MEF2C Deficiency

Disease Overview

Summary

MEF2C deficiency, also known as MEF2C haploinsufficiency syndrome (MCHS) is a rare neurodevelopmental disorder.

People with MCHS often present with global developmental delays, low muscular tone (hypotonia), seizures, brain abnormalities and distinctive facial features. Behavioral symptoms, including stereotypic movements and sleep problems, are also common.

MCHS is caused by changes (variants) in the MEF2C gene or by deletions (losses) of a part of the chromosome 5 that involves the MEF2C gene, leading to insufficient production of the MEF2C protein. This protein plays a vital role in the development and function of the brain, heart, muscles and immune system.

Inheritance is autosomal dominant. Diagnosis is confirmed through genetic testing.

While there is currently no cure, management focuses on supportive therapies and symptom-specific treatments. Anti-seizure medications are prescribed for seizures, melatonin may be used for sleep difficulties, and physical, occupational and speech therapy are prescribed for developmental delays.

Introduction

The MEF2C gene was discovered in 2008 by Dr. Stuart Lipton and his research team at the Burnham Institute. Originally, Dr. Lipton’s study demonstrated that disruption of the function of the MEF2C gene resulted in mice having smaller brains, fewer neurons and severe autism-like abnormalities. Variants in the MEF2C gene are included in the list of variants associated with a Rett-like phenotype, such as Rett syndrome, Angelman syndrome, Pitt-Hopkins syndrome, CDKL5 deficiency disorder and many autism-linked genes.

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Synonyms

• 5q14.3 microdeletion syndrome
• MEF2C haploinsufficiency syndrome
• MEF2C-related disorders
• MEF2C haploinsufficiency syndrome (MCHS)
• MEF2C-related neurodevelopmental disorder
• MEF2C-related syndrome
• MEF2C disorders
• neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL)
• brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome due to MEF2C mutation
• autosomal dominant non-syndromic intellectual disability caused by mutation in MEF2C
• chromosome 5q14.3 deletion syndrome
• intellectual disability, autosomal dominant 20 (former)
• intellectual disability, autosomal dominant type 20 (former)
• MEF2C autosomal dominant non-syndromic intellectual disability

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Signs & Symptoms

Typically, there are no distinctive signs during pregnancy or delivery of a child with MEF2C deficiency. The baby seems to develop normally, and it is not until infancy or early childhood when symptoms such as low muscular tone (hypotonia), feeding difficulties and poor eye contact appear. Seizures may occur, especially when the baby has an illness or fever. Global developmental delay is found in nearly all people with MEF2C deficiency. Developmental delays are seen with speech, gait, cognitive abilities and social skills. There are also some mild to severe distinctive facial features.

Children with MEF2C deficiency usually have a variety of brain abnormalities. Brain MRIs of people with MEF2C deficiency may show a loss of brain cells, enlargement of the cavities of the brain (ventricles) or abnormal corpus callosum, the structure that connects both the cerebral hemispheres. MEF2C protein has been found to play a role in decreased forebrain development both dorsally and ventrally.

People with MEF2C deficiency will likely have epilepsy, but the age of onset and type of seizures varies. Seizures usually start in infancy. The type of seizures may include infantile spasms, febrile, partial, absence, tonic clonic, and myoclonic seizures.

The severity of symptoms may be associated with the site of the specific variant within the MEF2C gene.

• Neurological problems (brain and nerve-related)

• • Abnormalities of the brain (brain scan [MRI] findings)
    • Abnormal corpus callosum, the structure that connects the two halves (hemispheres) of the brain
    • Shrinkage or loss of brain cells in the front part of the brain (frontal cortical atrophy)
    • Unusual size or shape of the fluid-filled spaces in the brain (ventricles)
  • Less common brain findings may include:
    • Irregular brain development
    • Changes in the white matter in the brain (helps with communication in the brain)
    • Delayed or reduced development of the substance responsible for brain insulation (delayed myelination or hypomyelination)
    • Underdeveloped cerebellum (area of the brain that helps with movement and balance)
    • Unusual growth in the front part of the brain (forebrain)

• Unusual reflex responses
• Unsteady or wide-based gait
• Coordination and balance problems

