What is the expected number of children that need to be born for every possible point mutation to occur once?

I'm reading The Perfect Health Diet, and in it the author says that the probability of a point mutation is (175/3*10^9) per new child. He then goes on to write:

In the Paleolithic, with 100000 children per generation, it would have taken 8000 generations, or 160000 years, for each possible mutation to occur once.

Today, with more than a billion children per generation, every possible point mutation now appears about twenty times per generation, or almost yearly.

Using his probability, I get that you need 1 / (175 / (3 * 10^9)) (which is about 17 million children). But he writes that for the Paleolithic era, you need 10000 * 8000 = 80 million children! Can someone help me reason out how he got that number?

EDIT My math was wrong :-) leaving up the og calculation. Here's the reference that he cites:

"Estimate of the Mutation Rate per Nucleotide in Humans" by Michael W. Nachman and Susan L. Crowell In the abstract they write "The average mutation rate was estimated to be 2.5x10^-8 mutations per nucleotide site or 175 mutations per diploid genome per generation."

I don't think the book's reasoning is correct.

There are about 3 billion base pairs in the human genome, but only ca 25.000 protein-coding genes. From the top of my head, I recall that each child has about 30 mutations. If that's in the total genome and if they were all point mutations and there's 4 options for the base pair, then we have \$30\$ mutations out of 12 billion options in each child. So that each possible point mutation has a probability of \$30/12 ext{ billion} = 2.5 imes 10^{-9}\$ or \$1/(2.5 imes 10^{-9})\$ if you like. The book's number is 23 times larger but in the same ballpark range. Lets call this probability \$p\$.

Now the probability of a mutation occuring in n children at least once is equal to one minus the probability of it never occuring in n children. In other words: \$\$1 - (1 - p)^n =\$\$ \$\$1 - (1 - 2.5 imes 10^{-9})^n =\$\$ \$\$1 - (0.9999999975)^n\$\$

If we want the mutation to occur with probability 95%, we have to solve: \$1 - (0.9999999975)^n = 0.9\$ This has the solution \$n = 1 imes 10^9\$

In other words, with 1 billion children, each point mutation has a 95% probability of having occured at least once. Mathematically this is not the same as saying that every mutation will have occured. In fact, this implies that 5% of the mutations will not have occured. But perhaps surprisingly, we only need 4-5 billion to up the chance to 99.999%. That still leaves out thirty thousand point mutations, but is sufficiently close to "everyone".

Compare this to the numbers you mentioned: n = 17 million gives each gene a 4% chance of occuring n = 80 million gives each gene an 18% chance of occurring.

Secondly, a mandatory rant. :-) "The Perfect Health Diet" is written by Paul and Shou-Ching Jaminet, an astrophysicist and molecular biologist respectively. This has the potential to marry the physicist's penchance for oversimplification with the biologist's lack of mathematical prowess. We see both in the passage you ask about. A shoddy calculation about an oversimplification of what mutations and evolution is about. Both the book's dustcover use of a word like "detoxifying" and mention of how diseases spontaneously resolve if you eat right, are both strong crackpot indicators. It's the kind of thinking that killed Steve Jobs because he didn't seek medical help soon enough but tried to eat his way out of his illness.

Achondroplasia

Achondroplasia is a genetic disorder whose primary feature is dwarfism. [3] In those with the condition, the arms and legs are short, while the torso is typically of normal length. [3] Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females. [3] Other features include an enlarged head and prominent forehead. [3] Complications can include sleep apnea or recurrent ear infections. [3] The disorder does not generally affect intelligence. [3]

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in its protein being overactive. [3] The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. [6] About 80% of cases result from a new mutation, which originates in the father's sperm. [5] The rest are inherited from a parent with the condition. [3] The risk of a new mutation increases with the age of the father. [4] In families with two affected parents, children who inherit both affected genes typically die before birth or in early infancy from breathing difficulties. [3] The condition is generally diagnosed based on the symptoms but may be confirmed by genetic testing. [5]

Treatments may include support groups and growth hormone therapy. [5] Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections or spinal stenosis may be required. [5] Life expectancy of those affected is about 10 years less than average. [5] Achondroplasia is the most common cause of dwarfism [4] and affects about 1 in 27,500 people. [3]

Mitosis vs. Meiosis

Both mitosis and meiosis result in eukaryotic cell division. The primary difference between these divisions is the differing goals of each process. The goal of mitosis is to produce two daughter cells that are genetically identical to the parent cell. Mitosis happens when you grow. You want all your new cells to have the same DNA as the previous cells. The goal of meiosis is to produce sperm or eggs, also known as gametes. The resulting gametes are not genetically identical to the parent cell. Gametes are haploid cells, with only half the DNA present in the diploid parent cell. This is necessary so that when a sperm and an egg combine at fertilization, the resulting zygote has the correct amount of DNA&mdashnot twice as much as the parents. The zygote then begins to divide through mitosis.

Table (PageIndex<1>): comparison of mitosis and meiosis
Mitosis Meiosis
Purpose To produce new cells To produce gametes
Number of Cells Produced 2 4
Rounds of Cell Division 1 2
Haploid or Diploid Diploid Haploid
Are daughter cells identical to parent cells? Yes No
Are daughter cells identical to each other? Yes No

Figure (PageIndex<2>) shows a comparison of mitosis, meiosis, and binary fission.

• Binary fission occurs in bacterial. Note that bacterial cells have a single loop of DNA. The DNA of the cell is replicated. Each loop of DNA moves to the opposite side of the cell and the cell splits in half.
• Mitosis and Meiosis both occur in eukaryotic cells. In the example below the cell has 4 total chromosomes. These are replicated during the S phase.
• In mitosis, the chromosomes line up in the center of the cell. Then, sister chromatids separate and move to the opposite poles of the cell. The cell divides, producing two cells with 4 total chromosomes
• In meiosis, the homologous chromosomes line up in the center of the cell. Then each chromosome moves to opposite poles and the cell divides.
• Next, the chromosomes line up in the center of the cell. Then, sister chromatids separate and move to the opposite poles of the cell. This produces four cells with 2 chromosomes each. These are the gametes.
• Two gametes combine to form a zygote with 4 total chromosomes.

Figure (PageIndex<2>): A comparison between binary fission, mitosis, and meiosis.

Microcephaly is a birth defect where a baby&rsquos head is smaller than expected when compared to babies of the same sex and age. Babies with microcephaly often have smaller brains that might not have developed properly.

Typical Head Size, Microcephaly and Severe Microcephaly Comparison

The images are in the public domain and thus free of any copyright restrictions. As a matter of courtesy we request that the content provider (Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities) be credited and notified in any public or private usage of this image.

What is microcephaly?

Microcephaly is a condition where a baby&rsquos head is much smaller than expected. During pregnancy, a baby&rsquos head grows because the baby&rsquos brain grows. Microcephaly can occur because a baby&rsquos brain has not developed properly during pregnancy or has stopped growing after birth, which results in a smaller head size. Microcephaly can be an isolated condition, meaning that it can occur with no other major birth defects, or it can occur in combination with other major birth defects.

What is severe microcephaly?

Severe microcephaly is a more serious, extreme form of this condition where a baby&rsquos head is much smaller than expected. Severe microcephaly can result because a baby&rsquos brain has not developed properly during pregnancy, or the brain started to develop correctly and then was damaged at some point during pregnancy.

Other Problems

Babies with microcephaly can have a range of other problems, depending on how severe their microcephaly is. Microcephaly has been linked with the following problems:

• Seizures
• Developmental delay, such as problems with speech or other developmental milestones (like sitting, standing, and walking)
• Intellectual disability (decreased ability to learn and function in daily life)
• Problems with movement and balance
• Feeding problems, such as difficulty swallowing
• Hearing loss
• Vision problems

These problems can range from mild to severe and are often lifelong. Because the baby&rsquos brain is small and underdeveloped, babies with severe microcephaly can have more of these problems, or have more difficulty with them, than babies with milder microcephaly. Severe microcephaly also can be life-threatening. Because it is difficult to predict at birth what problems a baby will have from microcephaly, babies with microcephaly often need close follow-up through regular check-ups with a healthcare provider to monitor their growth and development.

How Many Babies are Born with Microcephaly?

Microcephaly is not a common condition. Researchers estimate that about 1 in every 800-5,000 babies is born with microcephaly in the United States.

Causes and Risk Factors

The causes of microcephaly in most babies are unknown. Some babies have microcephaly because of changes in their genes. Other causes of microcephaly, including severe microcephaly, can include the following exposures during pregnancy:

• Certain infections during pregnancy, such as rubella, toxoplasmosis, or cytomegalovirus
• Severe malnutrition, meaning a lack of nutrients or not getting enough food
• Exposure to harmful substances, such as alcohol, certain drugs, or toxic chemicals
• Interruption of the blood supply to the baby&rsquos brain during development

Some babies with microcephaly have been reported among mothers who were infected with Zika virus while pregnant. CDC scientists announced that enough evidence has accumulated to conclude that Zika virus infection during pregnancy is a cause of microcephaly and other severe fetal brain defects.

CDC continues to study birth defects, such as microcephaly, and how to prevent them. If you are pregnant or thinking about becoming pregnant, talk with your doctor about ways to increase your chances of having a healthy baby.

For information about the effects of Zika virus infection during pregnancy, visit CDC&rsquos Zika and Pregnancy web page.

Diagnosis

Microcephaly can be diagnosed during pregnancy or after the baby is born.

During Pregnancy

During pregnancy, microcephaly can sometimes be diagnosed with an ultrasound test (which creates pictures of the body). To see microcephaly during pregnancy, the ultrasound test should be done late in the 2nd trimester or early in the third trimester. For more information about screening and confirmatory tests during pregnancy, visit CDC&rsquos birth defects diagnosis web page.

After the Baby is Born

To diagnose microcephaly after birth, a healthcare provider will measure the distance around a newborn baby&rsquos head, also called the head circumference, during a physical exam. The provider then compares this measurement to population standards by sex and age. Microcephaly is defined as a head circumference measurement that is smaller than a certain value for babies of the same age and sex. This measurement value for microcephaly is usually more than 2 standard deviations (SDs) below the average. The measurement value also may be designated as less than the 3rd percentile. This means the baby&rsquos head is extremely small compared to babies of the same age and sex.

Head circumference growth charts for newborns, infants, and children up to age 20 years in the United States can be found on CDC&rsquos growth charts website. Head circumference growth charts based on gestational age at birth (in other words, how far along the pregnancy was at the time of delivery) are also available from INTERGROWTH 21st external icon . CDC recommends that health care providers use the WHO growth charts to monitor growth for infants and children ages 0 to 2 years of age in the United States.

Microcephaly can be determined by measuring head circumference (HC) after birth. Although head circumference measurements may be influenced by molding and other factors related to delivery, the measurements should be taken on the first day of life because commonly-used birth head circumference reference charts by age and sex are based on measurements taken before 24 hours of age. The most important factor is that the head circumference is carefully measured and documented. If measurement within the first 24 hours of life is not done, the head circumference should be measured as soon as possible after birth. If the healthcare provider suspects the baby has microcephaly, he or she can request one or more tests to help confirm the diagnosis. For example, special tests like like magnetic resonance imaging can provide critical information on the structure of the baby&rsquos brain that can help determine if the newborn baby had an infection during pregnancy. They also can help the healthcare provider look for other problems that might be present .

Treatments

Microcephaly is a lifelong condition. There is no known cure or standard treatment for microcephaly. Because microcephaly can range from mild to severe, treatment options can range as well. Babies with mild microcephaly often don&rsquot experience any other problems besides small head size. These babies will need routine check-ups to monitor their growth and development.

