Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease.
Natalie KellerCem PaketciJanine AltmuellerNico FuhrmannGilbert WunderlichBertold SchrankOlcay UnverSanem YilmazReza BoostaniEhsan Ghayoor KarimianiSusanne MotamenyHolger ThielePeter NürnbergReza MaroofianUluc YisBrunhilde WirthMert KarakayaPublished in: Human mutation (2021)
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.
Keyphrases
- copy number
- genome wide
- peripheral nerve
- spinal cord injury
- oxidative stress
- single cell
- case report
- high throughput
- skeletal muscle
- stem cells
- small molecule
- genome wide identification
- neuropathic pain
- clinical practice
- spinal cord
- cell therapy
- depressive symptoms
- physical activity
- transcription factor
- genome wide analysis
- single molecule
- cell free