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Item does not contain fulltext Nemaline myopathy and myofibrillar myopathy are heterogeneous myopathies that both comprise early-onset forms. We present two sisters from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. We performed homozygosity mapping in both siblings using an Affymetrix 250K Nspl SNP array. One of the overlapping homozygous regions harbored the gene CFL2. Because a mutation in CFL2 was identified in a family with nemaline myopathy, we performed sequence analysis of the gene and a novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in both siblings. CFL2 encodes the protein cofilin-2, which plays an important role in regulation of sarcomeric actin filaments. To our knowledge, this is the second family in which a mutation in CFL2 causes an autosomal recessive form of congenital myopathy with features of both nemaline and myofibrillar myopathy. Given the clinical variability and the multitude of histological features of congenital myopathies, CFL2 sequence analysis should be considered in patients presenting with an autosomal recessive form of congenital myopathy. 01 juli 2012

We describe a family of four members (a mother and her three sons) diagnosed with a skeletal muscle disease with biopsy findings consistent with nemaline myopathy (NM) in two, one with non-specific myopathy and one with neurogenic atrophy and myopathic features. Interestingly, some of the clinico-pathological findings were consistent with involvement of the peripheral nerves. Sanger sequencing did not identify a pathogenic mutation in genes associated with NM. Given the atypical presentation not attributable to a known NM gene, linkage analysis was performed on DNA samples from the four affected members along with whole genome sequencing (WGS) on mother’s DNA (proband). On bioinformatic analysis, she was identified to carry a heterozygous mutation c.1261C>T in the NEFL gene predicted to cause premature termination of the transcript and a truncated neurofilament light polypeptide protein (p.R421X). This mutation was not present in dbSNP Build 137 or Exome variant server, Washington University, and it was confirmed to be present in all the four affected members of the family by Sanger sequencing. Further, Autosomal dominant mutations in NEFL are associated with Charcot–Marie–Tooth (CMT) disease, subtypes CMT2E/CMT1F. Most of the pathogenic NEFL mutations are missense changes postulated to cause dominant negative effects. Quantitative real-time PCR was performed on cDNA, extracted from muscle samples from an affected family member and an age-matched control, and the mutant transcript was found to be stable. We hypothesize that the mutant transcript does not undergo nonsense-mediated decay, thereby encoding a truncated protein that interferes with the function of the wild type NEFL protein. Further work is underway to understand the molecular basis of the disease. This finding further expands the spectrum of NEFL mutation-associated phenotypes to NM.

Centronuclear myopathies (CNM) are a group of rare heterogeneous congenital myopathies characterized by muscle weakness and low tone of varying onset, often requiring respiratory, feeding and/or ambulatory assistance. Frequent central nuclei are the primary pathological finding in affected skeletal muscles. CNM may be caused by mutations in the MTM1, DNM2, RYR1 and BIN1 genes. MTM1 mutations, which cause X-linked myotubular myopathy, are thought to account for about 50% of CNM cases, while DNM2 and RYR1 account for ∼15% each, and BIN1 for