Aggressive FUS-Mutant Motor Neuron Disease Without Profound Spinal Cord Pathology.

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons.
• Genetic factors, including mutations in the FUS gene, are implicated in some ALS cases.
• Autosomal dominant forms of ALS often present with varying clinical and pathological features.

Observation:

• A young man exhibited rapid progression of severe neck and limb weakness, bulbar dysfunction, and muscle wasting.
• Clinical progression led to dependence on gastrostomy and mechanical ventilation, with wheelchair confinement.
• Electrophysiology indicated motor neuron disease, and whole exome sequencing identified a pathogenic FUS gene variant (c.1574C>T, p.R525L).

Findings:

• Autopsy revealed extensive skeletal muscle denervation atrophy.
• Surprisingly, minimal motor neuron depletion and preserved spinal cord tracts were observed in the cervico-thoracic region.
• TDP-43 inclusions were absent, but cytoplasmic FUS inclusions were present in motor neurons.
• A significant discrepancy was noted between profound clinical weakness and the limited neuropathological changes in the spinal cord.

Implications:

• This case expands the understanding of FUS-associated ALS, presenting an atypical pathological profile.
• The findings suggest that FUS mutations can lead to severe clinical manifestations with less pronounced neuronal loss than typically observed in ALS.
• Further research is needed to elucidate the mechanisms underlying the disconnect between clinical presentation and neuropathology in this FUS-ALS variant.