetic use of BTX has skyrocketed in recent years, especially since the approval of BTX-A for treatment of glabellar lines. Until recently, Botox ® use was mainly confined to correct muscles of facial expression over the upper one-third of the face. Presently it's application ranges from correction of lines, creases and wrinkling all over the face, chin, neck, and chest, depressor anguli oris, nasolabial folds, mentalis, medial and lateral brow lifts, to lessen shadows on one's face and maintain a smooth outline of the jaw and cheeks from all directions, to dermatological applications such as localized axillary or palmar hyperhidrosis that is nonresponsive to topical or systemic treatment [ Table 1 ].

Adverse effects

Injections with botulinum toxin are generally well tolerated and side effects are few. Generalized idiosyncratic reactions are uncommon, generally mild, and transient. There can be mild injection pain and local edema, erythema, transient numbness, headache, malaise or mild nausea. Its effect diminishes with increasing distance from the injection site, but spread to nearby muscles and other tissues is possible. The most feared adverse effect is temporary unwanted weakness/paralysis of nearby musculature caused by the action of the toxin. It usually resolves in several months and in some patients in a few weeks, depending on the site, strength of the injections, and the muscles made excessively weak. Approximately 1-3% of patients may experience a temporary upper lid or brow ptosis. This results from migration of the botulinum toxin to the levator palpebrae superioris muscle. Patients often are instructed to remain in an upright position for three to four hours following injection and avoid manual manipulation of the area. Active contraction of the muscles under treatment may increase the uptake of toxin and decrease its diffusion.

The ptosis usually lasts two to six weeks. It can be treated with apraclonidine 0.5% eyedrops. This is an alpha-adrenergic agent that stimulates the Müller muscle and immediately elevates the upper eyelid. This treatment usually can raise the eyelid 1-3 mm. The treatment of one to two drops three times per day continues until the ptosis resolves. To avoid ptosis, place injections 1 cm above the eyebrow and do not cross the midpupillary line. Apraclonidine is contraindicated in patients with documented hypersensitivity. Phenylephrine 2.5% can be used alternatively. Neo-Synephrine is contraindicated in patients with narrow-angle glaucoma and in patients with aneurysms.

Weakness of the lower eyelid or lateral rectus can occur following injection of the lateral orbicularis oculi. If severe lower lid weakness occurs, an exposure keratitis may result and if the lateral rectus is weakened, diplopia results. Treatment is symptomatic.

Patients receiving injections into the neck muscles for torticollis may therefore develop dysphagia because of diffusion of the toxin into the oropharynx. When this occurs, it usually lasts only a few days or weeks. Some patients may require soft foods. Although a swallowing weakness does not herald systemic toxicity, if it is severe, patients may be at risk of aspiration. Some patients experience neck weakness, which is especially noticeable when attempting to raise the head from a supine position. This occurs after weakening of the sternocleidomastoid muscles, either from direct injection or diffusion. This is more common in women with long thin necks. Avoid these adverse effects by using the lowest effective doses and precisely placing toxin into the platysma.

Distant effects shown by specialized electromyographic tests can also occur, but weakness of distant muscles or generalized weakness, possibly due to the toxin spreading in the blood, is very rare.[29,30] however, avoid intravascular injections because diffuse spread of large amounts of toxin can mimic the symptoms of botulism.

Bruising can occur, particularly if a small vein is lacerated or a patient is taking aspirin, vitamin E, or NSAIDs. Ideally, patients should stop taking these products two weeks before the procedure. Headaches can occur after Botox ® injections however, in one study by Carruthers et al,[31] this did not exceed the placebo group. This is thought to be due to the trauma of the injection and not something inherent in the toxin. In fact, botulinum toxin injections are extremely safe. To date, no significant long-term hazards of botulinum toxin injections have been identified in excess of placebo groups.

Other systemic side effects include an influenza-like illness and, rarely, brachial plexopathy, which may be immune mediated.[32] No severe allergic reactions have been reported, however, patient may be allergic to any of its components. Gallbladder dysfunction attributed to autonomic side effects of the toxin and a case of necrotizing fasciitis in a immunosuppressed woman with blepharospasm have been noted.[33,34]

Contraindications to botulinum toxin injection

Botulinum toxin is contraindicated in patients afflicted with a preexisting motor neuron disease, myasthenia gravis, Eaton-Lambert syndrome, neuropathies, psychological unstability, history of reaction to toxin or albumin, pregnancy and lactating females, and infection at the injection site. Careful monitoring should be done in children as it might alter cell functions such as axonal growth.[35]

Relative contraindications

Some medications decrease neuromuscular transmission and generally should be avoided in patients treated with botulinum toxin. These include aminoglycosides (may increase effect of botulinum toxin), penicillamine, quinine, chloroquine and hydroxychloroquine (may reduce effect), calcium channel blockers, and blood thining agents eg. warfarin or aspirin (may result in bruising).

Therapeutic failure

Some patients do not respond to injections and, having never previously responded, are designated as primary nonresponders. Many reasons may lead to a lack of response. Patients with rhytids that are not dynamic in origin (eg, photodamage, age-related changes) do not respond. Improper injection technique or the denatured toxin may also result into therapeutic failure. Some patients may have neutralizing antibodies from prior subclinical exposure, or individual variations in docking proteins may exist.[36] Secondary nonresponders respond initially but lose the response on subsequent injections. Most of these patients may have developed neutralizing antibodies.


Types of Myopathies

Metabolic myopathies usually manifest as one of the following presentations:

Metabolic myopathies presenting with exercise intolerance, cramps, and myoglobinuria

Cramps and myalgia may occur after brief exercise or after prolonged physical activity.

Glycogen is the main source of energy during brief exercise, while free fatty acids are the most important source of fuel during prolonged exercise. Hence, muscle cramps during strenuous brief exercise are the hallmark of glycogen storage diseases (eg, McArdle disease). However, in lipid storage disease (eg, CPT deficiency), muscle cramps and exercise intolerance occur only after prolonged exercise and are worse during fasting.

Metabolic myopathies presenting with progressive muscle weakness

These metabolic myopathies may mimic limb-girdle muscular dystrophy or polymyositis.

They are a common presentation of deficiencies of acid maltase, debrancher enzyme, and carnitine.

Glycogen storage diseases (glycogenoses) are named according to their specific defective enzyme function, an eponym, or by Roman numerals that correlate to the time of their discovery (see Table 1). They are as follows:

Glycogenosis type I - Glucose-6-phosphatase deficiency

Glycogenosis type II - Acid maltase deficiency (AMD) Pompe disease autosomal recessive (17q23)

Glycogenosis type III - Debrancher enzyme deficiency Cori-Forbes disease autosomal recessive (1p21)

Glycogenosis type IV - Brancher enzyme deficiency Andersen disease autosomal recessive (3p12)

Glycogenosis type V - Muscle phosphorylase deficiency McArdle disease autosomal recessive (11q13)

Glycogenosis type VI - Liver phosphorylase deficiency

Glycogenosis type VII - Phosphofructokinase deficiency Tarui disease autosomal recessive (12q13.3)

Glycogenosis type VIII - Phosphorylase b kinase deficiency X-linked recessive (Xq12)

Glycogenosis type IX - Phosphoglycerate kinase deficiency X-linked recessive (Xq13)

Glycogenosis type X - Phosphoglycerate mutase deficiency autosomal recessive (7p12-p13)

Glycogenosis type XI - Lactate dehydrogenase deficiency autosomal recessive (11p15.4) (isozyme LDH-M on chromosome 11/ LDH-H on chromosome 12)

Glycogenosis type XII - Aldolase A deficiency autosomal recessive (16q22-q24)


Rare Disease Database

NORD gratefully acknowledges Joseph Kim, NORD Editorial Intern from the University of Notre Dame, and Albert La Spada, MD, PhD, FACMG, Professor of Neurology, Neurobiology, and Cell Biology Director, Duke Center for Neurodegeneration & Neurotherapeutics and Vice Chair, Department of Neurology Duke University School of Medicine, for assistance in the preparation of this report.

