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Here we describe a patient with limb girdle muscular dystrophy 1A (LGMD1A) due to a novel myotilin gene ( MYOT) mutation with late onset, rapid progression, loss of ambulation and respiratory failure. The onset of weakness in proximal muscles and muscle MRI findings are clearly different from the pattern identified in myofibrillar myopathies (MFM) related to MYOT mutations. Moreover, there was very limited evidence of myofibrillar pathology in several muscle biopsies obtained during the disease course. We conclude, that MYOT mutations need to be considered as a rare cause of adult-onset, dominant LGMD without clear-cut MFM pathology. [ABSTRACT FROM AUTHOR]

Polymerase gamma 1 ( POLG) mutations are a frequent cause of both autosomal dominant and recessive complex neurological phenotypes. In contrast, only a single pathogenic mutation in one patient was reported in POLG2 so far. Here we describe a 62-year-old woman, carrying a novel heterozygous sequence variant in the POLG2 gene. She developed bilateral ptosis at 30 years of age, followed by exercise intolerance, muscle weakness and mild CK increase in her late forties. Muscle histology and respiratory chain activities were normal. Southern blot and long range PCR detected multiple mtDNA deletions, but no depletion in muscle DNA. Sequencing of POLG, PEO1, ANT1, OPA1 and RRM2B showed normal results. A novel heteroallelic 24 bp insertion (c.1207_1208ins24) was detected in POLG2. This 24 bp insertion into exon 7 causes missplicing and loss of exon 7 in myoblast cDNA. We did not detect POLG2 mutations in 62 patients with multiple mtDNA deletions in muscle DNA, suggesting that POLG2 mutations may represent a rare cause of autosomal dominant PEO. [ABSTRACT FROM AUTHOR]

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. [ABSTRACT FROM AUTHOR]

Telethoninopathy is one of the rarest forms of Limb-girdle muscular dystrophy (LGMD). So far, only a small number of LGMD type 2 G (LGMD2G) patients have been described, mostly patients from Brazil. Here we present a 35-year-old female patient of Turkish ethnicity with LGMD2G due to a novel homozygous frame-shift mutation c.90_91del (p.Ser31Hisfs*11) in the telethonin gene, probably leading to truncated protein or nonsense mediated decay. Myalgia and walking on tiptoes were the first symptoms starting in early childhood, around age 22 proximal, later distal leg muscles became affected. Muscle biopsy showed a degenerative myopathy with lobulated fibers, creatine kinase levels were elevated to 1200 U/l. No cardiomyopathy has been detected but ventricular extrasystoles were treated with verapamil. Even though telethoninopathy represents a rare condition, testing for LGMD2G should be included into the diagnostic work-up of mild myopathies with early toe walking and distal and proximal involvement. [ABSTRACT FROM AUTHOR]