A slowly progressive motor neuron phenotype with a SOD1 variant


What’s New in ALS and CMT - molecular pathways, mutations, phenotype-genotype correlations

Poster Number: 211


Bjorn Oskarsson, MD, FAAN, Jaimin Shah, MD, Sarah Macklin, M.S., C.G.C, Marka M., Van Blitterswijk, MD , PhD


1. Mayo Clinic, 2. Mayo Clinic, 3. Mayo Clinic, 4. Mayo Clinic

Background: Motor neuron disease can be a slowly progressive hereditary disease, possibly mimicking Charcot-Marie-Tooth disease (CMT).
Objective: To describe a patient with slowly progressive distal weakness referred to our MDA clinic for CMT; this patient was found to harbor a variant in superoxide dismutase 1 (SOD1).
Results: A 58-year-old woman presented with a 33-year history of slowly progressive distal weakness in her legs, most prominently in her left leg. Similar neurological symptoms were not reported in her family members. A gene panel for neuropathies uncovered a duplication of uncertain significance of exons 14 to 46 in the kinesin family member 1A (KIF1A) gene and a heterozygous variant of uncertain significance in a gene called solute carrier family 25 member 46 (SLC25A46; c.148C>A; p.Pro50Thr), which did not appear to explain her phenotype.
Physical examination revealed mild distal atrophy in the left calf and tibialis anterior muscles as well as 4/5 left plantarflexion weakness and 4+/5 dorsiflexion weakness. Reflexes were fairly brisk in the upper extremities and absent at the ankles. Sensory examination was normal, and a chronic generalized motor neuropathy was detected on electromyography (EMG), which was more severe distally than proximally.
Additional genetic testing for genes related to amyotrophic lateral sclerosis (ALS), led to the identification of an SOD1 variant (c.448>G; p.Ile150Val) that is likely pathogenic and that has been reported previously in patients with autosomal dominant ALS.
Conclusions: Our case report demonstrates that SOD1 variants can be observed in patients with slowly progressive lower motor neuron phenotypes. We will continue to study this variant and we are collecting specimens from unaffected relatives. Given the unusually slow progression, it is important to consider SOD1 mutations in patients with a similar phenotype. This of particular relevance due to new therapeutic advancements, including the development of antisense oligonucleotides targeting SOD1. Thus, we are hopeful that this patient, and many other patients, will live to experience the approval of a drug for their progressive neurodegenerative disorder.