• • Seizures (epilepsy) which are common and may happen more often with fever and that may include:
    • Quick muscle jerks (myoclonic seizures)
    • Seizures with stiffening and shaking and loss of awareness (tonic-clonic)
    • Short spells of staring or zoning out (absence seizures)
    • Sudden loss of muscle strength (atonic seizures)
    • Abnormal patterns in brain activity tests (EEGs)

• Behavioral problems

• • Repetitive movements like:
    • Unusual hand motions such as clapping, wringing, biting, or putting hands in the mouth
    • Nodding the head
    • Grinding teeth
    • Rocking in a chair
    • Pushing the tongue out
    • Staring at the ceiling
  • Other abnormal behaviors that may include:
    • Laughing at unusual times
    • Abnormal fascination by running water
    • Trouble focusing
    • Avoiding eye contact
    • Preferring to be alone
    • Challenges with eating (like stuffing the mouth)
    • Sleep problems (like not sleeping well or laughing at night)

• Developmental delays including:

• • Speech delays such as serious difficulty speaking or understanding language
  • Loss of ability to use words
    • Movement (motor) delays that may include late sitting or walking (sometimes not until 2 or 3 years)

• Muscle and bones problems

• • Low muscle tone (hypotonia) more common in females
  • Sudden or uncontrolled muscle movements
  • Unusual hand shape
  • Very flexible joints

• Vision problems

• Blurry distance vision (nearsightedness)
• Pale blue eye color
• Lazy or crossed eyes (strabismus)
• Vision loss or blindness

• Respiratory problems

• Irregular breathing patterns (like pauses, fast breathing, or over-breathing)
• Frequent upper respiratory infections (like colds or sinus issues)

• Gastrointestinal (stomach and intestines) problems

• Severe acid reflux (GERD) where stomach acid comes up into the throat
• Constipation

• Head and face (craniofacial) differences

• Wide forehead
• Flattened area between the eyes (nasal bridge)
• Large mouth with full lips
• Clearly defined area between nose and upper lip (philtrum)
• Upper lip that may stick out
• Short tissue (columella) between nostrils (the holes of the nose)

• Down-turned corners of the mouth

• Extra skin on the upper eyelids (epicanthus)
• Small chin
• Short nose
• Low-set ears
• Thick eyebrows
• Eyes that may slant upward (up slanted palpebral fissure)

• Skin (dermatological) problems

• Red birthmarks (hemangiomas)
• Skin that appears thin or fragile (atrophic skin)

• Heart and vascular (cardiovascular) problems

• Abnormal blood flow (like patent ductus arteriosus)
• Rare heart condition where both main arteries leave from the same heart chamber (double outlet right ventricle)
• Hole in the wall between the heart’s lower chambers (ventricular septal defect)
• Narrowing of the valve or artery that carries blood from the heart to the lungs (pulmonary stenosis)
• Enlarged heart with loss of function due to a stretching and thinning of the left chamber (ventricle) of the heart (adult-onset dilated cardiomyopathy) which can result in heart failure.

Less common reported symptoms include:

• Unusually high tolerance for pain
• A small pit or dent near the neck
• Soft or floppy voice box (larynx)
• Cold hands and feet
• Opening in the roof of the mouth (cleft palate)
• Anomalies of ureters (urine drainage tubes) or kidneys (duplex kidney)

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Causes

MEF2C deficiency is caused by changes (variants) in the MEF2C gene or by the loss (deletion) of a segment on the long arm of chromosome 5, specifically the region called 5q14.3, which includes the MEF2C gene.

The MEF2C gene contains instructions to make a protein called MEF2C. This protein is a transcription factor, which means it helps control when and how other genes are turned on or off. This control process is essential during early development, especially for forming the brain, muscles, heart, blood vessels, immune system and facial structures. The MEF2C protein influences the activity of hundreds of other genes across different parts of the body.

When there is a variant or deletion affecting the MEF2C gene or the nearby regulatory regions known as promoter and enhancer elements, the gene may stop working properly. This can result in a reduced amount of MEF2C protein or dysfunctional MEF2C protein.  A malfunctioning MEF2C protein may be unable to bind to DNA correctly, which prevents it from activating other important genes. This disruption in gene regulation affects how the brain and other body systems develop and can lead to symptoms such as intellectual disability, developmental delays, seizures, behavioral challenges and distinctive facial features.

One of the regions that controls MEF2C gene activity, the enhancer region, is especially active in glial cells, supportive cells in the brain and nervous system that are essential for healthy brain function. Disruption in these cells may contribute to the neurological symptoms seen in MEF2C deficiency.

