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

• MEF2C Gene Syndrome
• Mental Retardation, Autosomal Dominant 20 (MRD20)
• MRD20 (Mental Retardation, Autosomal Dominant 20)

What is MEF2C Haploinsufficiency Syndrome? (Definition/Background Information)

• MEF2C Haploinsufficiency Syndrome is a rare genetic disorder that manifests as developmental delays, repetitive limb movements, speech impairment, seizures, and low muscle tone in newborn children. It develops when the normal function of the MEF2C gene, which is responsible for skeletal muscular tissue formation and brain development during embryonic development and located on chromosome 5, is disrupted
• This chromosomal anomaly is usually known to develop from sporadic mutations; presently, only a few cases of inheritance (from one’s parents) is reported. MEF2C Haploinsufficiency Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed
• 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, seizure control, behavior modification, and surgery (if needed)
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with MEF2C Haploinsufficiency Syndrome are able to cope well through adequate treatment and lifelong supportive care

Who gets MEF2C Haploinsufficiency Syndrome? (Age and Sex Distribution)

• The incidence of MEF2C Haploinsufficiency Syndrome is presently unknown, but about 60 cases are reported in the medical literature
• 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
• MEF2C Haploinsufficiency 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 MEF2C Haploinsufficiency Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for MEF2C Haploinsufficiency Syndrome.

• A positive family history may be an important risk factor, since MEF2C Haploinsufficiency Syndrome can be rarely inherited
• 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 MEF2C Haploinsufficiency Syndrome? (Etiology)

MEF2C Haploinsufficiency Syndrome is caused when the normal functioning of the MEF2C gene (or myocyte enhancer factor 2C gene) is affected due to mutational changes, thereby resulting in a variable set of signs and symptoms. This gene dysfunction may take place in the following manner:

• The copy of the gene is altered leading to a loss of function or abnormal function. A vast majority of cases occur de novo i.e., spontaneously, in the absence of any family history
• A positive family history (genetic inheritance) in MEF2C Haploinsufficiency Syndrome is generally uncommon. However, in such cases, when the syndrome is inherited, it occurs in an autosomal dominant manner

MEF2C gene dysfunction causes developmental abnormalities that may be mild or severe depending on the extent of dysfunction.

• The MEF2C gene regulates many other genes that are involved in the development of the brain, skeletal muscles, blood vessels, immune system, apart from the heart and face. The gene is located on chromosome 5 in the long arm (q) at band 14.3
• There are two chromosomes numbered 5. Children with MEF2C Haploinsufficiency Syndrome typically will have one (chromosome 5) 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 MEF2C Haploinsufficiency Syndrome?

The signs and symptoms of MEF2C Haploinsufficiency 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 the genes affected and/or its dysfunction.

The commonly noted signs and symptoms of MEF2C Haploinsufficiency Syndrome in children include:

• Developmental delays that may be moderate or severe - affecting almost all the children
• Speech and language delays that are mostly significant; absent or severely delayed speech
• Small head size and short stature
• Low muscle tone (hypotonia) affecting the motor skills
• Feeding difficulties
• Constipation
• Repetitive movements (stereotypic movements) - may be noted in about 70% of the cases
• Mobility issues
• Hand and foot deformities
• Vision defects are seen in 88% of the cases
• Epileptic seizures are seen in over 80% of the cases with onset from a few days of birth to early childhood
• Sleep disturbances in over 55% of the cases
• Behavioral issues
• Intellectual disability
• Hemangiomas are commonly noted; but these are known to disappear without the need for any treatment
• In rare cases, heart abnormalities may be noted

How is MEF2C Haploinsufficiency 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 MEF2C Haploinsufficiency Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

MEF2C Haploinsufficiency 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
• 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
• Hearing and vision assessment
• Assessment of cardiac function
• 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 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 MEF2C Haploinsufficiency Syndrome?

The complications of MEF2C Haploinsufficiency Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Delayed milestone achievement that may affect when a child rolls, sit, crawl, or walk
• Some individuals may have significant mobility issues
• Recurrent respiratory infections (in over 60% of the cases)
• Increased fall risk from seizures
• Severe communication difficulties
• Severe heart anomalies (in rare cases)
• Mental health deficiencies
• Overall reduced quality of life

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

How is MEF2C Haploinsufficiency Syndrome Treated?

There is no cure for MEF2C Haploinsufficiency 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, ophthalmologists, otolaryngologists, neurologists, internists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for MEF2C Haploinsufficiency Syndrome may involve:

• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet Employing suitable learning strategies
• Speech and language therapy
• For feeding difficulties, medications, feed thickeners, bottle-feeding expressed milk, including special diets and nutritional supplements
• Use of walking aids
• Use of suitable glasses and surgical rectification of vision defects, if necessary
• Antibiotic therapy for infections
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Occupational therapy
• Social skills training support groups and exercises

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

How can MEF2C Haploinsufficiency Syndrome be Prevented?

MEF2C Haploinsufficiency 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 MEF2C Haploinsufficiency Syndrome? (Outcomes/Resolutions)

The prognosis of MEF2C Haploinsufficiency Syndrome is dependent upon 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
• Children usually require lifelong medical support and care; it may also take some children a long time (several years) to gain a measure of independence

Additional and Relevant Useful Information for MEF2C Haploinsufficiency Syndrome:

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

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