Synonyms of Kennedy Disease

  • KD
  • Kennedy's syndrome
  • SBMA
  • spinal and bulbar muscular atrophy
  • spinal bulbar muscular atrophy
  • X-linked spinal and bulbar muscular atrophy
  • X-linked spinal bulbar muscular atrophy
  • spinobulbar muscular atrophy
  • X-linked spinobulbar muscular atrophy

General Discussion

Kennedy disease is a rare, X-linked slowly progressive neuromuscular disorder. Kennedy disease is typically an adult-onset disease, where symptoms occur mainly between the ages of 20 and 50. The disease is characterized by symptoms such as muscle weakness and cramps in the arms, legs, and facial area, enlarged breasts, and difficulty with speaking and swallowing (dysphagia). Kennedy disease affects fewer than 1 in 350,000 males and does not typically occur in females, who are protected by their low levels of circulating testosterone, accounting for the sex-limited inheritance pattern in this disorder. Treatment is symptomatic and supportive, and life expectancy is normal, though a small percentage of patients (

10%) succumb to the disease in their 60’s or 70’s due to swallowing complications (aspiration pneumonia, asphyxiation) resulting from the bulbar weakness. Kennedy disease is named after William R. Kennedy, MD, who described this condition in an abstract in 1966 and a full report in 1968.

Signs & Symptoms

Affected individuals begin to develop neurological symptoms between 20 to 50 years of age. These early symptoms include:

· Weakness/cramps in arm and leg muscles (proximal > distal)
· Face, mouth, and tongue muscle weakness
· Difficulty with speaking and swallowing (dysphagia)
· Twitching (Fasciculations)
· Tremors and trembling in certain positions
· Enlarged breasts (gynecomastia)
· Numbness
· Infertility
· Testicular atrophy

The disease affects the lower motor neurons that are responsible for the movement of many muscles in the legs, arms, mouth, and throat. Affected individuals will show signs of twitching, often in the tongue and/or hand, followed by muscle weakness and problems with facial muscles. These neurons, which connect the spinal cord to the muscles, become defective and die, so the muscles cannot contract. The destruction of these nerves is the main reason for the numbness, muscle weakness, and inability to control muscle contraction. With lack of normal neuromuscular function, a patient may experience hypertrophied calves in which the calf muscles thicken due to muscle cramps. In some cases, patients may also have one side of the body more affected than the other side.

The disease also affects nerves that control the bulbar muscles, which are important for breathing, speaking, and swallowing. Androgen insensitivity can also occur, sometimes beginning in adolescence and continuing through adulthood, characterized by enlarged breasts, decreased masculine appearance, and infertility. Patients may experience problems such as low sperm count and erectile dysfunction.

Causes

Kennedy disease is caused by a change (mutation) in the AR gene that encodes for a protein known as the androgen receptor on the X chromosome. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). Individuals with the disease have an abnormal section in the AR gene, which is due to an excessive number of CAG trinucleotide repetitions in the DNA sequence. An unaffected individual has 10-35 CAG repeats in the AR gene while a person with Kennedy disease has more than 36 CAG repeats in the gene.

The androgen receptor is in the cytoplasm of a cell where it responds to signals from male sex hormones (androgens). These receptors are abundant in many body tissues such as the skin, kidney, prostate, skeletal muscle, and the central nervous system motor neurons in the spinal cord and brainstem. In an unaffected person, the androgen hormone will bind to the receptor, and then the hormone-receptor complex will translocate into the nucleus, where it will signal genes to increase protein production for various functions.

In Kennedy disease, the exact mechanism for neuronal impairment is unknown, but it has to do with an altered functioning of the mutant androgen receptor.

Kennedy disease is an X-linked genetic disorder that occurs primarily in males. Very rarely, female carriers of the abnormal gene may show symptoms.

Normal females have two X chromosomes, in which one is an activated chromosome and the other is inactivated. Female carriers for Kennedy disease typically do not show symptoms because the androgen receptor must bind to its ligand, testosterone, to translocate to the nucleus and perform its functions. As females have low circulating levels of testosterone, Kennedy disease female carriers do not activate their mutant androgen receptors, thus rendering the mutant state of the androgen receptor protein innocuous. Males have only one X chromosome and will develop Kennedy disease if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease, while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease, while daughters have a 50 percent chance of becoming carriers.

Affected Populations

Kennedy disease affects fewer than 1 in 350,000 males and is very rare in females. Kennedy disease has been diagnosed in the USA, Europe, Asia, South America, and Australia. The Japanese population appears to have a very high prevalence of Kennedy Disease because of a founder effect.

Related Disorders

Symptoms of the following disorders can be similar to those of Kennedy disease. Comparisons may be useful for a differential diagnosis:

Adrenoleukodystrophy (ALD) is one of many different leukodystrophies. The adolescent or adult onset form of the disorder is called adrenomyeloneuropathy (AMN), and symptoms of this form of ALD may be similar to those of Kennedy disease. Symptoms typically appear between the ages of 21 and 35. They may include progressive leg stiffness, spastic partial paralysis of the lower extremities and ataxia (clumsiness in walking). Decreased function of the sex glands may be present. Adult onset ALD progresses slowly, however, it can ultimately result in deterioration of brain function. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.)

Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.) As it turns out, as many as 10% of Kennedy disease patients may be misdiagnosed with ALS prior to determining that they really have Kennedy disease.

Kugelberg-Welander syndrome is a type of spinal muscular atrophy and is inherited as an autosomal recessive genetic trait. Major symptoms may include wasting and weakness in the muscles of the arms and legs, twitching, clumsiness in walking, and eventually loss of reflexes. Kugelberg-Welander syndrome is not apparent at birth but typically appears during the first ten to twenty years of life. (For more information on this disorder, choose “Kugelberg-Welander syndrome” as your search term in the Rare Disease Database.)

Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis) weakness of eye muscles, resulting in double vision (diplopia) and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles impaired articulation of speech (dysarthria) difficulties chewing and swallowing (dysphagia) and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of cases, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)

Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic muscle disorder with onset during adulthood most often between 40 and 60 years of age. OPMD is characterized by slowly progressive muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Affected individuals may develop drooping of the eyelids (ptosis), double vision (diplopia) and/or difficulty swallowing (dysphagia). Eventually, additional muscles may become involved including those of the upper legs and arms (proximal limb weakness). In some cases, muscle weakness of the legs may eventually cause difficulty walking. OPMD is typically inherited in an autosomal dominant pattern. OPMD belongs to a group of rare genetic muscle disorders known as the muscular dystrophies. These disorders are characterized by weakness and atrophy of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns. Unlike OPMD, most forms of muscular dystrophy have onset during childhood or adolescence. (For more information on this disorder, choose “oculopharyngeal muscular dystrophy” as your search term in the Rare Disease Database.)

