Two Patients With Juvenile‐Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant ( p.Asp125Gly ) With Incomplete Penetrance

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) patients are rarely encountered before age 25 years, often associated with genetic variants. SOD1 gene variants are well-known to account for a subset of adult-onset ALS but have only been described in a handful of early onset patients. Variants affecting residue 125 in SOD1 have been described in adult-onset ALS patients with a rapid progression. Here we report two such patients. METHODS: The clinical, genetic, and electrodiagnostic findings of two unrelated adolescents with juvenile onset rapidly progressive SOD1-ALS are described. RESULTS: Patient 1 presented at 16 and patient 2 at 15 years-of-age with lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions. Both patients underwent extensive laboratory, electrophysiologic, and radiologic testing ruling out any alternate etiologies. For both patients, whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers. DISCUSSION: These two patients expand the phenotypic spectrum of SOD1-ALS, demonstrating a rapidly progressive juvenile lower limb onset phenotype associated with the p.Asp125Gly variant inherited with incomplete penetrance. Recognition and further characterization of juvenile SOD1-ALS are important in light of the advances in targeted therapies.