For more severe microcephaly, babies will need care and treatment focused on managing their other health problems (mentioned above). Developmental services early in life will often help babies with microcephaly to improve and maximize their physical and intellectual abilities. These services, known as early intervention external icon , can include speech, occupational, and physical therapies. Sometimes medications also are needed to treat seizures or other symptoms.

Other Resources

The views of these organizations are their own and do not reflect the official position of CDC.

Mother To Baby external icon (on behalf of the Organization of Teratology Information Specialists)
This website provides comprehensive information to mothers, healthcare professionals, and the general public about exposures during pregnancy.

Is Rett syndrome inherited?

Although Rett syndrome is a genetic disorder, less than 1 percent of recorded cases are inherited or passed from one generation to the next. Most cases are spontaneous, which means the mutation occurs randomly. However, in some families of individuals affected by Rett syndrome, there are other female family members who have a mutation of theirMECP2 gene but do not show clinical symptoms. These females are known as &ldquoasymptomatic female carriers.&rdquo

Every Family Has Children Until They Have A Boy: Probability Stumper

In a country in which people only want boys every family continues to have children until they have a boy. If they have a girl, they have another child. If they have a boy, they stop. What is the proportion of boys to girls in the country?

The question is ill-posed as stated because it includes several unstated assumptions. One set might be, and the one I’ll use, is that the country begins with no kiddies and with n couples, all the same age and who never die during their reproductive years and can reproduce at will and do, always on New Year’s Day, a day of celebration. Further, no babies are killed or die before they are born and none or killed or die once they escape into the wild. Babies are born once per year for every couple until success (a boy!). And no immigration nor emigration.

One last assumption is no genetic engineering or other meddling: forget the kind of things that happen in China and India. Why complicate things? Now, something causes each child to be a boy or girl, but we do not know what this something is in each case. Probability is a measure of information, not of biology. Therefore, given there are only two concrete choices, we deduce from our assumptions the probability (which I repeat measures our uncertainty, not the biology) is 1/2 for boys, same for girls.

So, Year 0, there are no boys, no girls and no ratio neither.

Year 1, the uncertainty in the number of boys will (given our assumptions) follow a binomial, characterized with p = 1/2 and n chances. Pr(0 boys | assumptions) = (1/2) n , Pr(1 boy | assumptions) = n * (1/2) n , Pr(2 boys | assumptions) = (n choose 2) * (1/2) n and so forth. The “(1/2) n ” is always there because of a nifty quirk of the binomial with p = 1/2.

The proportion of boys to girls follows right from this. If there are 0 boys, the proportion is 0/n, because there must be, given our assumptions, n girls. The probability of seeing this proportion is the same as seeing 0 boys. And so on for all the other proportions, 1/(n-1), 2/(n-2), etc., except if all boys are born then the proportion is infinite (well, n/0 anyway). Lastly, assuming n is even, the most likely occurrence is (if n is even, or within rounding if not) n/2 boys, giving a proportion of 1/1. This follows because p = 1/2.

Visually (with n = 8), we might have seen this:

With a (for boys) b1 = 3 and (for girls) n – b1 = 5 and thus a ratio of 3/5.

Year 2. Those couples who have had a boy exit the competition, the remainder have another go. The uncertainty in the number of boys in this new crop will again be characterized with a binomial with the same p but with n – b1 chances. Again, the most likely outcome, to our knowledge, is (n – b1)/2 new boys. That’s again because p = 1/2.

This year might have given, say, a b2 = 3, thus

The ratio counts Year one’s b1 boys and n – b1 girls plus this year’s crop, for a total of b1 + b2 = 6 boys and (n – b1) + (n – b1 – b2) = 7. The ratio is 6/7.

Year 3 is a repeat, our uncertainty another binomial but with (n – b1 – b2) = 2 chances. The most likely number of boys is 1. Suppose we see two boys:

The total boys is 8, the total girls 7, for a ratio of 8/7.

If you are mathematically inclined, you will notice this ratio is not 1/1, which (I’m guessing) is the answer the examiner wants. It’s close, though.

The reason it is close is that each year the most likely occurrence, to within rounding, is half boys, half girls from the couples who are still going at it. Adding all those halfs up, as it were, gives half-and-half boys and girls as the most likely final outcome. But this isn’t necessarily the outcome.

We could figure the probability of seeing 8 total boys and 7 total girls easily but tediously enough. It involves calculating the probability of seeing 3 boys and 5 girls in Year one and 3 boys and 2 girls in Year two and 2 boys and 0 girls in Year 3. But then we’d have to figure the other ways (if any exist) to get 8b/7g in three years. Conceptually simple, because each combination follows a binomial with known parameters, but, as claimed, tedious to run through.

Now it could have been, for whatever sized n, that Year 1 saw all boys. We know the probability of this is (1/2) n , which is always greater than 0 for any finite n (which it always will be). Meaning, our knowledge does not preclude an infinite ratio: it could happen, especially with small n.

For large n, we follow the same pattern as above. But eventually two things happen: the kiddies become adults and pair off and begin producing their own children, and eventually the thus created grandpas and grandmas cease their efforts. How many child bearing years does a woman have, after all, assuming she’s pushing out a kid a year?

Ceasing to produce is easy to account for, but figuring the number of new couples is hard, because that depends on—you guessed it—the proportion of extant boys-now-men to girls-now-women. If the proportion of boys and girls is not 1/1, and while this is the most likely it is not certain, then some boys or girls will go marriageless. You then have to assume if they’re going to remain that way (easy), or if the strays can marry the strays which probably will come along the next year (hard, because how long will they remain fecund?).

Now all this is discrete and tedious, but if one has the energy and time it could all be ploughed through. We also have the sense that, because of the symmetries and clear assumptions, that the “system” will reach a limit where the proportions of boys to girls is roughly equal.