Sandhoff disease is a lipid storage disorder characterized by a progressive deterioration of the central nervous system. The clinical symptoms of Sandhoff disease are identical to Tay-Sachs disease. Sandhoff disease is an autosomal recessive genetic disorder caused by an abnormal gene for the beta subunit of the hexosaminidase B enzyme. This gene abnormality results in a deficiency of hexosaminidase A and B that results in accumulation of fats (lipids) called GM2 gangliosides in the neurons and other tissues. (For more information on this disorder, choose “Sandhoff disease” as your search term in the Rare Disease Database.)

Polymyositis is a systemic connective tissue disorder characterized by inflammatory and degenerative changes in the muscles, leading to symmetric weakness and some degree of muscle atrophy. The areas principally affected are the hip, shoulders, arms, pharynx and neck. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)

Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, and acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain-Barré syndrome” as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of Kennedy disease is suspected based on physical signs and symptoms, and sometimes family history. Diagnosis can be confirmed by molecular genetic testing on a blood sample for CAG trinucleotide repeat expansion in the AR gene. Individuals with greater than 36 CAG trinucleotide repeats in the AR gene are diagnosed with the condition.

Clinical Testing and Work-Up
Annual examinations to assess muscle strength may be appropriate.

Standard Therapies

Treatment
Currently, there is no known treatment or cure for Kennedy disease. Physical therapy, occupational therapy, and speech therapy are commonly used to adapt to the progressing disease and maintain an individual’s skills. Braces, walkers, and wheel chairs are used for ambulation. Breast reduction surgery is sometimes used as needed in patients with gynecomastia. Testosterone is not an appropriate treatment, as it can make the disease worse.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about Kennedy disease:

Albert La Spada, MD, PhD, FACMG
Professor of Neurology, Neurobiology, and Cell Biology
Director, Duke Center for Neurodegeneration & Neurotherapeutics
Vice Chair, Department of Neurology
Duke University School of Medicine
Bryan Building, Room 401-E, DUMC 2900
Durham, NC 27710
Phone: (919)-684-7128
Email: [email protected]

NORD Member Organizations

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    • Phone: 85553277627342885580
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    • Website: http://www.kennedysdisease.org
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    Other Organizations

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      References

      TEXTBOOKS
      Russman BS. Spinal Bulbar Muscular Atrophy. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins 2003: 636.

      INTERNET
      La Spada A. Spinal and Bulbar Muscular Atrophy. 1999 Feb 26 [Updated 2017 Jan 26]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1333/ Accessed July 25, 2018.

      Barkhaus PE, Verman S. Kennedy Disease. Medscape. http://emedicine.medscape.com/article/1172604-overview Updated Jun 08, 2016. Accessed July 31, 2018.

      NINDS Kennedy’s Disease Information Page. National Institute of Neurological Disorders and Stroke (NINDS). https://www.ninds.nih.gov/Disorders/All-Disorders/Kennedys-Disease-Information-Page Last updated June 15, 2018. Accessed July 31, 2018.

      Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spinal and Bulbar Muscular Atrophy, X-Linked 1 SMAX1. Entry No: 313200. Last Edited 09/23/2010. Available at: http://omim.org/entry/313200 Accessed July 31, 2018.

      Spinal and bulbar muscular atrophy . Genetics Home Reference. http://ghr.nlm.nih.gov/condition/spinal-and-bulbar-muscular-atrophy Reviewed December 2012. Accessed July 31, 2018.

      Years Published

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      Molecular Mechanisms of Treadmill Therapy on Neuromuscular Atrophy Induced via Botulinum Toxin A

      Botulinum toxin A (BoNT-A) is a bacterial zinc-dependent endopeptidase that acts specifically on neuromuscular junctions. BoNT-A blocks the release of acetylcholine, thereby decreasing the ability of a spastic muscle to generate forceful contraction, which results in a temporal local weakness and the atrophy of targeted muscles. BoNT-A-induced temporal muscle weakness has been used to manage skeletal muscle spasticity, such as poststroke spasticity, cerebral palsy, and cervical dystonia. However, the combined effect of treadmill exercise and BoNT-A treatment is not well understood. We previously demonstrated that for rats, following BoNT-A injection in the gastrocnemius muscle, treadmill running improved the recovery of the sciatic functional index (SFI), muscle contraction strength, and compound muscle action potential (CMAP) amplitude and area. Treadmill training had no influence on gastrocnemius mass that received BoNT-A injection, but it improved the maximal contraction force of the gastrocnemius, and upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and acetylcholine receptor (AChR) subunits α and β was found following treadmill training. Taken together, these results suggest that the upregulation of genes associated with neurite and AChR regeneration following treadmill training may contribute to enhanced gastrocnemius strength recovery following BoNT-A injection.

      1. Introduction

      Treadmill exercise, both full weight-bearing and partial weight-bearing, is a dynamic training approach that provides intervention for walking and gait analysis. In patients with neuromuscular disorders, such as stroke, spinal cord injury (SCI), or cerebral palsy (CP), treadmill exercise is a frequently used rehabilitation training model that has been shown to yield functional improvements [1–4]. Clinical investigations showed that in patients with CP, treadmill training can improve walking endurance, walking speed, and standing performance [5, 6]. In stroke rehabilitation, partial-support treadmill training is also a widely used training mode for gait correction [7, 8]. Spasticity is a sign of upper motor neuron lesion with increased stretch reflex depending on movement velocity, which can be caused by stroke, spinal cord injury, brain injury, cerebral palsy, or other neurological conditions [9]. One of the treatment choices for spasticity is the intramuscular injection of botulinum toxin A (BoNT-A) [10, 11]. Although several studies support the beneficial effects of treadmill training, most excluded BoNT-A-treated patients or did not mention these patients [12–14]. The effects of treadmill training on the physiological adaptation to paralysis effects caused by BoNT-A remain poorly understood. In this paper, we review the mechanisms of treadmill exercise and BoNT-A treatment and discuss their combined effects on the central nervous system, physiological activity, and changes in the muscle and neuromuscular junction (NMJ). This may contribute to our understanding of the mechanisms underlying currently used treatments and, possibly, suggest directions for future research.

      2. The Therapeutic Effects of Treadmill Training and Mechanism

      In neurorehabilitation, locomotor training is based essentially on principles that promote the movement of the limbs and trunk to generate sensory information consistent with locomotion. Whether full weight-bearing or partial-weight bearing, treadmill training can be used as a strategy for locomotor training in people with certain disabilities to improve muscle adaptation and walking ability. A major focus of research has been to elucidate the benefits of treadmill training, such as functional recovery or restoration in neural plasticity. One of the major questions limiting the rehabilitative implementation of treadmill training pertains to the molecular mechanisms through which treadmill training promotes synaptic plasticity and functional recovery. Clinical investigations have shown beneficial effects of treadmill training, which is often used in patients with cerebral palsy (CP) or stroke for walking and gait training [13–16]. In patients with CP, walking speed and gross motor function improved significantly after treadmill training [17]. A recent systemic review showed that gait impairment and activity level were improved after body weight supported treadmill training [16]. Recently, robotic-assisted treadmill training was developed and was found to improve walking and standing performance in patients with CP [18]. In patients with CP, the neural modulation of soleus H-reflex suppression was proposed as the mechanism accounting for the improvement in functional gait pattern after treadmill training therapy [19].

