MEF2C Deficiency

Disease Overview

Summary

MEF2C deficiency is an extremely rare genetic disorder caused by a change (mutation) in the MEF2C gene. This mutation, often a deletion, leads to the dysfunction of MEF2C protein which is essential to the proper functioning of the musculoskeletal, cardiovascular, neurological, craniofacial, and immune systems. A deletion mutation occurs when a portion of a chromosome is missing. Signs and symptoms vary greatly and usually first present when the patient is between one and two years old. Some of the most common presenting symptoms are decreased muscle tone (hypotonia), global developmental delay, seizures and brain abnormalities. Currently, there is no treatment for MEF2C deficiency and care is individualized based on symptoms. 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, a decreased number of neurons, and severe autism-like abnormalities. Mutations in the MEF2C gene are included in the list of mutations 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
• MRD20

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Signs & Symptoms

Typically, there are no distinctive signs during pregnancy or delivery of a child with MEF2C deficiency. The individual seems to develop normally in the neonatal period and it is not until infancy or early childhood when symptoms such as 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 MEF2C deficiency patients. There is variety in these developmental delays, specifically with speech, gait, cognitive abilities and social skills. These patients also present with some mild to severe distinctive facial features.

Children with MEF2C deficiency usually have a variety of brain abnormalities. Brain MRIs of patients with MEF2C deficiency may show a loss of brain cells, enlargement of ventricles, or abnormal corpus callosum. MEF2C protein has been found to play a role in decreased forebrain development both dorsally and ventrally.

MEF2C patients will likely have epilepsy, but the age of onset and type of seizures varies. Most commonly, the patient develops seizures in infancy. Some of the seizures that patients experience are infantile spasms, febrile, partial, absence, tonic clonic, and myoclonic seizures. It has been found that phenotypic (symptom) severity may be associated with the site of mutation within the MEF2C gene.

Summary of symptoms:

NEUROLOGICAL

• Brain (MRI) abnormalities
  • Abnormal corpus callosum
  • Loss of brain cells (frontal cortical atrophy)
  • Enlargement or asymmetry of ventricles
• Less common
  • Cerebral or cortical malformations
  • Abnormalities of white matter
  • Delayed myelination or hypomyelination
  • Underdeveloped cerebellum (mild cerebellar vermis hypoplasia)
  • Abnormal forebrain development
• Epilepsy – may include the following types and are often associated with fever:
  • Brief jerking of muscles (myoclonic seizures)
  • Generalized tonic clonic seizures involving loss of consciousness and muscle contractions
  • Absence seizures involving a brief and sudden lapse of consciousness
  • Atonic seizures involving a sudden loss of tone
  • EEGs of patients may show bilateral temporal slow waves, bilateral parietal spike waves or other generalized spike-wave discharges

BEHAVIORAL

• Wide variety of stereotypic movements
  • Unpurposeful hand use such as hand clapping, wringing, biting and mouthing
  • Head nodding
  • Teeth clenching (bruxism)
  • Chair rocking
  • Tongue thrusting
  • Ceiling gazing
• Other behavioral symptoms include
  • Inappropriate laughter, excessive enjoyment of running water, short attention span, poor eye contact, social isolation, feeding difficulties such as overfilling mouth with food or sleep difficulties such as insomnia and night laughter

DEVELOPMENTAL DELAY

• Speech delays
  • Severe speech disabilities
  • Loss of expressive language
• Gross motor delays
  • Sitting and walking skills are absent or delayed until two to three years of age
  • Unstable and wide-based gait
  • Poor coordination

MUSCULOSKELETAL

• Decreased muscle tone (hypotonia), more severe in females
• Muscle spasms (hyperkinesis)
• Abnormal hand shape
• Large range of movement (hypermobility)
• Abnormal reflexes

VISION

• Nearsightedness(myopia)
• Pale blue eyes
• Cross-eyed (strabismus)
• Blindness

RESPIRATORY

• Episodic breathing abnormalities (apnea, hyperpnea or hyperventilations)
• Recurring upper respiratory infections

GASTROINTESTINAL

• Severe GERD (gastroesophageal reflux disease)
• Constipation

CRANIOFACIAL

• Broad forehead
• Depressed nasal bridge
• Large mouth with full lips
• Distinct philtral pillars (space between upper lip and nose)
• Tented upper lip
• Short columella (space that separates nostrils)
• Down-turned corners of the mouth
• Skin folds of the upper eyelid (epicanthic folds)
• Small chin
• Short nose
• Low-set ears
• Prominent eyebrows
• Upwards slanting of space between eyelids (upslanted palpebral fissure)

CARDIOVASCULAR

• Possible correlations between MEF2C mutations and heart disorders
• Patent ductus arteriosus (abnormal blood flow)
• Double outlet right ventricle (both the aorta and pulmonary artery exit from the right ventricle)
• Ventricular septal defect (hole in the heart)

DERMATOLOGICAL

• Red birthmarks (hemangiomas)
• Thinning of skin (atrophic skin)

OTHER LESS COMMON SYMPTOMS

• High pain tolerance
• Jugular pit (empty space near neck/throat)
• Floppy larynx
• Cold hands and feet
• Cleft palate
• Duplex left kidney (two ureters from a single kidney)

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Causes

MEF2C deficiency is caused by mutations in the MEF2C gene or in the gene’s promoter and enhancer regions, resulting in a lack or total absence of functional MEF2C protein. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in DNA sequence and not inherited from a patient’s parents. The MEF2C gene codes for a transcription factor that is involved in normal development of the heart, brain, craniofacial, vascular (blood flow), and immune systems of the body. The MEF2C enhancer region is widely expressed in glial cells, which are cells that support brain and nervous system cells.

