A pathologically confirmed case of combined amyotrophic lateral sclerosis with C9orf72 mutation and multiple system atrophy

Abstract

Hexanucleotide repeat expansions in C9orf72 account for a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. There have been occasional reported cases associated with this expansion but also additional extrapyramidal clinical features. However, only very rarely has there been pathological confirmation of a parkinsonian syndrome associated with a C9orf72 repeat expansion. To date, as far as we are aware, there have been no reported pathologically confirmed cases of ALS with C9orf72 mutation and multiple system atrophy (MSA). We report a case of a man who initially presented with extrapyramidal features, including cogwheel rigidity, and, therefore, was clinically considered likely to have Parkinson's disease or a parkinsonian syndrome. Subsequent examination six months later revealed additional abnormal upper and lower motor neuron signs, raising the strong possibility of ALS. He had a rapid clinical decline and died 16 months after the first presentation. It was noted that his father also had ALS, and that his mother had a parkinsonian syndrome, suggestive of progressive supranuclear palsy. The macroscopic and microscopic examination of the brain and spinal cord revealed ALS pathology with neuronal loss, especially of the anterior horns of the cord and the motor cortex. This was associated with numerous neuronal cytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA‐binding protein of 43 Da (TDP43). There were additional pathological features, including p62‐immunoreactive cerebellar neuronal cytoplasmic inclusions, fully in keeping with a C9orf72 repeat expansion, and this was confirmed on molecular analysis. However, there was also α‐synuclein pathology in the form of oligodendroglial cytoplasmic inclusions in the basal ganglia, cerebellum, and brainstem, indicative of MSA. To our knowledge, this is the first reported case of pathologically confirmed combined ALS‐C9orf72 and MSA.