Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families.

BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.

GNE-Myopathy in a Greek Romani Family with Unusual Calf Phenotype and Protein Aggregation Pathology.

BACKGROUND: GNE-myopathy is increasingly diagnosed in different ethnicities worldwide. No clear genotype-phenotype correlation has been established to date. CASE REPORTS: We describe two affected members of the same family from Balkan population carrying an already known homozygous pathogenic mutation in the kinase domain of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamime kinase (GNE) gene. The patients presented with severe distal weakness of lower legs combined with rimmed vacuoles in muscle biopsy. However, in contrast to the typical pattern of muscle involvement, one of them showed severe involvement of posterior calf muscles with spared anterior compartment of the lower leg muscles. CONCLUSIONS: These patients provide evidence for a larger variability and further extend the phenotypic spectrum of GNE-myopathy to include preferential calf involvement.

Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5.

OBJECTIVE: Description of 8 new ANO5 mutations and significant expansion of the clinical phenotype spectrum associated with previously known and unknown mutations to improve diagnostic accuracy. METHODS: DNA samples of 101 patients in 95 kindreds at our quaternary referral center in Finland, who had undetermined limb-girdle muscular dystrophy (LGMD), calf distal myopathy, or creatine kinase (CK) elevations of more than 2,000 IU/L, were selected for ANO5 genetic evaluation, and the clinical findings of patients with mutations were retrospectively analyzed. RESULTS: A total of 25 patients with muscular dystrophy caused by 11 different recessive mutations in the ANO5 gene were identified. The vast majority of mutations, 8 of 11, proved to be previously unknown new mutations. The most frequent mutation, c.2272C>T (p.R758C), was present in 20 patients. The phenotypes associated with this and the common European mutation, c.191dupA, varied from nearly asymptomatic high hyperCKemia to severe LGMD with consistently milder phenotypes in female patients. CONCLUSIONS: Mutations in ANO5 are a frequent cause of undetermined muscular dystrophy, with both distal and proximal presentation. Other types include high hyperCKemia, myalgia, or calf hypertrophy over decades without significant weakness, especially in female patients. Mutations are distributed all over the gene, indicating that muscular dystrophy caused by ANO5 can be expected to occur in all populations.