Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating degenerative neurological disease primarily targeting the motor system, with average survival of 16 months from diagnosis. Those with genetic/familial ALS (fALS) usually progress more rapidly, but not as quickly as the patient presented here. 

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Case Presentation

Patient was a 41 y.o. female who initially presented to the Penn State Hershey Medical Center in May 2020. Her father passed at age 44 from ALS, 8 months after symptom onset. Symptoms initially began in late March 2020 with hand weakness. Within one month, she developed progressive R>L extremity weakness with weight loss and  weakness in her bulbar muscles and eyes. Inpatient workup was unremarkable.  Nerve conduction studies showed low compound motor action potential amplitudes in motor nerve conduction in upper extremities, R>L, normal to prolonged distal latencies and slowed conduction velocities. EMG needle exam showed  fibrillation potentials and positive sharp waves. Motor unit action potentials had reduced recruitment. Positive sharp waves were in right thoracic paraspinal muscles.

Genetic testing demonstrated mutations in both SOD1 (heterozygous, pathogenic, c.304G>C (p.Asp102His)) and PFN1 (heterozygous, variant of uncertain significance, c.350_351delinsGT (p.Glu117Gly)). The patient passed away in September 2020, less than 6 months after symptom onset. 

Discussion

This case is unique because of the speed and polygenic nature of her disease. In mice, PFN1 has been linked to significant and rapid neurodegeneration. Only one paper has compared SOD1 and PFN1 in three patients, noting similarities between their pathological phenotypes, and PFN1 remains classified as a variant of uncertain significance.

Research is needed to assess potential synergistic effects between SOD1 and PFN1 and other polygenic fALS. This case demonstrates the utility of timely genetic testing, which offers quick answers to guide goals-of-care conversations with family, and offers a unique presentation of ALS to inform future practice and research.