Sporadic ALS with compound heterozygous mutations in the SQSTM1 gene
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Accumulating evidence suggests that heterozygous mutations in the SQSTM1 gene, which encodes p62 protein, are associated with amyotrophic lateral sclerosis (ALS). Here, we report a Japanese patient with sporadic, late-onset ALS who harbored compound heterozygous SQSTM1 mutations (p.[Val90Met];[Val153Ile]). Autopsy examination revealed that although TDP-43 pathology was rather widespread, the selective occurrence of p62-positive/TDP-43-negative cytoplasmic inclusions in the lower motor neurons (LMNs) was a characteristic feature. No Bunina bodies were found. Ultrastructurally, p62-positive cytoplasmic inclusions observed in the spinal anterior horn cells were composed of aggregates of ribosome-like granules and intermingled bundles of filamentous structures. Another feature of interest was concomitant Lewy body pathology. The occurrence of distinct p62 pathology in the LMNs in this patient indicates the pathogenic role of SQSTM1 mutations in the development of a subset of ALS.
KeywordsAmyotrophic lateral sclerosis SQSTM1 gene Compound heterozygote Neuropathology p62 TDP-43
We thank C. Tanda, J. Takasaki, H. Saito, T. Fujita, S. Nigorikawa, and S. Egawa for their technical assistance, and M. Machida and Y. Ueda for secretarial assistance. This work was supported by Grants-in-Aid 23590390 (to Y.T.), 22249036 (to M.N.), and 23240049 (to H.T.) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and grants (to O.O. and H.T.) from the Research Committee for CNS Degenerative Diseases, the Ministry of Health, Labor and Welfare, Japan.
Conflict of interest
The authors declare that they have no conflict of interest.