It may be equal in any year, but it’s more likely, we guess, to only “near” equal, where we can work out what it means to be near.

Developmental disabilities are a group of conditions due to an impairment in physical, learning, language, or behavior areas. These conditions begin during the developmental period, may impact day-to-day functioning, and usually last throughout a person&rsquos lifetime. 1

Developmental Milestones

Skills such as taking a first step, smiling for the first time, and waving &ldquobye-bye&rdquo are called developmental milestones. Children reach milestones in how they play, learn, speak, behave, and move (for example, crawling and walking).

Children develop at their own pace, so it&rsquos impossible to tell exactly when a child will learn a given skill. However, the developmental milestones give a general idea of the changes to expect as a child gets older.

As a parent, you know your child best. If your child is not meeting the milestones for his or her age, or if you think there could be a problem with the way your child plays, learns, speaks, acts, and moves talk to your child&rsquos doctor and share your concerns. Don&rsquot wait. Acting early can make a real difference!

Developmental Monitoring and Screening

A child&rsquos growth and development are followed through a partnership between parents and health care professionals. At each well-child visit, the doctor looks for developmental delays or problems and talks with the parents about any concerns the parents might have. This is called developmental monitoring.

Any problems noticed during developmental monitoring should be followed up with developmental screening. Developmental screening is a short test to tell if a child is learning basic skills when he or she should, or if there are delays.

If a child has a developmental delay, it is important to get help as soon as possible. Early identification and intervention can have a significant impact on a child&rsquos ability to learn new skills, as well as reduce the need for costly interventions over time.

Causes and Risk Factors

Developmental disabilities begin anytime during the developmental period and usually last throughout a person&rsquos lifetime. Most developmental disabilities begin before a baby is born, but some can happen after birth because of injury, infection, or other factors.

Most developmental disabilities are thought to be caused by a complex mix of factors. These factors include genetics parental health and behaviors (such as smoking and drinking) during pregnancy complications during birth infections the mother might have during pregnancy or the baby might have very early in life and exposure of the mother or child to high levels of environmental toxins, such as lead. For some developmental disabilities, such as fetal alcohol syndrome, which is caused by drinking alcohol during pregnancy, we know the cause. But for most, we don&rsquot.

Following are some examples of what we know about specific developmental disabilities:

• At least 25% of hearing loss among babies is due to maternal infections during pregnancy, such as cytomegalovirus (CMV) infection complications after birth and head trauma.
• Some of the most common known causes of intellectual disability include fetal alcohol syndrome genetic and chromosomal conditions, such as Down syndrome and fragile X syndrome and certain infections during pregnancy.
• Children who have a sibling with autism are at a higher risk of also having autism spectrum disorder.
• Low birthweight, premature birth, multiple birth, and infections during pregnancy are associated with an increased risk for many developmental disabilities.
• Untreated newborn jaundice (high levels of bilirubin in the blood during the first few days after birth) can cause a type of brain damage known as kernicterus. Children with kernicterus are more likely to have cerebral palsy, hearing and vision problems, and problems with their teeth. Early detection and treatment of newborn jaundice can prevent kernicterus.

The Study to Explore Early Development (SEED) is a multiyear study funded by CDC. It is currently the largest study in the United States to help identify factors that may put children at risk for autism spectrum disorders and other developmental disabilities.

Who Is Affected

Developmental disabilities occur among all racial, ethnic, and socioeconomic groups. Recent estimates in the United States show that about one in six, or about 17%, of children aged 3 through 17 years have one or more developmental disabilities, such as:

For over a decade, CDC&rsquos Autism and Developmental Disabilities Monitoring (ADDM) Network has been tracking the number and characteristics of children with autism spectrum disorder, cerebral palsy, and intellectual disability in several diverse communities throughout the United States.

Living With a Developmental Disability

Children and adults with disabilities need health care and health programs for the same reasons anyone else does&mdashto stay well, active, and a part of the community.

Having a disability does not mean a person is not healthy or that he or she cannot be healthy. Being healthy means the same thing for all of us&mdashgetting and staying well so we can lead full, active lives. That includes having the tools and information to make healthy choices and knowing how to prevent illness. Some health conditions, such as asthma, gastrointestinal symptoms, eczema and skin allergies, and migraine headaches, have been found to be more common among children with developmental disabilities. Thus, it is especially important for children with developmental disabilities to see a health care provider regularly.

CDC does not study education or treatment programs for people with developmental disabilities, nor does it provide direct services to people with developmental disabilities or to their families. However, CDC has put together a list of resources for people affected by developmental disabilities.

Mutations in the HTT gene cause Huntington disease. The HTT gene provides instructions for making a protein called huntingtin. Although the function of this protein is unclear, it appears to play an important role in nerve cells (neurons) in the brain.

The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat . This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder.

An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.

Key Points

Germline base substitution mutations occur more frequently in males than in females, especially in older males.

The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood.

Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined.

For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females.

The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one.

It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost.

Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.

Causes

DMD is caused by a problem in one of your genes. Genes contain the information your body needs to make proteins, which carry out many different body functions.

Continued

If you have DMD, the gene that makes a protein called dystrophin is broken. This protein normally keeps muscles strong and protects them from injury.

The condition is more common in boys because of the way parents pass DMD genes to their children. It’s what scientists call a sex-linked disease because it’s connected to the groups of genes, called chromosomes, that determine if a baby is a boy or a girl.

It’s rare, but sometimes people who don't have a family history of DMD get the disease when their genes get defects on their own.

Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare form of intractable epilepsy that begins in infancy and proceeds with accumulating morbidity that significantly impacts individuals throughout their lifetime. Dravet syndrome has an estimated incidence rate of 1:15,700 individuals, 80% of whom have a mutation in their SCN1A gene [1]. While seizures persist, other comorbidities such as developmental delay and abnormal EEGs are often not evident until the second or third year of life. Common issues associated with Dravet syndrome include:

• Prolonged seizures
• Frequent seizures
• Behavioral and developmental delays
• Movement and balance issues
• Orthopedic conditions
• Delayed language and speech issues
• Growth and nutrition issues
• Sleeping difficulties
• Chronic infections
• Sensory integration disorders
• Dysautonomia, or disruptions of the autonomic nervous system which can lead to difficulty regulating body temperature, heart rate, blood pressure, and other issues

Current treatment options are limited, and the constant care required for someone suffering from Dravet syndrome can severely impact the patient’s and the family’s quality of life. Patients with Dravet syndrome face a 15-20% mortality rate due to SUDEP (Sudden Unexpected Death in Epilepsy), prolonged seizures, seizure-related accidents such as drowning, and infections [2,3]. Research for a cure offers patients and families hope for a better quality of life for their loved ones.

Whether you are a doctor, parent, grandparent or friend, we can use your help.

DIAGNOSIS

Dravet syndrome is a clinical diagnosis that was recently determined to affect 1:15,700 infants born in the U.S. [1]. Approximately 80% of those diagnosed with Dravet syndrome have an SCN1A mutation (1:20,900), but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude the diagnosis. Dravet syndrome lies at the severe end of the spectrum of SCN1A-related disorders but can be associated with other mutations as well [4,5].

In the 2015 study, clinical diagnostic criteria included at least 4 of the following:

• Normal or near-normal cognitive and motor development before seizure onset
• Two or more seizures with or without fever before 1 year of age
• Seizure history consisting of myoclonic, hemiclonic, or generalized tonic-clonic seizures
• Two or more seizures lasting longer than 10 minutes
• Failure to respond to first-line antiepileptic drug therapy with continued seizures after 2 years of age

Other earmarks of the syndrome include seizures associated with vaccinations, hot baths, or warm temperatures developmental slowing, stagnation, or regression after the first year of life behavioral issues and speech delay.

GENETIC TESTING

Because many of these criteria are not apparent in the first year of life and infants with Dravet syndrome initially experience typical development, the study determined genetic testing via an epilepsy panel should be considered in patients exhibiting any of the following:

• 2 or more prolonged seizures by 1 year of age
• 1 prolonged seizure and any hemi-clonic (sustained, rhythmic jerking of one side of the body) seizure by 1 year of age
• 2 seizures of any length that seem to affect alternating sides of the body
• History of seizures prior to 18 months of age and later emergence of myoclonic and/or absence seizures

If you suspect your loved one might have Dravet syndrome, ask your neurologist about testing, which is available through your doctor or commercially. An epilepsy panel will test for SCN1A as well as many other genes commonly associated with epilepsy. Following testing, consultation with a genetic counselor is recommended.

1. Wu, E., et. al. (2015). Incidence of Dravet Syndrome in a US Population. Pediatrics 136(5): 1310-e1315. doi: 10.1542/peds.2015-1807. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621800/
2. Cooper, M.S., et. al. (2016). Mortality in Dravet Syndrome. Epilepsy Research Oct 26128:42-47. doi: 10.1016/j.eplepsyres.2016.10.006.
3. Skluzacek, et. al. (2011). Dravet syndrome and parent associations: The IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia Apr52 Suppl 2:95-101. doi: 10.1111/j.1528-1167.2011.03012.x.
4. Ian O Miller, MD, Marcio A Sotero de Menezes, MD. SCN1A-Related Seizure Disorders. Gene Reviews. Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA):University of Washington, Seattle 1993-2016.
5. Silberstein, S.D., Dodick, D.W. (2013). Migraine genetics: Part II.2013 Sep53(8):1218-29. doi: 10.1111/head.12169. Epub 2013 Aug 6.

TREATMENT

Dravet syndrome is a spectrum disorder, meaning patients present with a wide range of severity and seizure types, and no two patients respond to treatment the same way. What helps one may not help another, and vice versa. Still, several medications have proven beneficial in many patients (sometimes called “first line treatments”) and some medications have been known to exacerbate seizures in many patients (called “contraindicated” medications) due to their effects on the sodium ion channel. Several medications with indications specifically for Dravet syndrome have been approved since this consensus statement was formed. In 2018, two medications were granted US FDA approval for the treatment of Dravet syndrome due to positive results in clinical trials: Epidiolex, which is a cannabidiol (CBD) extract, and Diacomit (stiripentol). In 2020, another medication, Fintepla (fenfluramine) also received FDA approval for the treatment of seizures in Dravet syndrome.

Rescue Medications

Many patients with Dravet syndrome experience prolonged seizures (status epilepticus) that require emergency intervention. For this reason, your neurologist may prescribe a rescue medication, typically a benzodiazepine, that is given during the seizure to help stop it.

Rescue medications include:

• Clonazepam (Klonopin)
• Diazepam (Diastat)
• Lorazepam (Ativan)
• Midazolam (Versed)

Treatments

Other treatments and therapies have shown positive results in the overall care and management of Dravet syndrome in some patients, even though they have not been fully studied. These include IVIG (Intravenous Immunoglobulin) Therapy, dietary interventions such as the Ketogenic Diet, and VNS (Vagus Nerve Stimulation) Therapy. Epidiolex, an oral solution of cannabidiol (CBD), received indication and FDA approval for the treatment of Dravet syndrome in 2018 and is available by prescription. Fintepla, a low-dose oral solution of fenfluramine, received indication and FDA approval for the treatment of Dravet syndrome in 2020 and is available by prescription with enrollment in a REMS program to monitor heart health while taking this medication.

Establish an Emergency Protocol

It is important to design and implement an emergency protocol with your neurologist, including a fast onset benzodiazepine such as Diastat, nasal versed, or lorazepam, for any convulsive seizure lasting longer than five minutes. It is helpful to have a written copy of this protocol with the child at all times, in case of emergency. This protocol should include instructions on seizure treatment and when to call for emergency services, as well as parent and physican contact information.