      In animal models of SCI, locomotor training using a body weight supported treadmill (BWST) suggested that interneurons in the lumbar cord formed circuits for rhythmic and alternating hindlimb flexion-extension movement [20, 21]. Because this conceptual mechanism included the responsiveness of the spinal central pattern generators to sensory input with locomotion, BWST training provides an environment in which one can learn to execute the stepping leg movement [22–24]. The amplitude and coordination of the firing of motor units in leg muscles were also found to increase after considerable BWST training in patients with complete or incomplete chronic SCI. The animal and human studies led to the suggestion that BWST training may tap into this central pattern generator subsystem and contribute to enabling walking in highly impaired patients [25–28]. Treadmill training also increased the expression of nerve-associated factors, such as the brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in the spinal cord this expression may be related to the improvement in local neural circuitry [29–33]. Although an isolated spinal cord learned to stand on a stationary treadmill or step on a moving treadmill [34], the training effect for SCI did not transfer to the other task [35]. Hence, the cord has a limited capacity for relearning multiple tasks in the absence of supraspinal input [36]. Thus, factors such as task specificity, training intensity, or training duration are issues that warrant attention in future experiments [37].

      Although injured axons in peripheral nerves have better regeneration than those in the central nervous system and despite the recent advances in microsurgical techniques, the functional outcomes in injured peripheral nerves are clinically poor [38–40]. Some studies had evaluated the effects of treadmill training on axon regeneration following peripheral nerve injury. In animal studies of nerve transection following repair, treadmill training was shown to facilitate growth in the length of regenerating axons, to retrieve restoration of H-reflex, and to increase the amplitude of CMAP in injured peripheral nerves [41, 42]. In the sciatic nerve crush animal model, Ilha et al. [43] found improvement in sciatic functional index (SFI) scores and a better morphology of regenerating nerve fibers after treadmill training. As BDNF is highly expressed in active neurons, BDNF-mediated machinery may be responsible for the spinal central pattern generation induced using treadmill locomotor training [44–46]. Both the Wilhelm group [47] and Ying and colleagues [30] provided evidence that the effect of treadmill training on axon regeneration requires BDNF produced by the regenerating axons themselves. This neurotrophic factor was a likely mechanism of the effect of treadmill training in enhancing axon regeneration following peripheral nerve injury.

      In normal rats, the adaptation of the energy transportation system was found after treadmill training. Chow and colleagues demonstrated that after 8 weeks of training, a significant increase in mitochondrial-related mRNAs was observed [48]. They also found that mitochondrial DNA and mitochondrial transcription factor A were upregulated in the trained muscle. Safdar and colleagues have advocated treadmill endurance exercise as a medicine and a lifestyle approach to improve systemic mitochondrial function. They showed that 5 months of exercise resulted in a substantial increase in mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondria morphology, blunted the process of apoptosis, and prevented mitochondrial DNA depletion and mutations [49].

      Several muscle adaptation mechanisms have been observed in normal or diseased animal models following treadmill training. In one recent study that measured changes in denervated soleus muscle via sciatic nerve resection and treadmill training, Jakubiec-Puka et al. [50] showed that the number of capillary blood vessels, amount of myosin heavy chains, and muscle fiber nuclei were increased, with concomitant decreases in the number of severely damaged muscle fibers and amounts of collagen. These training effects were more evident in the animals with longer training [50]. In diabetic rats, treadmill running has been shown to increase the level of nerve growth factor in the soleus muscle, and apoptotic cell death was suppressed via accelerating p-PI3-K activation [51]. In summary, the adaptation mechanisms induced via treadmill exercise are multifactorial with cellular changes inside the muscle fibers as well as changes in peripheral and central nervous systems.

      3. Efficacy and Reliability of Current Measures of Spasticity

      Spasticity is a clinical symptom of upper motor neuron lesion that is characterized by a velocity-dependent increase in stretch reflexes [9]. Although some objective methods of measuring spasticity such as the Hoffmann reflex (H-reflex), the Tendon reflex (T-reflex), and the Stretch Reflex (SR) have been developed, the clinical and experimental use of the three methods is limited due to moderate reliability and sensitivity [52]. Clinically, the six-point-ordinal Modified Ashworth Scale (MAS) is now the most commonly used measure of spasticity [53]. Mutlu et al. showed that in cerebral palsy, the MAS is a marginally reliable assessment of spasticity. They suggested that the use of the scale should therefore be interpreted with great caution [54]. In another study evaluating the reliability for ankle plantar flexor in patients with traumatic brain injury, a low reliability was concluded [55]. Although some controversy to the MAS approach has been recognized, most of the literature supports the reliability of the MAS. Ghotbi et al. [53] showed that the reliability was good for the distal ankle plantar flexors but not for the proximal hip adductors. Bohannon and Smith [56] have advocated the MAS as a reliable test of elbow flexor muscle spasticity. In an assessment of knee extensor, Ansari and colleagues [57] showed a good reliability for MAS evaluation on the poststroke knee extensor. Pandyan and colleagues [58] showed that the reliability of the scale is better in the upper limb. Platz et al. [59] suggested that a high interrater reliability of the MAS can be clinically achieved but not in all circumstances. Therefore, we contend that the clinical reliability of applying the MAS for spasticity evaluation may depend on the joints and muscles tested [54, 60].

      4. Neuromuscular Junction: Structure and Molecular Mechanism

      The neuromuscular junction (NMJ) in vertebrates is a favorable model system for investigating the molecular mechanisms of synapse formation and neural plasticity. The NMJ is a region where the axons of motor nerves connect with the skeletal muscles and serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction [61, 62]. Neurotransmitters, such as acetylcholine (ACh), are formed in the neuron body and then transported to the synapse along the axon. In the terminal axon of a nerve, neurotransmitters are packed in vesicles. When an impulse from the central nervous system is transmitted to the NMJ, ACh is released, which binds with acetylcholine receptors on the postsynaptic muscle fibers [63]. Calcium-related signal transduction will be recruited, causing muscle contraction.

      The nicotinic acetylcholine receptor (AChR) is a transmembrane ligand-gated ion channel. This receptor is composed of four homologous subunits: α, β, δ, and γ or ε [64]. During myogenesis, the expression of the muscle regulatory factors (MRFs) family is associated not only with activated satellite cells and myonuclei but is also crucial in regulating the ongoing rates of AChR gene transcription [65–67]. The expression of the AChR subunits and the distribution of these receptors among muscular fibers are regulated developmentally, with AChR gene expression at its highest levels during myogenic differentiation [68]. The soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) is the most widely studied element of the intracellular machinery involved in intracellular trafficking [69]. SNARE proteins are a large protein superfamily consisting of more than 60 members. The core exocytotic machinery is composed of three SNAREs: (1) vesicle-associated membrane protein synaptobrevin (VAMP), (2) synaptosomal-associated protein of 25 kD (SNAP-25), and (3) syntaxin-1 on the plasma membrane [70–73].

