We report a case of amyotrophic lateral sclerosis - ‘fused in sarcoma’(ALS-FUS)subtype with a striking disparity between its clinical manifestation and histopathologic findings.

ALS is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, resulting in progressive weakness, atrophy, and paralysis of skeletal muscles. It is a clinical syndrome named for its neuropathological hallmark – degeneration of motor neurons in the spinal anterior horns with TDP43 & ubiquitinated inclusions, accompanied by loss of axons in the lateral columns. 

We reviewed a case of a29-year-old male who presented with rapidly progressive severe neck weakness, asymmetrical bilateral upper extremity weakness, profound muscle wasting, bulbar dysfunction, and weight loss.

Within one year, his speech became unintelligible, he became gastrostomy and tracheostomy/ventilator dependent, and wheelchair bound. Electrophysiology suggested a motor neuron disease. Whole exome sequencing revealed a heterozygous pathogenic variant in the ‘fused in sarcoma gene (FUS), c.1574C>T, p.R525L, which was inherited in an autosomal dominant pattern,  consistent with the diagnosis of ALS. Autopsy revealed extensive denervation atrophy of skeletal musculature. Surprisingly, there was only mild patchy depletion of motor neurons within the cervical cord anterior horns. TDP43 inclusions was absent. Increased expression of FUSmutation product (cytoplasmic inclusions) was demonstrated within anterior horn neurons of the upper, mid, lower cervical segments, and glial cells. The most prominent finding was a disparity between profound neck muscle weakness, atrophy and relatively low-grade anterior horn cell loss in the cervical cord.

This s a case of a rare ALS-FUS subtype with an unusually aggressive clinical course and absent TDP43 inclusion. The disparity between phenotype and relatively preserved motor neuron cell population may suggest a secondary cause of anterior horn cell dysfunction. In addition, we noted increased FUS expression in glial cells, a feature that has not been well documented in such cases.