Monitor & Treat Secondary Health Conditions

Be aware of secondary health conditions common to the syndrome to make sure they are properly managed. These conditions vary from patient to patient and may include:

• Cardiovascular conditions
• Dental health concerns
• Dysautonomia
• Orthopedic & scoliosis issues
• Sleep disturbances
• Weakened immunity

Growth and weight should also be followed closely and parents should be aware of treatment options such as gastrostomy tubes (g-tubes) when appropriate.

Learn & Avoid Seizure Triggers

Avoid seizure triggers whenever possible. Common triggers for patients with Dravet syndrome include rapid changes in environmental and/or body temperature, illness, stress, over-excitement, patterns, and flickering lights. Fevers should always be treated aggressively with a plan established with your pediatrician and/or neurologist.

Other Challenges

Children with Dravet syndrome often also face developmental challenges such as autism or autistic-like characteristics, cognitive and/or communication delays, social skills, and behavioral issues. Regular developmental assessments and early and aggressive therapies (speech, OT, PT, developmental, etc.) may help with the overall outcome for the child.

Day-to-Day Management

Children with Dravet syndrome typically need constant care and supervision, as well as help in avoiding seizure triggers. Equipment that has been found by families to be useful in the day-to-day management of Dravet syndrome includes video monitoring, protective helmets, cooling vests, pulse oximeters, seizure alarms, and glasses with colored lenses (for photosensitivity).

Coping as a Family

A child’s chronic illness will have both direct and indirect effects on family members and their relationships. It is not uncommon for family members to feel denial, anger, fear, shock, confusion, self-blame, and helplessness. Family and grief counseling can help families deal with having a child with a chronic illness.

GENETICS OF DRAVET SYNDROME

More than 75% of patients diagnosed with Dravet syndrome have an SCN1A mutation [1]. The SCN1A gene codes for the production of sodium ion channels, which are pore-like proteins embedded in the cell membrane that allow sodium ions into and out of the cell, propagating electrical signals. Some patients have other mutations including SCN2A and PCDH19.

• 90% of SCN1A mutations are de novo, meaning they are not found in the patient’s parents
• 4-10% of SCN1A mutations are inherited from the parent. In this case, there is a 50% chance of passing the mutation on to future children
• There are over 6,000 places for a mutation to occur on the SCN1A gene. Therefore, most patients’ mutations have not been reported in other people
• Any type of SCN1A mutation can be seen in Dravet syndrome, and mutation type does not predict the severity of the disease
• SCN1A mutations are also associated with migraines, febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+)

After a positive genetic test result, consultation with a genetic counselor is recommended.

While a mutation is not necessary for diagnosis, it can support a clinical diagnosis and it is helpful to understand what DNA, genes, and mutations are. Each person has two copies of the SCN1A gene: one from each parent. Many mutations found in Dravet syndrome render one copy dysfunctional, leaving only one functional copy. This results in a condition called haploinsufficiency, which means that one functioning copy is not sufficient to prevent symptoms. Approximately 90% of Dravet mutations are de novo, meaning they are not inherited from a parent, but rather are new mutations in the child [1,4].

What is DNA?

DNA is the set of instructions contained within each of our body’s cells. The instructions tell the cell how to build the proteins it needs to function. A strand of DNA is a long chain of 4 different nucleotides (abbreviated A, T, C, and G) strung together in a particular order, billions of nucleotides long. Because there is so much DNA in our cells, it is organized into 23 pairs of chromosomes, much like two sets of encyclopedias would be organized into 23 volumes each. When a sperm and an egg, each containing 23 chromosomes, combine, the result is 46 total chromosomes, organized into 23 matching pairs.

What is a gene?

The 23 pairs of chromosomes are further divided into smaller segments called genes. A gene is much like a chapter in an encyclopedia and contains the instructions for producing a specific protein. Each gene is a small segment of DNA and is thus also a long chain of 4 different nucleotides strung together in a particular order. Because our cells have one copy of each gene from each parent, every cell has two copies of each gene unless the gene is carried on the sex-determining X or Y chromosome. SCN1A is not on the X or Y chromosome.

Genes are read in groups of 3 nucleotides called codons. Each codon is translated into one of twenty amino acids, which are then strung together like beads on a necklace. The amino acids interact with each other based on their chemical properties similar to how magnetic beads attract and repel each other when folded up in one’s hand. As the amino acids interact, the long chain folds on itself to form a very specific 3-D shape. In the case of SCN1A, this 3-D shape is an ion channel that functions as a gated channel in the cell membrane, letting sodium ions into and out of the cell. The influx and efflux of ions allows electrical signals to propagate along neurons.

What is a mutation?

A mutation is a change in the expected sequence of nucleotides within a gene. This change in the original sequence of DNA may alter the sequence of amino acids, which may cause the chain to terminate prematurely, fold improperly, or otherwise alter the functionality of the sodium ion channel. Dysfunctional sodium ion channels can result in improper electrical activity and seizures.

Although SCN1A has 160,000 nucleotides, the body edits this sequence of 160,000 down to about 6,000 in the final SCN1A transcript that serves as the instructions for the sodium ion channel [2]. Still, with over 6,000 nucleotide positions, it is no wonder that most mutations reported in the literature have not yet been seen in another patient.

Remember that every cell actually contains two copies of SCN1A one from each parent. Usually, only one copy is mutated, a condition termed heterozygosity [3]. Approximately 4% of the mutations seen in Dravet syndrome are inherited directly from parents, with the parent often experiencing fewer and less severe symptoms than the child in a phenomenon known as reduced penetrance [1].

There are three main types of mutations: missense, nonsense, and insertions/deletions.

Missense:

A missense mutation is a simple substitution of one nucleotide for another at a single location in a gene. This slight change in the sequence of nucleotides may or may not result in one changed amino acid in the long chain.

