Última actualización:
July 26, 2022
Años publicados: 2020
NORD gratefully acknowledges Megan McCabe, NORD Editorial Intern from the University of Notre Dame, and Elizabeth Berry-Kravis, MD, PhD, Co-Director, Molecular Diagnostics Section of the Genetic Laboratory, Professor, Department of Pediatrics, Rush Medical College, for the preparation of this report.
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.
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
BEHAVIORAL
DEVELOPMENTAL DELAY
MUSCULOSKELETAL
VISION
RESPIRATORY
GASTROINTESTINAL
CRANIOFACIAL
CARDIOVASCULAR
DERMATOLOGICAL
OTHER LESS COMMON SYMPTOMS
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.
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.
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.
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:
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.
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/
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
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report