Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease. Issue 4 (3rd March 2021)

• Record Type: Journal Article
• Authors: Keller, Natalie; Paketci, Cem; Altmueller, Janine; Fuhrmann, Nico; Wunderlich, Gilbert; Schrank, Bertold; Unver, Olcay; Yilmaz, Sanem; Boostani, Reza; Karimiani, Ehsan Ghayoor; Motameny, Susanne; Thiele, Holger; Nürnberg, Peter; Maroofian, Reza; Yis, Uluc; Wirth, Brunhilde; Karakaya, Mert
• Is Part Of: Human mutation. Volume 42:Issue 4(2021)
• Page Start: 460
• Page End: 472
• Publication Date: 2021-03-03
• Subjects: axonal CMT -- exome sequencing -- hereditary neuropathy -- lower motor neuron disease -- mitochondrial dysfunction -- non‐5q‐SMA; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24181
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Hereditary lower motor neuron diseases (LMND) other than 5q‐spinal muscular atrophy (5q‐SMA) can be classified according to affected muscle groups. Proximal and distal forms of non‐5q‐SMA represent a clinically and genetically heterogeneous spectrum characterized by significant overlaps with axonal forms of Charcot–Marie–Tooth (CMT) disease. A consensus for the best approach to molecular diagnosis needs to be reached, especially in light of continuous novel gene discovery and falling costs of next‐generation sequencing (NGS). We performed exome sequencing (ES) in 41 families presenting with non‐5q‐SMA or axonal CMT, 25 of which had undergone a previous negative neuromuscular disease (NMD) gene panel analysis. The total diagnostic yield of ES was 41%. Diagnostic success in the cohort with a previous NMD‐panel analysis was significantly extended by ES, primarily due to novel gene associated‐phenotypes and uncharacteristic phenotypic presentations. We recommend early ES for individuals with hereditary LMND presenting uncharacteristic or significantly overlapping features. As mitochondrial dysfunction was the underlying pathomechanism in 47% of the solved individuals, we highlight the sensitivity of the anterior horn cell and peripheral nerve to mitochondrial imbalance as well as the necessity to screen for mitochondrial disorders in individuals presenting predominant lower motor neuron symptoms. Abstract : Mitochondrial dysfunction is the underlying pathomechanism in 47% of our cohort. We highlight the sensitivity of the anterior horn cell and peripheral nerve to mitochondrial imbalance as well as the necessity to screen for mitochondrial disorders in individuals presenting predominant lower motor neuron symptoms.