Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

PURPOSE: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency. METHODS: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy". RESULTS: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms. CONCLUSION: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.

Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4).

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type.

SEPN1-related myopathy in three patients: novel mutations and diagnostic clues.

UNLABELLED: Mutations in SEPN1 cause selenoprotein N (SEPN)-related myopathy (SEPN-RM) characterized by early-onset axial and neck weakness, spinal rigidity, respiratory failure and histopathological features, ranging from mild dystrophic signs to a congenital myopathy pattern with myofibrillar disorganization. We report on clinical and instrumental features in three patients affected with a congenital myopathy characterized by prevalent neck weakness starting at different ages and mild myopathy, in whom we performed diagnosis of SEPN-RM. The patients presented myopathic signs since their first years of life, but the disease remained unrecognized because of a relatively benign myopathic course. In two cases, myopathic features were stable after 2 years of follow-up, but respiratory involvement worsened. The muscle MRI and muscle biopsy showed a typical pattern of SEPN-RM. Molecular diagnosis revealed two novel homozygous mutations in SEPN1, c.1176delA and c.726_727InsTCC. CONCLUSION: This report underlines the clinical diagnostic clues of early neck and axial weakness to suspect a SEPN-RM and the usefulness of muscle MRI in conjunction with clinical features to achieve the diagnosis. Our data confirm the slow progression of respiratory involvement in spite of the relatively stable course of myopathy. We report two previously undescribed mutations in SEPN1. WHAT IS KNOWN: • Mutations in SEPN1 cause myopathy characterized by early-onset axial and neck weakness spinal rigidity and respiratory failure. • SEPN-related myopathies have been initially associated with four distinct histopathological entities that however appear more mixed in recently described cases. What is New: • SEPN-related myopathies can remain unrecognized because of the normal early motor development and relatively benign myopathic course of the disease. • Our study adds two novel homozygous mutations to the number of reported pathogenic SEPN1 variants.

Early neurodevelopmental assessment in Duchenne muscular dystrophy.

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7-47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity.