Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

Julia L Keith; Emily Swinkin; Andrew Gao; Samira Alminawi; Ming Zhang; Philip McGoldrick; Paul McKeever; Janice Robertson; Ekaterina Rogaeva; Lorne Zinman

doi:10.1212/NXG.0000000000000394

Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

Neurol Genet. 2020 Jan 13;6(1):e394. doi: 10.1212/NXG.0000000000000394. eCollection 2020 Feb.

Authors

Affiliation

¹ Laboratory Medicine and Molecular Diagnostics (J.L.K., A.G., S.A.), Division of Anatomical Pathology, Sunnybrook Health Sciences Centre, University of Toronto; Department of Medicine (E.S., L.Z.), Division of Neurology, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada; School of Medicine and Institute for Advanced Study (M.Z.), Tongji University, Shanghai, China; and Tanz Centre for Research in Neurodegenerative Diseases (M.Z., P. McGoldrick, P. McKeever, J.R., E.R.), University of Toronto, Ontario, Canada.

Abstract

Objective: To present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.

Methods: A 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.

Results: Postmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.

Conclusions: The neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.