Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of...

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Bibliographic Details
Published in:Acta neuropathologica 2012-11, Vol.124 (5), p.749-760
Main Authors: Tada, Mari, Coon, Elizabeth A., Osmand, Alexander P., Kirby, Patricia A., Martin, Wayne, Wieler, Marguerite, Shiga, Atsushi, Shirasaki, Hiroe, Tada, Masayoshi, Makifuchi, Takao, Yamada, Mitsunori, Kakita, Akiyoshi, Nishizawa, Masatoyo, Takahashi, Hitoshi, Paulson, Henry L.
Format: Article
Language:English
Subjects:
Adult
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - complications
Amyotrophic Lateral Sclerosis - pathology
Brain
Brain - metabolism
Brain - pathology
Brain research
DNA-Binding Proteins - metabolism
Female
Humans
Huntington Disease - complications
Huntington Disease - pathology
Huntingtons disease
Indexing in process
Macrophages - pathology
Male
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Middle Aged
Neuroglia - pathology
Neurons - pathology
Neurosciences
Original Paper
Pathology
Peptides - metabolism
Retrospective Studies
Spinal Cord - metabolism
Spinal Cord - pathology
Ubiquitin
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Summary:We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50’s in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-012-1005-5