Juvenile-onset amyotrophic lateral sclerosis due to homozygous COQ7 variants

Abstract

Coenzyme Q10 (CoQ10) biosynthesis defects may lead to primary CoQ10 deficiency. This rare inherited metabolic disorder has been associated with a heterogeneous genetic basis, including rare pathogenic variants in the COQ7 gene. CoQ10 deficiency leads to dysfunction of mitochondrial energy, resulting in several distinct neuromuscular phenotypes, such as myopathy, axonal and demyelinating chronic polyneuropathy and hereditary motor neuronopathy. Herein, we present the first clinical association of COQ7 pathogenic variants with Juvenile Amyotrophic Lateral Sclerosis. A 38-year-old Brazilian man started at age 11 years with a slowly progressive history of distal lower extremity weakness that evolved to the proximal segment, distal extremities of upper limbs and speech disorders. His parents were first degree cousins. His father and brother had similar motor symptoms. Neurological examination disclosed dysarthria, lower limb and distal-dominant quadriparesis, global amyotrophy with dominant distal involvement, and brisk tendon reflexes in the lower limbs. Neuroimaging studies were unremarkable, as well as cerebrospinal fluid analysis. Needle electromyography disclosed diffuse chronic denervation involving cervical, thoracic, and lumbosacral myotomes, and acute denervation (positive sharp waves and fibrillation) in the four limbs; preserved sensory neuroconduction studies. Broad next-generation sequencing-based gene panel testing disclosed the homozygous pathogenic variant c.1A>G in the COQ7 gene. This description expands the pathophysiological basis associated with JALS. COQ7 variants should be included in the differential diagnosis of juvenile-onset motor neuron disease.