What are the other Names for this Condition? (Also known as/Synonyms)

• SCN2A-Associated Syndrome
• SCN2A Gene Syndrome
• SCN2A Related Conditions

What is SCN2A Syndrome? (Definition/Background Information)

• SCN2A Syndrome is a rare genetic disorder that develops when the normal function of the SCN2A gene, which is responsible for the sodium channel function of the brain. The gene allows sodium in and out of the nerve cells (neurons), and the gene is located on chromosome 2, in the region known as 2q24.3
• The disruption of the gene can result in various brain-related abnormalities that may be mild or severe. SCN2A Syndrome can manifest as infantile seizures, severe epileptic attacks, developmental delays, and learning disorders. Seizures are observed in nearly all of the children with the condition. The epilepsy syndromes caused by SCN2A gene mutations include:
  • Ohtahara syndrome
  • Epilepsy of infancy with migrating focal seizures (EIMFS)
  • West syndrome
• This chromosomal anomaly may develop from sporadic mutations (majority of cases), or it may be inherited from one’s parents (very rarely). The inherited form of SCN2A Syndrome is known to cause milder signs and symptoms than the sporadic (de novo) form. The syndrome may be diagnosed through specialized genetic testing
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment may involve physician experts from several specialties, and can include the speech and language therapy, physiotherapy, and seizure control using anticonvulsant medication
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with SCN2A Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets SCN2A Syndrome? (Age and Sex Distribution)

• The incidence of SCN2A Syndrome is presently unknown but it is a very rare disorder
• In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• SCN2A Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females are equally affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for SCN2A Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for SCN2A-Associated Syndromes.

• In some individuals, a positive family history may be an important risk factor for SCN2A Syndrome
• Currently, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of SCN2A Syndrome? (Etiology)

SCN2A Syndrome is caused when the normal functioning of the SCN2A gene (or sodium voltage-gated channel alpha subunit 2 gene) is affected resulting in a variable set of signs and symptoms. This gene dysfunction may take place in the following manner:

• Loss of one copy of the gene due to deletion of chromosomal material on which it is located
• The copy of the gene is altered leading to a loss of function or abnormal function. The changes may be a result of genetic inheritance (family history) or taking place spontaneously (de novo) in the absence of any family history
• A majority of cases are known to occur de novo. However, when the disorder is inherited, the associated signs and symptoms are milder, than when it occurs sporadically

SCN2A gene dysfunction causes brain and neurological abnormalities that may be mild or severe depending on the extent of dysfunction.

• The SCN2A gene, located on chromosome 2 on the long arm q at band q24.3, is involved in proper functioning of the sodium channel that is responsible for the generation and propagation of action potentials, mainly in the nerves and muscles
• There are two chromosomes numbered 2. Children with SCN2A Syndrome typically will have one (chromosome 2) in normal condition, while the other is abnormal

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

What are the Signs and Symptoms of SCN2A Syndrome?

The signs and symptoms of SCN2A Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material involved and to what extent is the gene affected.

The commonly noted signs and symptoms of SCN2A Syndrome in children include:

• Benign familial neonatal/infantile seizure (BFNIS) - seizures may start within a few weeks of childbirth, or later into childhood
• Severe epileptic conditions known as:
  • Ohtahara syndrome
  • West syndrome
  • Epilepsy of infancy with migrating focal seizures
• Learning difficulties including slow learning, in the absence of epilepsy
• Developmental delays; delays in reaching milestones
• Autistic spectrum disorder (ASD) without epilepsy
• Movement disorder (abnormal and rapid movements of one’s limbs termed chorea)
• Abnormal posturing (dystonia)
• Children are known to have low muscle tone (hypotonia) causing floppiness of the body
• Moderate to severe speech and language delays
• Feeding difficulties, including vomiting and gastroesophageal reflux disease (GERD)
• Sleep disturbances

Heart abnormalities are generally not observed in SCN2A Syndrome.

How is SCN2A Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider SCN2A Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

SCN2A Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
• Hearing and vision assessment
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed
• Brain scans: These may include prenatal ultrasounds and MRI scans, and CT/MRI scans after development of the child
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral and psychological studies
• Prenatal studies including abdominal ultrasonography
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of SCN2A Syndrome?

The complications of SCN2A Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Absent speech and severe communication challenges
• Delayed milestone achievement that may affect when a child rolls, sit, crawl, or walk
• Seizures causing fall injuries
• Poor growth due to malnutrition caused by weak suckling
• Increased risk for sudden unexplained death (SUDEP) from severe epileptic seizures
• Overall reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is SCN2A Syndrome Treated?

There is no cure for SCN2A Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, otolaryngologists, neurologists, internists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for SCN2A Syndrome may involve:

• For feeding difficulties, use of feeding tubes (temporary), medications, feed thickeners, including special diets and nutritional supplements
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet. Seizure control is important to ensure that the child’s learning ability is not significantly affected.
• Employing learning strategies via music therapy, visual and tactile books, learning through fun and play, and lots of repetition
• Speech and language therapy
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, hydrotherapy, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• Sleep disorders may require medication; daytime naps may be advised
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Social skills training support groups and exercises
• Occupational therapy

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can SCN2A Syndrome be Prevented?

SCN2A Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. A majority of cases are sporadic occurrences, which means there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic (chromosome) testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of SCN2A Syndrome? (Outcomes/Resolutions)

The prognosis of SCN2A Syndrome is dependent upon the type of epilepsy syndrome noted, the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook.

• Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older. Some of the abnormalities are known to resolve or improve with time
• Weak muscle tone (hypotonia) severity may determine motor function delays; it generally improves with physiotherapy and as the child gets older
• Children usually require lifelong medical support and care

Additional and Relevant Useful Information for SCN2A Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/