A 29-year-old man presented with rapidly progressive severe neck weakness, asymmetrical bilateral upper extremity weakness, bulbar dysfunction, profound muscle wasting, and weight loss. Within 1 year, his speech became unintelligible, he became gastrostomy- and tracheostomy/ventilator-dependent, and wheelchair bound. Electrophysiology suggested motor neuron disease. Whole exome sequencing revealed a heterozygous pathogenic variant in the fused in sarcoma gene (FUS), c.1574C>T,p. R525L, consistent with autosomal dominant amyotrophic lateral sclerosis. Autopsy revealed extensive denervation atrophy of skeletal musculature. Surprisingly, there was only minimal patchy depletion of motor neurons within the cervico-thoracic spinal cord anterior horn cells, and the tracts were largely preserved. TDP-43 inclusions were absent. Abnormal expression of FUS mutation product (cytoplasmic inclusions) was demonstrated by immunohistochemistry within anterior horn motor neurons. The most prominent finding was a disparity between profound neck weakness and relatively low-grade anterior horn cell loss or tract degeneration in the cervico-thoracic cord.
Keywords: Amyotrophic lateral sclerosis (ALS); Cytoplasmic inclusions; Fused in sarcoma gene (FUS).
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