The most common genetic mutation associated with fALS is a hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72). C9orf72-associated fALS tends to present with relatively more rapid progression than sporadic ALS and typically progresses to compromise both limb and bulbar function, though clinical heterogeneity can occur.

We describe the case of a 50-year-old woman with C9orf72-associated fALS manifesting as slowly progressive, mostly monomelic amyotrophy of the right lower extremity emerging over 15 years.

A 50-year-old woman presented in 2010 with weakness and wasting of the right leg that began in 2007. Her mother passed away at the age of 65 years-old, about 6 months after being diagnosed with apparently sporadic limb-onset ALS. Her initial neurological examination showed diffuse weakness, wasting, and fasciculations isolated to the right leg only, associated with diminished deep tendon reflexes in that extremity. She had an electromyographic study on presentation which showed widespread acute and chronic denervation in the right leg only. A diagnosis of fALS was confirmed by genetic testing which demonstrated a pathogenic mutation in the C9orf72 gene. To date, she continues to demonstrate slow progression of weakness and wasting of the right lower extremity, with more recent minimal involvement of the proximal left lower extremity, and no upper motor neuron signs or upper extremity, respiratory, or bulbar involvement.

Unlike most repeat expansion disorders, C9orf72-related fALS is not clearly associated with anticipation. Our case illustrates the extreme degree of clinical heterogeneity that can occur with this mutation and raises the possibility of other factors besides repeat expansion length being implicated, such as DNA methylation patterns and specific epigenes.