Hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis (ALS). Patients with C9orf72-ALS commonly present initially with bulbar weakness and/or frontotemporal dementia. Respiratory onset of ALS is extremely uncommon and portends a poor prognosis. To our knowledge, respiratory onset has not been reported in patients with C9orf72-ALS.

A 69-year-old male presented with a 9-month history of progressive, severe orthopnea and dyspnea culminating in hypercapnic respiratory failure. Four months prior to presentation, he was started on supplemental oxygen and eventually required noninvasive ventilatory support. He denied symptoms pertaining to limb, bulbar, or cognitive dysfunction. A paternal cousin and paternal grandmother had passed away from early-onset dementia in their fifth and sixth decades, respectively.

Neurologic examination revealed mild asymmetric weakness and atrophy primarily involving the upper limbs, with hyperreflexia and fasciculations diffusely. There was no evidence of bulbar or cognitive impairment. Electrodiagnostic testing showed absent phrenic nerve conduction responses. Needle examination revealed fasciculation and fibrillation potentials with neurogenic motor unit potentials in cervical and lumbar segments with the most severe abnormalities in the diaphragm. Neuromuscular ultrasound showed paradoxical thinning of the diaphragm with inspiration. The ALS gene panel identified >30 expanded GGGGCC hexanucleotide repeats in the C9orf72 gene.

Respiratory-onset disease occurs in <5% of ALS and has not been a previously reported presentation in patients with C9orf72-ALS. This case highlights the growing importance of genetic testing in ALS patients, even in those with respiratory-onset disease.