If a missense mutation occurs near a pore-forming region of the sodium ion channel, it is likely to significantly alter the ion channel’s function and cause a more severe case of SCN1A-related epilepsy such as Dravet syndrome [5]. If a missense mutation occurs at a less critical location on the gene, it may produce milder clinical symptoms or no symptoms at all. Approximately 47% of the mutations seen in Dravet patients are missense mutations [1].

A missense mutation reported by a testing company may look like this:

• Variant 1: Transversion G>T
• Nucleotide Position: 4073
• Codon Position: 1358
• Amino Acid Change: Tryptophan>Leusine
• Variant of Unknown Significance (heterozygous)

This says that the mutation was a substitution of T for G at the 4073rd nucleotide position (of 6000 in the final gene that is read) [6]. Remember that nucleotides are read in groups of 3, called codons, so 4073 divided by 3 gives you the amino acid or codon position of 1358. The amino acid Leucine was substituted for the amino acid Tryptophan. The lab is unable to determine the significance because missense mutations can be associated with both mild and severe clinical presentations. The patient has only one copy of this mutation and is thus heterozygous. This real-life mutation is indeed in a pore region of the sodium ion channel, and this patient does have Dravet syndrome.

Nonsense:

Nonsense mutations are similar to missense mutations in that one nucleotide is substituted for another. However, in the case of a nonsense mutation, that substitution causes the codon to be read as a “STOP” signal. The cell stops reading the gene prematurely, and the protein is significantly shortened, or truncated. Nonsense mutations are often associated with more severe SCN1A-related epilepsies such as Dravet syndrome [5]. Approximately 20-40% of mutations in Dravet syndrome are nonsense (truncation) mutations [1,10]. A nonsense mutation may be reported like this:

“The mutation c.3985C>T (heterozygous) resulting in a termination or stop codon at Arg 1329 was detected in exon 20 of the patient sample and is associated with Dravet syndrome.”

This says that the nucleotide C was replaced with a T at position 3985, which resulted in the amino acid Arginine being replaced with a stop codon at position 1329. (3985 nucleotides, read in groups of 3, correspond to 1329 amino acids.) Only one of the two copies of SCN1A in the patient is mutated (heterozygous), as is usually the case. “Amber,” “Opal,” and “Ochre” may appear on the lab report and are some of the names for stop codons. The lab can be fairly confident this mutation is disease-producing because of the high correlation between truncation mutations and Dravet syndrome.

This same mutation may be reported by another lab like this:

This report does not specify the nucleotide position, but it identifies the amino acid position as 1329, and the asterisk (*) next to the amino acid position indicates a stop codon. Again, the lab is confident this mutation will result in Dravet syndrome.

Insertions/Deletions:

Sometimes, one or more nucleotides are deleted from the gene. If one or two nucleotides are inserted or deleted, the reading frame of codons is shifted, and every amino acid is incorrect from that point in the chain on. This usually causes a dysfunctional sodium ion channel. In addition, the shift in reading frame will often cause one of the codons farther down the chain to be interpreted as a stop codon, prematurely terminating an already dysfunctional chain.

If a group of 3 nucleotides is inserted or deleted, only one codon is added or deleted, respectively, and the protein may still be functional depending on the location of that insertion or deletion.

Large segments of DNA may be inserted or deleted including the entire SCN1A gene and/or nearby genes. These mutations have varying phenotypes, and account for roughly 2-5% of Dravet mutations [1,5].

Mosaicism:

When the mutation occurs in the sperm, egg, or very soon after fertilization, all of the daughter cells derived from the growing embryo will contain the mutation. This is the case for most mutations found in Dravet syndrome [1].

However, if the mutation occurs later in the development of the embryo, only the cells descended from the mutated cell will carry the mutation. The cells descended from the non-mutated cells of the embryo will remain healthy. This results in an individual who is mosaic for the mutation. The later the mutation took place, the lower the percentage of cells descended from the mutated cell, and the lower the “% mosaicism” or “mosaic load.” (This is a broad generalization: In reality, the degree of specialization of the cells at the time of mutation plays a significant role in where the mutated cells are concentrated in the patient’s body and what the ultimate mosaic load is.) One study reported that SCN1A mutations with 12-25% mosaic load were potentially pathogenic, with reduced penetrance, meaning not all who carried the mutation in mosaic form exhibited signs or symptoms [5].

SNP’s:

Mutations are actually a natural phenomenon that has been occurring in all organisms for thousands of years. Most changes in DNA sequence have little to no effect on the final protein products because they occur in regions that are edited out during gene processing, or their location in the final protein does not alter its function. In fact, many members of the healthy population have variants in their genes that are shared with a significant percentage of the population. Because these variants have no obvious clinical symptoms, they are called single nucleotide polymorphisms (SNP’s) and are not considered mutations. Your lab report may include these SNP’s, but their presence is not considered a positive SCN1A test.

What does this mean for the patient?

Researchers and epileptologists are learning more about the role SCN1A mutations play in Dravet syndrome and related epilepsies every day. At this point, it is clear that SCN1A mutations of any kind can be responsible for Dravet syndrome. However, because some SCN1A mutations are present in individuals with mild symptoms, there are probably many modifying factors that determine the severity of symptoms that result from the mutation. SCN1A mutations are helpful in supporting a clinical diagnosis, but remember that roughly 20% of patients with Dravet syndrome have no detected mutation, and a mutation is not required for diagnosis.

No! There is so much active research on SCN1A and related epilepsies that scientists are uncovering new knowledge and potential therapeutic pathways every day. The fact that an epilepsy syndrome like Dravet can be traced to a root cause, despite many unknown factors and modifiers, makes it an appealing target for research and gives patients hope for a cure.