MEF2C deficiency is described as a haploinsufficiency disorder, meaning that one working copy of the gene is not enough to produce enough of the MEF2C protein. Everyone has two copies of most genes, one from each parent. In this condition, one of these copies is altered or missing, and the remaining copy can’t make enough of the protein to support normal development. This is a characteristic of autosomal dominant inheritance.

When MEF2C protein is missing or non-functional, the genes it normally activates, such as MECP2 and CDKL5, which are also linked to other developmental disorders, are not properly turned on. As a result, children with MEF2C deficiency may have symptoms that overlap with Rett syndrome or CDKL5 deficiency disorder. The severity of symptoms often depends on how much of the MEF2C gene is affected and whether nearby genes are involved. Larger deletions, which remove more genetic material, usually lead to more severe symptoms.

Some affected people have a “contiguous gene syndrome” which means that other neighboring genes are deleted along with MEF2C. These people may have additional signs and symptoms, depending on which other genes are involved.

In rare situations, changes can occur in parts of the MEF2C gene, known as deep intronic regions, which are non-coding areas of DNA. These variants may not be detected by some standard genetic tests.

Inheritance

In most people, MEF2C deficiency happens due to a new (de novo) variant, which means the change occurred spontaneously during early development and was not inherited from either parent. These are new genetic changes that happen by chance, often during the formation of reproductive cells or in the early stages of embryonic growth.

Rarely, the genetic change can be passed down from a parent who either has the condition or is mosaic, meaning the genetic change is present in only some of their cells and may not cause noticeable symptoms in the parent.

Someone affected with MEF2C deficiency has a 50% chance with each pregnancy to pass the condition to their child. This follows a pattern known as autosomal dominant inheritance. However, most people with this disorder are still children or adolescents, and many have not yet had children.

Once a genetic change in MEF2C has been identified in a family, prenatal testing during pregnancy can be considered. Additionally, preimplantation genetic testing and in vitro fertilization (IVF) may be available for families. This allows testing embryos for the condition before pregnancy.

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Affected populations

As of 2024, there were around 150 people identified with MEF2C deficiency. This number should likely be larger due to misdiagnosis of subtle symptoms that present similarly to other more well-known disorders. MEF2C deficiency is often misdiagnosed as Rett syndrome due to its Rett-like features.

MEF2C deficiency appears to affect males and females equally and it does not seem to occur more often in any particular ethnic group.

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Disorders with Similar Symptoms

MEF2C deficiency has clinical overlap with Rett Syndrome, Angelman Syndrome, Pitt-Hopkins syndrome and CDKL5 deficiency disorder. Often, these syndromes are grouped under the term “Rett-like” but using this term has recently been discouraged because these syndromes are now recognized as clinically different from each other. Symptoms of the following disorders can be similar to those of MEF2C deficiency. Comparisons may be useful for a differential diagnosis.

Rett syndrome is a rare neurodevelopmental disorder that mostly affects females. Infants with Rett syndrome develop normally for about 7 to 18 months after birth but then begin to lose certain developmental milestones such as language and purposeful hand movements. Other symptoms may include uncontrolled hand movements, ataxia, microcephaly and features of autism spectrum disorder. Rett syndrome is caused by variants in the MECP2 gene. MEF2C deficiency may look similar at first, but unlike Rett syndrome, it usually does not present with microcephaly or loss of previously learned skills.

Angelman syndrome is a rare neurological disorder characterized by microcephaly, distinctive face, developmental delay, learning disabilities, speech difficulties, ataxia, jerky movements of limbs, seizures, sleep problems, happy mood and unexpected laughter episodes. It is caused by a UBE3A gene variant. Both Angelman syndrome and MEF2C deficiency can cause similar behavior and learning difficulties, but Angelman typically does not involve as many movement issues or abnormal breathing and people with MEF2C deficiency do not have microcephaly or the distinctive face of Angelman syndrome.

Pitt-Hopkins syndrome (PTHS) is a neurological disorder characterized by speech difficulties, seizures, abnormal breathing patterns, ataxia, distinctive facial features, intellectual disability and other delays in reaching developmental milestones. People with PTHS are often very social and happy. It is caused by a TCF4 gene variant. PTHS and MEF2C deficiency have similar motor and cognitive problems but can be differentiated because people with PTHS usually have more severe respiratory symptoms such as hyperventilation or breath-holding spells that may result in a loss of consciousness.