      5. Botulinum Toxin A (BoNT-A): Structure and Cellular Mechanism

      The botulinum toxin was first described as a “sausage poison” and “fatty poison” because this bacterium often caused toxicity by growing in improperly handled or prepared meat products [74]. In the late 1960s, Scott and Schantz were the first to work on a standardized botulinum toxin preparation for therapeutic purposes. Scott, an ophthalmologist, first applied tiny doses of the toxin to treat “crossed eyes” (strabismus) and “uncontrollable blinking” (blepharospasm) [75]. In December 1989, BoNT-A (Botox, Allergan Inc., Irvine, CA, USA) was approved by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old. Dysport (Ipsen Ltd., UK) is another brand of BoNT-A used for therapeutic purposes.

      In the peripheral and central nervous systems, neuronal plasticity plays a pivotal role in the recovery process after injury. However, the intrinsic neuronal determinants for the regulation of this fundamental process remain poorly defined. The intramuscular injection of botulinum toxin is a unique strategy for investigating the process of neuronal plasticity in motor nerves and entails the elimination of regulated neurotransmitters while leaving the viability of the nerve endings unaltered [76]. Seven botulinum neurotoxins (A to G) have been found, and all act in the postsynaptic cholinergic nerve terminals [10]. BoNT-A is a type of bacterial zinc-dependent endopeptidase that acts specifically at the neuromuscular junction [10, 77]. The complex of BoNT-A comprises a 150 kD neurotoxin protein, as well as nontoxin nonhemagglutinin proteins. The 150 kD neurotoxin protein is the biologically active component, while the nontoxin nonhemagglutinin protein stabilizes and protects the active neurotoxin component [78]. The 150 kD neurotoxin protein is pharmacologically inactive until the disulfide bond is cleaved to form one 100 kD heavy chain and one 50 kD light chain.

      After the endocytotic uptake of BoNT-A from postsynaptic terminals, the light chain of BoNT-A cleaves SNAP-25 [79, 80]. This renders ACh-containing vesicles unable to dock and fuse to the presynaptic membrane. By inhibiting the release of acetylcholine at the NMJ, neuroparalysis and denervation of the involved muscles occur, which decreases the ability of the muscles to generate force [79, 80]. Once paralysis has been produced by BoNT-A, new nerve sprouting is elicited, and the newly created synapses are responsible for the initial synaptic transmission [81]. A previous study showed that the effect of botulinum toxin lasts for approximately 3 to 6 months. The muscle that received the BoNT-A injection then regains muscle mass and recovers its contraction ability [82].

      6. Changes in Muscle Physiology, Neuromuscular Junction, and Gene Expression following BoNT-A Injection

      One to two weeks after BoNT-A injection, muscle mass and force were significantly reduced but returned to nearly normal at 3–6 months after injection. Studies showed that muscle mass following BoNT-A injection was reduced by approximately 70% to 30% within 1 to 6 months [82–84]. A 30% to 90% (approximately) reduction in muscle force was reported in animal studies [83, 85–87]. The wide range of reduction in muscle mass and force generation occurred in a dose-dependent manner [85, 88].

      The mass and structural integrity of contralateral muscles that received BoNT-A injection and those of noninjected peripheral muscles were affected in both clinical and animal studies. Clinically, the diffusion of the injected BoNT-A to adjacent muscles was reported in patients with spasmodic torticollis, facial hemispasm, blepharospasm, or palmar hyperhidrosis [89–91]. Fortuna et al. [83] showed that muscle atrophy and decreased muscle force were observed in the quadriceps muscles of the contralateral hindlimbs. In a rat model that used the contralateral gastrocnemius muscle for comparison, the injected toxin was found to have no effect on the force of the contralateral leg using a 1 unit/kg injection dose. This toxin spreading effect was suggested to be dependent on toxin dosage [92].

      Neuroparalysis produced via BoNT-A elicits nerve sprouting and newly created synapses that are responsible for the initial synaptic transmission at the onset of recovery [81, 93]. However, whether synaptic transmission occurs at the newly developed sprouts has not been directly demonstrated. Recently, Rogozhin and colleagues [94] advocated that the original synaptic sites play the predominant role in functional restoration after BoNT-A rather than the nerve sprouts, as previously thought. At approximately 90 days after exposure to BoNT-A, the restoration of parent NMJ functioning and a concomitant retraction of the outgrowth neurites could be found [76].

      Following BoNT-A injection, genes related to NMJ remodeling and myogenesis, including subunits of AChR, IGF-1, MRFs, MuSK, and p21, eventually lead to NMJ stabilization and muscle function recovery [95–97]. In neuromuscular disorders, an electrophysiological study is an objective evaluation tool. A treadmill walking study in cats showed that after a temporal reduction in ankle extensor activity via BoNT-A injection, the functional deficit recovery was not associated with the return of the electromyogram (EMG) pattern [98]. However, the EMG burst of the synergistic muscle that was not poisoned by BoNT-A was increased. The authors concluded that this early functional recovery is not due to muscle hypertrophy but is instead attributable to neuronal adaptation due to an increased gain in stretch reflex or central drive [99, 100]. The compound muscle action potential (CMAP) represents the summation of a group of nearly simultaneously activated action potentials from a muscle or a group of muscles that are innervated by the same nerve. The reduction in CMAP parallels the decrease in the mean rectified voltage during a maximal voluntary contraction [101]. A recent study showed that the CMAP amplitude was significantly reduced, while no changes of distal latency were found in the gastrocnemius following a BoNT-A injection for 4 weeks [84]. This result was compatible with the results of a previous study demonstrating that an injection of BoNT-A caused localized muscle paralysis but no disruption in axonal transport [102]. After BoNT-A injection, the CMAP amplitude typically requires more than 3 months for full recovery [101].

      7. Treadmill Training Models and the Training Effects on Muscle Activity and NMJ following BoNT-A Injection

      In rat exercise training models, the two most frequently used models are either voluntary wheel running or forced treadmill training. In the wheel running training model, voluntary running activity occurs in a nonstressed environment. However, the training speed and duration are technically challenging to monitor [103–105]. The alternative to wheel running is treadmill training. In the treadmill training model, different training paradigms have been used. Some groups use ramp protocols [106], and others use the model with a consistent speed and exercise duration [84, 107]. The advantage of treadmill training is that the animals can be made to exercise at a desirable training intensity and duration. However, the experimental conditions are often stressful, and the training pattern is far removed from normal mouse behavior [108].

      The interaction effect between treadmill and BoNT-A injection has not been clearly demonstrated. Combined BoNT-A injection and 7 days of voluntary wheel running exercise in juvenile rats attenuated the BoNT-A-induced loss in muscle fiber size [109]. Although the number of Myo-D positive nuclei was increased after BoNT-A injection, the results showed that exercise had no effects on myonuclear production. The authors concluded that this early effect of combined BoNT-A and exercise may be due to the passive stretching of paralyzed muscle fibers. This passive stretch effect was supported by a study that showed an increased expression of mechanosensitive CARP and the Ankrd2 gene in rats receiving BoNT-A gastrocnemius injection and 3 weeks of wheel running exercise [110].