1. 2012. Xu XJ, Zhang YH, Sun HH, Liu XY, Jiang YW, Wu XR. Genetic and phenotypic characteristics of SCN1A mutations in Dravet syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012 Dec29(6):625-30
2. http://ghr.nlm.nih.gov/gene/SCN1A
3. 2015. Brunklaus A, Ellis R, Stewart H, Aylett S, Reavey E, Jefferson R, Jain R, Chakraborty S, Jayawant S, Zuberi SM. Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families. Eur J Paediatr Neurol. 2015 Feb 21
4. 2003. Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E, Capovilla G, Chiron C, Cristofori G, Elia M, Fontana E, Gaggero R, Granata T, Guerrini R, Loi M, La Selva L, Lispi ML, Matricardi A, Romeo A, Tzolas V, Valseriati D, Veggiotti P, Vigevano F, Vallée L, Dagna Bricarelli F, Bianchi A, Zara F. Spectrum ofSCN1Amutations in severe myoclonic epilepsy of infancy. Neurology. 2003 Jun 2460(12):1961-7
5. 2015. Meng H, Xu HQ, Yu L, Lin GW, He N, Su T, Shi YW, Li B, Wang J, Liu XR1, Tang B, Long YS, Yi YH, Liao WP . TheSCN1AMutation Database: Updating Information and Analysis of the Relationships among Genotype, Functional Alteration, and Phenotype. Hum Mutat. 2015 Jun36(6):573-80
6. http://www.scn1a.info/Exons
7. http://igbiologyy.blogspot.com/2014/03/chromosomes-dna-genes-and-alleles.html
8. http://leavingbio.net/HEREDITY-ORDINARY%20LEVEL.htm

Updated 2016 by Nicole Villas

Related Epilepsies

Dravet syndrome presents differently in each patient. Individuals with Dravet syndrome are often misdiagnosed with another seizure disorder such as Lennox Gastaut or Myoclonic Astatic Epilepsy, or given a broad diagnosis of intractable epilepsy. Some epilepsy syndromes, like PCDH19, a rare x-linked epilepsy found more often in females than males, share many characteristics with Dravet syndrome. There are subtle differences between these epilepsy syndromes and Dravet, and you should consult with your child’s neurologist if you have any questions about related epilepsies.

Our brain uses electrical currents to spread communication. These electrical currents are maintained by a balance of positive and negative charges that are carried by small charged molecules like sodium, potassium, calcium, and chloride (also called “ions”). When the cells in our brain are unable to move these ions in the correct way at the correct time, it disrupts communications. Sometimes that means neurons communicate “too much,” spreading too much electrical activity to their neighbors, which can lead to seizure activity. In many individuals with Dravet syndrome, they have a mutation that affects the ability to regulate electrical currents using sodium ions. If you want to know more, the explanation below goes into detail about how this works at the level of individual brain cells.

1. Neurons communicate with electric current.

One of the major cell types in our brains are neurons . Neurons have long extensions that form connections with other neurons so they can communicate with each other. Neurons communicate using electrical currents that travel down their long extensions to the next neuron , similar to the wires that carry electricity to our appliances.

2. Neurons use ions to generate electric current.

How do neurons generate electricity. It’s all based on the movement of charged particles, or “ions,” that have positive charges (+) and negative charges (-) . Sodium (Na, + charge) and potassium (K, + charge) are two important ions that help neurons do this. When a neuron is “resting,” or not talking to a neighbor neuron, it is more negatively charged inside and is keeping more of the positive charged ions, like sodium (Na+), outside the cell.

When a neuron gets stimulated and needs to send a message, it suddenly lets a bunch of the sodium (Na+) rush into the cell to start an electrical current. All of these changes in the balance of positive and negative ions leads to an electrical current that can move very quickly down the long extensions of the neuron to communicate to the next cell.

When it’s time to stop communicating, the neuron has to reverse the ions so that there are more negative inside again and more positive outside . Balancing ion movement is an important step for the cell to stop the electrical activity. This means moving more positive ions out than it brings in.

3. Neurons use channels to move the ions that generate electric current.

To move ions inside and outside of the cell, the neuron needs special channels . There are specific channels for each type of ion (sodium, potassium, etc).

When these channels do not work properly, the neuron has a hard time making, regulating, and then stopping the electrical currents. When neurons are unable to regulate electrical currents it can lead to seizures.

The most common cause of Dravet syndrome results from a problem with a specific sodium (Na+) channel , called “Nav1.1” (Na for sodium, V for electrical voltage, 1.1 because there are several channels that are similar). Many patients with Dravet syndrome have a mutation in SCN1A, the gene that makes Nav1.1. The mutations in SCN1A in Dravet syndrome usually only affect one copy (we get two copies of every gene in our DNA). That means about half of the Nav1.1 sodium (Na+) channels that the neuron needs either (1) do not work correctly, or (2) do not get made at all. This ultimately means less sodium channels that work correctly. This makes it very hard for neurons to properly make and stop electrical currents for communication, which can lead to seizure activity.

4. Reduction in Nav1.1 affects the electrical activity of inhibitory neurons.

This last section gets into the very specifics of what can go wrong in Dravet syndrome. At this point, you may wonder:

• if you have to bring sodium (Na+) into the neuron to start an electrical current,
• and this channel to bring sodium (Na+) into the neuron does not work as well in Dravet syndrome,
• should the problem be with too little electrical current and not too much?!

To understand how this is working to cause seizures in Dravet syndrome, we have to step back and talk about how there are different TYPES of neurons in the brain.

• When some neurons use electrical currents to talk to their neighbors, they always tell them to “get excited” and keep spreading the message. These are called excitatory neurons .
• A different group of neurons always uses their electrical currents to tell their neighbors to “STOP signaling!”. These are called “inhibitory” neurons .

The sodium channel Nav1.1 is most important to inhibitory neurons . So in Dravet syndrome, these inhibitory neurons have trouble communicating. Normally, they should be telling the excitatory neurons when to STOP, but since they cannot do that properly, the excitatory neurons can get “too excited”, or generate too much electrical current, which leads to seizures.