Different clinical and neuropathologic phenotypes of familial ALS with A315E TARDBP mutation

To present the relationship between TARDBP gene mutation and clinicopathologic findings of a Japanese pedigree affected by familial amyotrophic lateral sclerosis (FALS).

The clinical, genetic, and neuropathologic characteristics of 4 members of a Japanese pedigree affected by FALS were examined.

All the patients showed motor neuron signs, and 2 of them also had parkinsonism. We identified A315E TARDBP mutation in one patient per clinical disease type and found loss of anterior horn cells, Bunina bodies, and phosphorylated TDP-43-positive neuronal and glial cytoplasmic inclusions in both the patients. However, the patient with only motor neuron signs had degeneration of the posterior column and spinocerebellar tracts as well as neuronal loss of the Clarke column, and the patient with both motor neuron signs and parkinsonism had severe nigral degeneration without Lewy pathology.

The clinical and neuropathologic phenotypes of FALS may differ even with the same mutation of TARDBP, encoding TDP-43. Isolated TDP-43 pathology can produce ALS-plus syndrome.