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

Abstract

Mutations in the ( ) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the gene, further cases with point mutations and partial gene deletions of the gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype. We aim to add to the current knowledge of the natural history of the "MEF2C haploinsufficiency syndrome" as well as of the differential diagnosis, clinical management, and genetic counseling in this diagnostically challenging group of patients.

MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review

“…2 The phenotype may resemble Rett's syndrome in some cases, with stereotypic behaviour, particularly hand flapping, but no microcephaly or neuroregression [3]. To the best of our knowledge, only 22 cases of MEF2C pathogenic and likely pathogenic variants or microdeletions without involvement of other contiguous or distant genes have been reported [1][2][3][4][5][6][7][8][9][10]. So far, the electroclinical patterns in MEF2C haploinsufficiency have been infrequently and inconsistently described.…”

MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

“…Deletions or mutations in MEF2C are assumed to create loss-of-function alleles that cause the symptoms of MCHS (Berland and Houge, 2010; Bienvenu et al, 2013; Engels et al, 2009; Le Meur et al, 2010; Mikhail et al, 2011; Novara et al, 2010; Paciorkowski et al, 2013; Tonk et al, 2011; Vrecar et al, 2017; Zweier et al, 2010; Zweier and Rauch, 2012). Given that microdeletions of 5q14.3 often include additional genes beyond MEF2C , we sought to identify individuals with mutations within the MEF2C protein-coding region, including an intragenic duplication ( i.e.…”

“…Conditional deletion of both Mef2c gene copies in forebrain excitatory neurons produces mice with dramatic changes in cortical synapse functions, including decreased glutamatergic synaptic transmission, and numerous alterations in typical mouse behaviors, including learning and memory, reward-related behavior, motor hyperactivity and repetitive behaviors, and differential gene expression (Adachi et al, 2015; Barbosa et al, 2008; Harrington et al, 2016; Li et al, 2008). In contrast to these Mef2c brain conditional knockouts, humans with MCHS possess deletions or mutations in a single gene copy throughout the entire body (Berland and Houge, 2010; Bienvenu et al, 2013; Engels et al, 2009; Le Meur et al, 2010; Mikhail et al, 2011; Novara et al, 2010; Paciorkowski et al, 2013; Tonk et al, 2011; Vrecar et al, 2017; Zweier et al, 2010; Zweier and Rauch, 2012). Since MCHS symptoms are reported predominantly from macro- and microdeletions that disrupt MEF2C and other neighboring genes, we sought to identify possible loss-of-function MEF2C mutations within its protein coding region to better understand the relationship between symptoms and MEF2C .…”

“…Microdeletions on chromosome 5q14.3 that include the MEF2C gene or point mutations within the protein-coding region of MEF2C are linked to a recently described neurodevelopmental disorder, termed MEF2C Haploinsufficiency Syndrome (MCHS) (Berland and Houge, 2010; Bienvenu et al, 2013; Engels et al, 2009; Le Meur et al, 2010; Mikhail et al, 2011; Novara et al, 2010; Paciorkowski et al, 2013; Tonk et al, 2011; Vrecar et al, 2017; Zweier et al, 2010; Zweier and Rauch, 2012). Common symptoms of MCHS include autism spectrum disorder (ASD), absence of speech, stereotypical behaviors, hyperactivity, intellectual disability, hypotonia, motor abnormalities, high pain tolerance, sleep disturbances, and epilepsy, and individuals with MEF2C point mutations typically present with fewer and/or milder symptoms (Berland and Houge, 2010; Bienvenu et al, 2013; Engels et al, 2009; Le Meur et al, 2010; Mikhail et al, 2011; Novara et al, 2010; Paciorkowski et al, 2013; Tonk et al, 2011; Vrecar et al, 2017; Zweier et al, 2010; Zweier and Rauch, 2012). Due to the abundance of neurological symptoms and neuronal-enriched expression of MEF2C, MEF2C haploinsufficiency in neurons is presumed to underlie most, if not all, of the MCHS symptoms.…”

Genetic interaction screen for severe neurodevelopmental disorders reveals a functional link between Ube3a and Mef2 in Drosophila melanogaster

“…Though the phenotypic overlap between the neurodevelopmental disorders investigated in this study is widely appreciated and discussed in the literature 7,46 , corresponding experimental follow-up of possibly underlying molecular commonalities is largely lacking. According to the mouse brain atlas 47 , there is overlapping expression of orthologues of UBE3A, MEF2C, ATRX, ZEB2 and TCF4 in several neuronal subtypes including excitatory neurons of the cerebral cortex and various cell types of the hippocampus.…”