A Mitochondrial tRNA Mutation Causes Axonal CMT in a Large Venezuelan Family.

OBJECTIVE: The objective of this study was to identify the genetic cause for progressive peripheral nerve disease in a Venezuelan family. Despite the growing list of genes associated with Charcot-Marie-Tooth disease, many patients with axonal forms lack a genetic diagnosis. METHODS: A pedigree was constructed, based on family clinical data. Next-generation sequencing of mitochondrial DNA (mtDNA) was performed for 6 affected family members. Muscle biopsies from 4 family members were used for analysis of muscle histology and ultrastructure, mtDNA sequencing, and RNA quantification. Ultrastructural studies were performed on sensory nerve biopsies from 2 affected family members. RESULTS: Electrodiagnostic testing showed a motor and sensory axonal polyneuropathy. Pedigree analysis revealed inheritance only through the maternal line, consistent with mitochondrial transmission. Sequencing of mtDNA identified a mutation in the mitochondrial tRNAVal (mt-tRNAVal ) gene, m.1661A>G, present at nearly 100% heteroplasmy, which disrupts a Watson-Crick base pair in the T-stem-loop. Muscle biopsies showed chronic denervation/reinnervation changes, whereas biochemical analysis of electron transport chain (ETC) enzyme activities showed reduction in multiple ETC complexes. Northern blots from skeletal muscle total RNA showed severe reduction in abundance of mt-tRNAVal , and mildly increased mt-tRNAPhe , in subjects compared with unrelated age- and sex-matched controls. Nerve biopsies from 2 affected family members demonstrated ultrastructural mitochondrial abnormalities (hyperplasia, hypertrophy, and crystalline arrays) consistent with a mitochondrial neuropathy. CONCLUSION: We identify a previously unreported cause of Charcot-Marie-Tooth (CMT) disease, a mutation in the mt-tRNAVal , in a Venezuelan family. This work expands the list of CMT-associated genes from protein-coding genes to a mitochondrial tRNA gene. ANN NEUROL 2020;88:830-842.

Flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia-induced cardiomyopathy in Andersen-Tawil syndrome.

Bidirectional ventricular tachycardia (BVT), although a rare arrhythmia in the general population, is frequently observed in patients with Andersen-Tawil syndrome and long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown. In the present study, we documented the favorable antiarrhythmic action of flecainide in a young woman with sustained BVT and Andersen-Tawil syndrome. She presented with incessant BVT that could only be terminated with flecainide. During sinus rhythm, a prolonged QT interval was observed. Genetic studies revealed a mutation in the K(+) channel gene KCNJ2. Over a 4-year follow-up period, recurrence of her arrhythmia occurred twice. The first episode was due to noncompliance and resolved with resumption of flecainide therapy. The second recurrence was associated with a tachycardia-induced cardiomyopathy and resolved when the dose of flecainide was increased from 200 to 300 mg daily. This report suggests that flecainide can be effective in controlling BVT associated with Andersen-Tawil syndrome and indicates that the left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypic manifestation of the disorder.