CDKL5 deficiency disorder is a rare X-linked disorder neurodevelopmental disorder, characterized by early onset seizures, severe motor and language problems, cognitive disabilities and stereotypic hand movements. CDKL5 deficiency disorder is caused by a CDKL5 gene variant. It shares many symptoms with MEF2C deficiency but tends to have earlier and more frequent seizures.

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Diagnosis

Doctors may suspect MEF2C deficiency if a child shows signs like poor muscle tone and seizures. Genetic testing is needed to confirm the diagnosis.

Several types of tests are available. A chromosomal microarray or FISH test can find small deletions in the region of chromosome 5 where the MEF2C gene is located.

If the changes are too small to be seen with those methods, a more sensitive test called MLPA (multiplex ligation-dependent probe amplification) can be used. It detects very small deletions or duplications within the gene that might be missed by other tests.

More advanced genetic tests such as whole exome sequencing (WES) or whole genome sequencing (WGS) can analyze all the protein-coding parts of the genes (WES) or the entire genetic code (WGS). This helps identify any subtle variants in the MEF2C gene or in nearby regulatory regions, which are parts of DNA that help control how the gene works.

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Standard Therapies

Treatment
There are currently no approved therapies that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is required involving the following specialists, therapies and tests:

• Ophthalmologist and audiologist to evaluate vision and hearing annually
• Cardiologist for annual exams to evaluate blood pressure and heart rate; electrocardiogram (EKG) and/or an echocardiogram (ECHO) to assess for diseases of the heart
• Electroencephalogram (EEG) and brain MRI to monitor seizure activity and other neurological symptoms
• Psychiatrist to assess behavioral symptoms
• Physical, occupational and speech therapy; developmental/behavioral therapy or music therapy may also be helpful
• Dermatologist may be seen for hemangiomas
• Immunologist may be needed for recurring infections

Many of the other treatments that these patients receive are similar to what children with autism spectrum disorder or other neurodevelopmental disorders would receive. Typically, seizures are well-controlled by various medications. Melatonin may be used for sleep difficulties.

Genetic counseling is recommended for families with affected children.

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Clinical Trials and Studies

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 website.

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]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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/

The MEF2C Foundation, in partnership with the Medical University of South Carolina, launched Pathways To Hope For MEF2C Haploinsufficiency Syndrome, a multi-year program aimed at developing therapeutics specifically targeting MEF2C Haploinsufficiency Syndrome (MCHS). Contact e-mail: [email protected]

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References

JOURNAL ARTICLES
Cooley Coleman JA, Sarasua SM, Moore HW, et al. Clinical findings from the landmark MEF2C-related disorders natural history study. Mol Genet Genomic Med. 2022;10(6):e1919. doi:10.1002/mgg3.1919

D’Haene E, Bar-Yaacov R, Bariah I, et al. A neuronal enhancer network upstream of
MEF2C is compromised in patients with Rett-like characteristics. Human Molecular Genetics. 2018;28(5):818-827. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381311/

Wang J, Zhang Q, Chen Y, et al. Novel MEF2C point mutations in Chinese patients with
Rett (−like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation. BMC Medical Genetics. 2018;19(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208086/

Vrečar I, Innes J, Jones E, et al. Further Clinical Delineation of the MEF2C
Haploinsufficiency Syndrome: Report on New Cases and Literature Review of Severe
Neurodevelopmental Disorders Presenting with Seizures, Absent Speech, and
Involuntary Movements. Journal of Pediatric Genetics. 2017;06(03):129-141.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548525/

Paciorkowski AR, Traylor RN, Rosenfeld JA, et al. MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways. Neurogenetics. 2013;14(2):99-111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773516/

Zweier M, Rauch A. TheMEF2C-Related and 5q14.3q15 Microdeletion Syndrome.
Molecular Syndromology. 2012;2(3-5):164-170.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366707/

INTERNET
Cooley Coleman J, Skinner SA. MEF2C-Related Disorder. 2024 Dec 12. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK610216/ Accessed June 3, 2025.

MEF2C Haploinsufficiency Syndrome (MHS) Community
E-mail: [email protected]
Facebook Group: https://www.facebook.com/groups/148387552018909/?fref=nf

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