Case report of intrafamilial variability in autosomal recessive centronuclear myopathy associated to a novel BIN1 stop mutation

Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive centronuclear myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations

Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

Megaconial congenital muscular dystrophy (OMIM 602541) is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK) levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES) after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB) gene c.1031G>A (p.R344Q) in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy

Friedreich Ataksili Olgularımızın Değerlendirilmesi

Friedreich ataksi otozomal resesif geçişli nörodejeneratif bir hastalık olup kalıtsal ataksilerin en sık nedenidir. Hastaların %95’inde kromozom 9q13 üzerinde bulunan FRDA geninin birinci intronunda GAA trinukleotid tekrar artışı mevcuttur. Bu durum demir homeostazında önemli bir role sahip olan frataksin proteininin düzeyinde azalışa yol açar. Friedreich ataksi hastalığının patogenezinden mitokondrilerde demir birikimi ve bunun neden olduğu spesifik mitokondriyal enzim eksiklikleri, oksidatif strese artmış duyarlılık ve serbest radikal aracılı hücre ölümü sorumludur. Günümüzde hastalığın etkin bir tedavisi yoktur, ancak antioksidan tedaviler özellikle kardiyak tutulumda umut vaat etmektedir. Friedreich ataksili olguların erken tanınması ve işlevsel kısıtlılıkların zamanında belirlenmesi rehabilitasyon, semptomatik tedavi ve genetik danışma açısından önemlidir. Bu yazıda homozigot GAA artışına sahip beş hastanın klinik özellikleri sunulmakta ve ilerleyici ataksi ile başvuran hastalarda ayırıcı tanıda Friedreich ataksinin düşünülmesinin gerekliliğini vurgulamaktır.Friedreich ataxia is an autosomal recessive neurodegenerative disease, which is the most common cause of inherited ataxias. About 95% of the patients demonstrate an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene on chromosome 9q13. This leads to reduced levels of frataxin which has an important role in iron homeostasis. Friedreich ataxia is the result of accumulation of iron in mitochondria leading to excess production of free radicals, defects in specific mitochondrial enzymes, enhanced sensitivity to oxidative stress, and eventually free- radical mediated cell death. Currently there is no effective therapy for the disease, but antioxidant therapy has shown promise especially in cardiac involvement. Early identification of individuals with Friedreich ataxia and precise characterization of impairments and functional limitations gain importance as symptomatic treatment, rehabilitation and genetic counseling are considered. Here, we present the clinical findings of five cases with Friedreich ataxia who had homozygous GAA trinucleotide expansion and emphasize that Friedreich ataxia should be considered in the differential diagnosis of cases who present with progressive ataxia