      In a study by Chen et al. [109], a muscle atrophy attenuation effect was observed in gastrocnemius following BoNT-A injection after 1 week of exercise. Another study found that muscle mass was not changed after 3 weeks of wheel running. Recently, Tsai et al. showed that after BoNT-A injection, the gastrocnemius mass did not increase after 4 weeks or 8 weeks of treadmill training [84, 86]. As previous studies have shown that there is no significant effect of treadmill training on muscle mass following BoNT-A injection, it is reasonable to postulate that the strength of muscle following BoNT-A with or without treadmill training is likely unchanged [84, 86, 110]. However, one recent study showed that after the intramuscular injection of BoNT-A into the gastrocnemius, treadmill training improved the recovery of muscle contraction strength [85]. In the study, an increase in CMAP amplitude was observed in the gastrocnemius of BoNT-A-injured rats after 4 weeks of treadmill running. This functional improvement was confirmed via the improvement of the sciatic functional index (SFI). In sciatic nerve injury, rats lose their ability to spread their hind toes. The SFI is an experimental method used for the functional assessment of the extent of sciatic nerve injury and for the monitoring of recovery [111–113]. In one recent study, Tsai et al. [87] demonstrated an increase in IGF-1, GAP-43, MyoD, Myf-5, and myogenin expression, as well as the upregulation of AChR α and -β subunit expression, in the BoNT-A-paralyzed gastrocnemius after 8 weeks of treadmill running. Synaptic transmission at the NMJ is mediated through the AChR, and control of AChR transcription is crucial for the regeneration and maintenance of synapses in muscle. The expression and transcription of AChR genes are governed by the sequential expression of MRFs [65–67]. Charbonnier et al. [66] showed that when the neuromuscular junction begins to differentiate, MyoD, Myf-5, and MRF4 display different specificities for the transactivation of the genes encoding the different subunits of the AChR. Taken together, after treadmill training the upregulation of IGF-1, GAP-43, MRFs, and AChR may be related to the increased activity of distal nerve sprouting, increased activity of AChR, and original NMJ regeneration, thus explaining the better recovery of muscle strength.

      8. Conclusion

      Although effort was put forth to create animal models simulating spasticity [114–117], there is currently no universally adopted free-moving animal model that can be used to mimic the spastic changes in clinical situations such as cerebral palsy or stroke [118]. In human clinical situations, a stroke may cause spasticity. In the rat stroke model, such as the suture method or the middle cerebral artery ligation, paralysis instead of spasticity is typically observed over the contralateral side of the brain lesion. Some commonly used spastic animal models, such as spinal cord transection and S2 transection spastic rat tail models, are generated for the purpose of observing neuronal overactivity [118]. Thus, many studies observing the effects of BoNT-A or combined effects of BoNT-A and exercise training in muscles use normal animals [82–85, 87, 94, 96, 109, 110]. To discover a free-moving spastic animal model is therefore an important pursuit for future research.

      The temporal blockade of neuromuscular function by BoNT-A is a useful method for investigating changes in muscle physiology from paralysis to recovery. Figure 1 summarizes the effects of treadmill training on muscle activity and the NMJ of BoNT-A-induced muscle atrophy. The major effect of BoNT-A is predominantly in the peripheral muscles, especially in the blockade of NMJ functions that cause muscle atrophy and weakness. The adaptation mechanisms induced via treadmill training are multifactorial and include enhanced axon regeneration, activation of the spinal central pattern generator, and functional recovery in the SFI, H-reflex, and CMAP [42, 43, 84, 119]. The molecular mechanisms through which treadmill training promotes synaptic plasticity and functional recovery include the enhancement of IGF-1, MRFs, AChR, and neurotrophin expression [29, 30, 44, 47, 87]. Based on the review, the muscle and nerve recovery effects of treadmill training may counteract the spasticity reduction effect from BoNT-A. When considering the therapeutic strategies of combining BoNT-A and treadmill training in the practice of neurorehabilitation, clinicians should take this potential counteractive effect into consideration. In this review paper, we highlighted the mechanisms of cellular effects following BoNT-A injection and treadmill training and further showed how the combined effects of both treadmill and BoNT-A influence muscle and NMJ activity. This work may improve our understanding of the mechanisms underlying currently used treatments.


      Rare Disease Database

      NORD gratefully acknowledges Douglas Gould, PhD, Professor, Director of Research, Denise B. Evans Endowed Chair in Ophthalmology, Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, and the COL4A1 Foundation, for assistance in the preparation of this report.

      Synonyms of COL4A1/A2-Related Disorders

      Subdivisions of COL4A1/A2-Related Disorders

      • HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773)
      • POREN1: autosomal dominant type 1 porencephaly porencephaly with infantile hemiplegia (OMIM #175780
      • RATOR: retinal arterial tortuosity (OMIM #180000)
      • BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595)
      • ICH: susceptibility to intracerebral hemorrhage (OMIM #614519)
      • schizencephaly: (OMIM #269160)

      General Discussion

      COL4A1/A2-related disorders are rare, genetic, multi-system disorders. They are typically characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology) however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients – even among members of a family who carry the same gene mutation. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. COL4A1/A2-related disorders follow an autosomal dominant pattern of inheritance.

      Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder.

      Signs & Symptoms

      The signs and symptoms can manifest at almost any age from before birth to old age. Some individuals do not have any observable symptoms (asymptomatic) others can develop severe, even life-threatening complications. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique.

      Clinical case reports suggest a syndrome with characteristic core findings however, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients.

      Autosomal Dominant Familial Porencephaly Type I

      The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in

      16% of patients with porencephaly. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. The size and location of cerebral cavities contributes to clinical variability. In some people, serious, life-threatening complications may occur in infancy in others, only minor complications may occur and intelligence is unaffected. Still other individuals may not develop any symptoms until well into adulthood. Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Migraines can occur with or without aura. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Additional features include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.

      Autosomal Dominant Brain Small Vessel Disease

      In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). This study clearly demonstrates that COL4A1 and COL4A2 mutations cause clinically variable cerebrovascular disease that includes characteristic features of cerebral small vessel disease. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). Affected individuals may have no observable symptoms or only isolated migraines with aura. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants).

      In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction.

      Additional Signs and Symptoms

      Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Some individuals develop cysts on the kidney. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. In most people, small vessel disease in the brain does not cause symptoms. Painful muscle cramps can occur and can develop before three years of age. Various muscles can be affected and muscle strength can become weakened. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations.

      COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. The retina is the light-sensitive membrane that lines the inside of the eyes. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss.

      A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia ¬(a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium).

      Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels.

      Congenital Cephalic Disorders
      In addition to porencephaly there can be other forms of damage to the brain present at birth. Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects).

      Causes

      COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. These genes are the blueprints for two proteins that wind together like a long rope inside cells. When these ‘ropes’ are secreted, they assemble into net-like structures outside the cells. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network.

      The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways.

      Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. COL4A1/A2-related disorders are dominant genetic disorders. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. However, there are exceptions that depend on precisely when and where the mutation arose. These exceptions are nuanced and should be discussed with a genetic counselor. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. If the mutation arises after fertilization, then some cells will carry the mutation and others will not – this is called mosaicism. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation. It is not uncommon for an unaffected parent to have a severely affected child. While there are other explanations, parental mosaicism should be considered. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot.

      When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) can also contribute.

      With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. This is called genotype-phenotype correlation. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in ‘functional subdomains’ can influence the likelihood of tissue-specific involvement (for example, muscle). These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans.

      Affected Populations

      COL4A1/A2-related disorders are believed to affect females and males in equal numbers. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently.

      Related Disorders

      Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Comparisons may be useful for a differential diagnosis:

      CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for: (C)erebral – relating to the brain (A)utosomal (D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy – disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical – relating to specific areas of the brain supplied by deep small arteries (I)nfarcts – tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy – lesions in the brain white matter caused by the disease and observed on MRI. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. (For more information on this disorder, choose “cadasil” as your search term in the Rare Disease Database.)

      A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

      Diagnosis

      A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. A diagnosis can be confirmed through molecular genetic testing. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories.

      Clinical Testing and Workup
      Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques.

      If individuals have muscle cramps, blood tests can reveal elevated levels creatine kinase, which is a muscle enzyme. When this enzyme is elevated, it is a sign of muscle damage. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected.

      Standard Therapies

      Treatment
      The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children) ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders) cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families.

      There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders.

      Therapies are based on the specific symptoms in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures, and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Surgery may be necessary for individuals with severe cataracts. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel.
      Early intervention is important in ensuring that children with reach their highest potential. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education.

      Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided.

      Investigational Therapies

      Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

      For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

      For information about clinical trials sponsored by private sources, contact:
      http://www.centerwatch.com/

      For information about clinical trials conducted in Europe, contact:
      https://www.clinicaltrialsregister.eu/

      NORD Member Organizations

      Other Organizations

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        References

        JOURNAL ARTICLES
        Zagaglia Selch C, Nisevic JR, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Neurology. 201891:e2078-e2088. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/

        Cavalin M, Mine M, Philbert M, et al. Further refinement of COL4A1 and COL4A2 related cortical malformations. Eur J Med Genet. 201861:765-772.

        Jeanne M, Gould DB. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. Matrix Biol. 201757-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/

        Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Clin Neurol Neurosurg. 2017155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515

        Alavi MV, Mao M, Pawlikowski BT, et al. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep. 20166:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/

        Rannikmae K, Davies G, Thomson PA, et al. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology. 201584:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/

        Meuwissen ME, Halley DJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Genet Med. 201517:843-853. https://www.nature.com/articles/gim2014210

        Yoneda Y, Haginoya K, Kato M, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. 201373:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343

        Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet. 201221:R97-R110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/

        Federico A, Di Donato I, Bianchi S, et al. Hereditary cerebral small vessel diseases: a review. J Neurol Sci. 2012322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088

        Shah S, Ellard S, Kneen R, et al. Childhood presentation of COL4A1 mutations. Dev Med Child Neurol. 201254:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627

        Lanfranconi S, Markus HS. COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke. 201041:e513-518. https://www.ncbi.nlm.nih.gov/pubmed/20558831

        Alamowitch S, Plaisier E, Favrole P, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology. 200973:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/

        Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. https://www.ncbi.nlm.nih.gov/pubmed/26610912

        INTERNET
        Plaisier E, Ronco P. COL4A1-Related Disorders. 2009 Jun 25 [Updated 2016 Jul 7]. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle 1993-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019.

        National Institute of Neurological Disorders and Stroke. Cephalic Disorders Fact Sheet. September 2003. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019.

        Years Published

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        Myotonic Dystrophy (DM)

        The classic form of DM1 becomes symptomatic between the second and fourth decades of life. In these patients, average lifespan is reduced. Patients diagnosed with DM1 have multiple sets of DNA bases repeats in their genome (known as the CTG repeats). The CTG repeat size in adult onset is generally in the range of 50 to 1,000. 1

        The mild form of DM1 is characterized by mild weakness, myotonia, and cataracts. Age at onset is between 20 and 70 years (typically onset occurs after age 40), and life expectancy is normal. The CTG repeat size is usually in the range of 50 to 150. 1

        Onset for DM2 ranges from the second to the seventh decade of life, often presenting with myotonia, weakness, or cataracts. In general, DM2 is a less severe disease than classic DM1. In most cases, weakness predominantly involves the proximal muscles, particularly the hip girdle muscles. 2

        Effects on the brain

        Research suggests that, in DM1, there may be abnormalities in the parts of the brain that determine the rhythm of sleeping and waking, making excessive daytime sleepiness a barrier to full participation in work, school, or social life for many adults with the disorder. In some people, there is a kind of overall "apathy" that may be due to changes in the brain related to DM1. Also, in patients with DM1, cognitive skills are diminished, and the IQ has been shown to be lower with younger age of onset. In both classic DM1 and DM2, frontal lobe cognitive impairment (attention deficit) worsens over time but does not extend to other areas of cognition. Thus, cognitive problems do not show the same degree of deterioration over time that is typical of muscle dysfunction in DM1.

        Although not as much is known about the effects of DM2 on personality, cognition, and sleepiness as with DM1, it appears that people with DM2 can have some of the same difficulties in these areas but to a lesser degree. Intellectual disability is rare in DM2.

        To learn more, read The Brain in DM (cognitive and emotional aspects of DM1) and Excessive Daytime Sleepiness Can Be 'Debilitating' in DM1 and DM2 (complex effects of DM on the brain's sleep-wake cycles and respiratory muscles).

        Breathing and swallowing muscle weakness

        Respiratory muscle weakness does not appear to be a common feature of DM2. However, in DM1, respiratory muscle weakness can affect lung function and deprive the body of needed oxygen. Weakness of the diaphragm and other breathing muscles can lead to problems getting enough oxygen when a person is asleep, even if they do not have any symptoms of breathing difficulty while awake. Thus, respiratory problems in DM1 can lead to a condition known as sleep apnea, in which people stop breathing for several seconds or longer many times a night while asleep.

        Swallowing muscles, if weakened, can lead to choking or “swallowing the wrong way” (called aspiration), with food or liquid going down the trachea (windpipe) to the lungs instead of down the esophagus to the stomach. Swallowing is partly voluntary and partly involuntary, and both voluntary and involuntary muscles can be affected.

        Respiratory failure may occur, sometimes precipitated by general anesthesia because of heightened sensitivity to sedatives, anesthetics, and neuromuscular blocking agents.

        Cataracts

        Cataracts — cloudy areas of the lens of the eye that eventually can interfere with vision — are extremely common in both DM1 and DM2. They generally occur earlier than typical age-associated cataracts seen in people without DM.

        Cataracts are caused by a chemical change in the lens, which gradually goes from clear to cloudy the way the clear white of an egg becomes opaque when cooked. The exact reason why cataracts occur in DM is not known.

        People with cataracts may notice their vision become blurry, hazy or dim, and that this worsens gradually over time. It often happens in both eyes, but not necessarily at the same time or at the same rate.

        Read Keeping Your Focus: Eye Care, particularly the section called Other vision problems: Not common, sometimes treatable, for additional information about eye care in neuromuscular disorders.

        Head, neck, and face muscle weakness

        The muscles of the neck, jaw, and parts of the head and face may weaken, especially in DM1. Facial weakness is less common and milder in DM2. Wasting of the sternocleidomastoid muscles in the neck are common in DM1 and typically absent in DM2. A "dropped head posture" is occasionally encountered.