The MEF2C gene can have these mutations within the gene or upstream in the enhancer or promoter regions. The enhancer and promoter regions of the gene are called regulatory elements. These are DNA elements that help “turn on” the gene in order to transcribe and translate more MEF2C protein. MEF2C deficiency may also be called MEF2C haploinsufficiency, which is a characteristic of an autosomal dominant disorder. This means that one functional copy of the gene is not sufficient to ensure that child will not have the disease.

MEF2C protein is a transcription factor, which means it helps activate the transcription of other genes. When MEF2C protein is absent or dysfunctional, the genes for which it promotes transcription are also affected. These genes include MECP2 and CDKL5, which also play a role in Rett syndrome and CDKL5 deficiency disorder. Therefore, loss of MEF2C function leads to diminished activation of these other genes, resulting in Rett-like or CDKL5 deficiency-like symptoms. The severity of symptoms of MEF2C deficiency are dependent upon the amount of gene affected by the mutation, with larger abnormalities reflective of more severe symptoms of the syndrome.

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Affected populations

MEF2C deficiency appears to equally affect males and females, and it does not seem to have an ethnic predisposition. The age of onset is most commonly in infancy or early childhood. MEF2C deficiency is often misdiagnosed as Rett syndrome due to its Rett-like phenotype. There have been around 50 patients identified with MEF2C deficiency, but this number should likely be larger due to misdiagnosis of subtle symptoms that present similarly to other more well-known disorders.

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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. Then, they begin to lose certain developmental milestones such as language production and purposeful hand movements. They also have other symptoms such as uncontrolled hand movements, ataxia, microcephaly, and many features of autism spectrum disorder. Rett syndrome is caused by mutations in the MECP2 gene and result in a wide range of disability. The symptoms of MEF2C deficiency present similar to Rett syndrome symptoms, such as motor delay and stereotypical behavior, but unlike Rett syndrome, there is typically no microcephaly or regression of development. Also, seizures begin later in development and are less severe in MEF2C deficiency compared to Rett syndrome. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)

Angelman syndrome is a rare neurological disorder that presents with developmental delay, learning disabilities, speech difficulties, ataxia, jerky movements of limbs, happy mood, and unexpected laughter episodes. More common symptoms include seizures and sleep difficulties. Angelman syndrome is caused by a mutation in the UBE3A gene. The symptoms of MEF2C deficiency are similar to the symptoms of Angelman syndrome, but unlike Angelman syndrome, there is typically no microcephaly. Neither syndrome involves neurodevelopmental regression. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database).

Pitt-Hopkins syndrome (PTHS) is a rare neurological disorder. Common symptoms of this disorder are 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. Pitt-Hopkins syndrome is caused by a mutation in the TCF4 gene. Pitt-Hopkins syndrome presents with similar motor and cognitive delays to patients with MEF2C deficiency. However, they can be differentiated because patients with Pitt-Hopkins typically experience more severe respiratory symptoms such as hyperventilation or breath-holding spells that may result in a loss of consciousness. (For more information on this disorder, choose “Pitt-Hopkins” as your search term in the Rare Disease Database).

CDKL5 deficiency disorder is a rare X-linked disorder causing neurodevelopmental impairment. People with this disorder will likely have seizures during their first few months of life. They have severe motor and language developmental disabilities. Additionally, these patients will experience cognitive disabilities and stereotypic hand movements. CDKL5 deficiency disorder is caused by a mutation in the CDKL5 gene. Many of the symptoms experienced by these patients are similar to those of MEF2C deficiency. (For more information on this disorder, choose “CDKL5 deficiency” as your search term in the Rare Disease Database).

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Diagnosis

Hypotonia and epilepsy are symptoms that may lead to a suspicion of MEF2C deficiency.

MEF2C deficiency can be diagnosed with a chromosomal microarray or fluorescence in situ hybridization (FISH) test to look for very small missing pieces in the region on chromosome 5 where the MEF2C gene is located. For even smaller chromosomal abnormalities, a multiplex ligation-dependent probe amplification (MPLA) test may also be used.

Molecular genetic testing using whole exome or whole genome sequencing is also available to look for pathogenic variants (mutations) in the MEF2C gene.

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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. The patient should also have an 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 if patient has 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. At this time, MEF2C deficiency is not being investigated in any clinical studies.

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/

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References

JOURNAL ARTICLES
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
MEF2C Haploinsufficiency Syndrome (MHS) Community
E-mail: [email protected]
Website:https://www.mef2c.org
Facebook Group: https://www.facebook.com/groups/148387552018909/?fref=nf

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Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

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