Genomic variants causing mitochondrial dysfunction are common in hereditary lower motor neuron disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Hereditary lower motor neuron diseases (LMND) excluding 5q-spinal muscular atrophy (5q-SMA) are diverse, often overlapping with axonal Charcot-Marie-Tooth (CMT) disease.
• The complex genetic landscape and overlapping phenotypes necessitate advanced diagnostic approaches.

Purpose of the Study:

• To evaluate the diagnostic utility of exome sequencing (ES) in hereditary LMND and axonal CMT.
• To assess the effectiveness of ES following negative neuromuscular disease (NMD) gene panel testing.

Main Methods:

• Exome sequencing (ES) was performed on 41 families with non-5q-SMA or axonal CMT.
• A subset of 25 families had previously undergone negative NMD gene panel analysis.

Main Results:

• Exome sequencing achieved a 41% overall diagnostic yield.
• ES significantly increased diagnostic success in patients with prior negative NMD panel tests, identifying novel gene-phenotype correlations and atypical presentations.
• Mitochondrial dysfunction was identified as the underlying cause in 47% of diagnosed cases.

Conclusions:

• Early exome sequencing is recommended for hereditary LMND with uncharacteristic or overlapping features.
• The anterior horn cell and peripheral nerve are sensitive to mitochondrial dysfunction, warranting screening for mitochondrial disorders in LMND patients.