        In men, early balding in the front part of the scalp is very common, adding to the distinct appearance of DM.

        Eyelids may droop (called ptosis the “p” is silent). The chewing muscles can be affected, which makes the temples appear hollow and the face look thin.

        Weak neck muscles, common in both types of DM, can make it hard to sit up quickly or lift one’s head straight up off a bed or couch. The stronger trunk muscles have to be used for these actions.

        Heart difficulties

        The heart can be affected in DM1 or DM2. Oddly, because DM is mostly a muscle disease, it is not the muscle part of the heart (which pumps blood) that’s most affected but rather the part that sets the rate and rhythm of the heartbeat — the heart’s conduction system.

        It is common in DM1, especially after many years, to develop conduction block, which is a block in the electricity-like signal that keeps the heart beating at a safe rate. This appears to occur in DM2 as well, although there are not as many studies in this form of the disease, (rates between 20% to 37% have been reported). Arrhythmias or heart block may occasionally be very early manifestations of DM1, even when neuromuscular symptoms are mild or even unrecognized.

        Fainting, near fainting, or dizzy spells are the usual symptoms of conduction block, and these should never be ignored. Such problems can be fatal.

        In both forms of DM, cardiac muscle impairment also can occur, although it is not as common as conduction abnormalities.

        To learn more, read Cardiac Care in DM: Lack of Symptoms May Mask Deadly Problems and Revising Cardiac Care in Muscular Dystrophies (covers different types of heart problems that occur in these disorders and how to monitor and treat them).

        Insulin resistance

        Fortunately, most people with DM1 and DM2 do not have diabetes, but they may develop a diabetes-like condition that is sometimes referred to as insulin resistance. This means the body makes insulin (a hormone needed for the cells to take up and use sugars), but for some reason, it takes more insulin to do the job because the muscle tissues do not respond normally to the usual amounts. High blood sugar may result from insulin resistance. The prevalence of diabetes is greater in DM2 patients than in patients diagnosed with DM1. 3

        Other common endocrine conditions in DM1 patients are testicular atrophy and associated low sperm count with infertility. 4 , 5 , 6 These conditions are less common in DM2. 7

        Effects on internal organs

        Most of the internal organs in the body are hollow tubes (such as the intestines) or sacs (such as the stomach). The walls of these tubes and sacs contain involuntary muscles that squeeze the organs and move things (food, liquids, a baby during childbirth, and so forth) through them.

        In DM1, many of the involuntary muscles that surround the hollow organs can weaken. These include the muscles of the digestive tract, uterus, and blood vessels. The digestive tract and uterus (womb) often are affected in type 1 myotonic dystrophy. Also, symptoms such as colicky abdominal pain, bloating, constipation, and diarrhea are common.

        Abnormal action of the upper digestive tract can impair swallowing, termed “dysphagia.” Once food is swallowed, the involuntary muscles of the esophagus should take over and move food into the stomach. However, in DM1, these muscles can have spasms and weakness, causing a feeling of food getting stuck and sometimes leading to inhaling food into the lungs (aspiration), which can lead to inhalation pneumonia.

        The gallbladder — a sac under the liver that squeezes bile into the intestines after meals — can weaken in DM1. People with DM probably are more likely than the general population to develop gallstones. Symptoms are difficulty digesting fatty foods and pain in the upper right part of the abdomen.

        These symptoms were considered uncommon in DM2, but dysphagia of solid food, abdominal pain, and constipation have been reported by 41% to 62% of patients, a similar rate to that found in patients with DM1. Dysphagia has been proved to be relatively mild, and history of aspiration pneumonia or weight loss is rather uncommon.

        Most people do not experience incontinence or urination problems in DM.

        Because of weakness and uncoordinated action of the muscle wall of the uterus, women with either type of DM may experience difficulties in childbirth that can be serious for both mother and baby. These may involve excessive bleeding or ineffective labor. Preterm labor and risk of miscarriage is also more common than in women without DM. Sometimes a caesarean operation (C-section) is advised, but surgery also can be a problem in DM (see Medical Management).

        Limb and hand muscle weakness

        Weakness of the voluntary muscles usually is the most noticeable symptom for people with adult-onset DM. The natural history of DM1 is that of gradual progression in weakness.

        The distal muscles (those farthest from the center of the body) usually are the first and sometimes the only limb muscles affected in DM1. Areas of the limbs affected may include the forearms, intrinsic muscles of the hands, and ankles. The muscles that pick up the foot when walking may weaken, allowing the foot to flop down and cause tripping and falling (foot drop). Falls and stumbles in patients with DM1 are 10 times more frequent than in a group of healthy volunteers. 8 Muscles of the pelvic girdle, the hamstrings, and ankle plantar flexors are relatively spared in most cases of DM1.

        In DM2, proximal muscles (closer to the center of the body) tend to show more weakness than in DM1. Weakness in the hip girdle region is often the presenting feature of DM2. 9 , 10 Weakness in the upper part of the leg (thigh) occurs early in DM2. Weakness of thigh, hip flexor, and extensor muscles frequently impairs the ability to arise from a squat, arise from a chair, or climb stairs. 7

        Myotonia and muscle pain

        Myotonia is a slowed relaxation following a normal muscle contraction. Myotonia is present in all patients with DM1, whereas myotonia is found in approximately 75% of patients with DM2. 2 , 11 Myotonia of voluntary muscles can make it hard for someone with DM1 or DM2 to relax their grip, especially in cold temperatures or under stress. 3 Door handles, cups, writing by hand, and using hand tools may pose a problem, although some people never notice it. Myotonia also can affect the muscles of the tongue and jaw, causing difficulty with speech and chewing.

        Myotonia can be uncomfortable and can even cause pain, although people with DM1 and DM2 also can have muscle pain that is not connected to the myotonia. Pain is more common in the legs, where myotonia cannot be demonstrated, and is one of the symptoms (along with stiffness and fatigue) that can bring patients to medical attention before the onset of symptomatic weakness. Pain in DM2 may be induced by exercise, palpation, or temperature changes. 7 , 12 , 13 Chest pain may trigger a work-up for heart disease.

        Cancer susceptibility

        Myotonia is associated with higher risk of cancer. In particular, significantly elevated risk (two-fold) has been reported for cancers of the endometrium, brain, ovary, and colon. This study was based on information collected by large Swedish and Danish patient registries with more than 14,170 patients. 14


        Getting Support

        To learn more about Duchenne muscular dystrophy or find a support group in your area, visit: Cure Duchenne, the Muscular Dystrophy Association, or the Parent Project Muscular Dystrophy.

        Sources

        Bushby, K. Lancet Neurology, November 2009.

        MDA: "Overview," "Signs and Symptoms," "Medical Management."

        National Human Genome Research Institute: "Learning About Duchenne Muscular Dystrophy."

        National Institute of Neurological Disorders and Stroke: "NINDS Muscular Dystrophy Information Page."

        Cure Duchenne: “Ataluren becomes the world’s first approved treatment for Duchenne muscular dystrophy.”

        FDA News Release. "FDA grants accelerated approval to first drug for Duchenne muscular dystrophy."