Clinical characterization of the proximal lower-limb ALS phenotype: a retrospective cohort study

This study characterizes a rare phenotype of Amyotrophic Lateral Sclerosis (ALS) presenting with predominant proximal lower limb weakness at onset, a presentation often mimicking myopathy. We retrospectively reviewed 1980 patients, identifying 15 (0.75%) with this atypical onset. The majority were males (73%) with a median age of onset of 58.7 years. Approximately half presented with symmetric proximal lower limb weakness. Nine of the 11 tested patients had higher CK. Follow-up (median 53.7 months) revealed that 6 patients maintained isolated lower limb weakness for a median of 60.1 months, while others progressed to upper limbs or bulbar regions. NSG sequencing (in nine patients) identified mutations in three patients (SOD1, VAPB, and C9ORF72). This pattern poses a diagnostic challenge. While limitations include a small sample size and retrospective design, the findings highlight a heterogenous but often slow-spreading and benign course for this specific ALS subtype, offering valuable clinical information for differential diagnosis.