Amsterdam, NL, 20 June 2014 Although significant progress has been made over the last 25 years to identify genetic abnormalities associated with congenital myasthenic syndromes (CMS), many patients remain genetically undiagnosed. A report in the inaugural issue of the Journal of Neuromuscular Diseases identifies a gene defect in mitochondria, specifically the citrate carrier SLC25A1, that may underlie deficits in neuromuscular transmission seen in two siblings.
"While mitochondrial gene defects can cause a myriad of neurological disorders including myopathies and neuropathies, these have not been specifically implicated in defects of the neuromuscular junction," says Hanns Lochmller, MD, Professor of Experimental Myology, Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, UK.
Of the 19 genes that have been implicated in CMS, most express proteins involved in neuromuscular synapse development and function. These mutations usually involve post-synaptic proteins. The current study shifts the area of impairment to the presynaptic region.
Investigators conducted genomic analyses of two patients who are brother and sister. The pair was born to healthy parents who were first cousins. "The family history was highly suggestive of autosomal recessive inheritance," notes Dr. Lochmller. Since childhood, the 33-year-old brother had displayed some speech and motor problems that worsened with exercise and improved with rest. He had mild bilateral ptosis (drooping of the eyelid), speech difficulties, and mild learning disabilities. His 19-year-old sister showed delayed development including recurrent falls, fatigable limb weakness, intermittent double vision, and some drooping of facial muscles.
The investigators performed homozygosity mapping and whole exome sequencing to determine the underlying genetic cause of the siblings' condition and successfully identified a hom
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