A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy

Hideshima, Makoto; Beck, Goichi; Yamadera, Misaki; Motoyama, Yuichi; Ikenaka, Kazuhiro; Kakuda, Keita; Tsuda, Hiroshi; Nagano, Seiichi; Fujimura, Harutoshi; Morii, Eiichi; Murayama, Shigeo; Mochizuki, Hideki

doi:10.1111/neup.12620

Cited by 7 publications

(5 citation statements)

References 23 publications

(40 reference statements)

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“…In our cohort, the mean age at onset was 48.4 years, and the mean disease duration was 4.9 years in patients with SOD1 mutations. The p.L126S mutation is characterized by rapid progression in homozygous cases [ 37 ] and relatively long course in heterozygous cases [ 38 ], with isolated inferior olivary hypertrophy in autopsy case [ 38 ]. The relatively frequent p.N86S mutation is characterized by phenotypic diversity and low penetrance even within families.…”

Section: The Elucidation Of Causative Genes Has Advanced Our Understa...mentioning

confidence: 99%

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing on SOD1, fused in sarcoma (FUS), and transacting response DNA-binding protein. The frequency of the C9ORF72 mutation is low in Japan, unlike in Europe and the United States, while SOD1 and FUS are more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.

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Section: The Elucidation Of Causative Genes Has Advanced Our Understa...mentioning

confidence: 99%

Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

et al. 2022

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“…9 In patients with other neurodegenerative diseases, inferior olivary hypertrophy has been rarely reported in some patients with pathologically diagnosed PSP [5][6][7][8] and in one patient with familial amyotrophic lateral sclerosis with a mutation in the gene for superoxide dismutase 1. 10 In addition, one patient with spinocerebellar ataxia type 2 showed bilateral inferior olivary hypertrophy on MRI findings. 20 Severity of neuronal loss in the dentate nucleus may not by itself contribute to inferior olivary hypertrophy, because it is unusual 6 in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, or any other neurodegenerative diseases, in which severe neurodegeneration can occur in the dentate nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Among the autopsied cases of neurodegenerative diseases, inferior olivary hypertrophy has been reported in some patients with progressive supranuclear palsy (PSP), [5][6][7][8] one with corticobasal degeneration (CBD), 9 and another patient with familial amyotrophic lateral sclerosis. 10 We report the case of a patient who was pathologically confirmed as having CBD with inferior olivary hypertrophy. In our patient, the severity of neurodegeneration and tau deposition was likely related to the topography of the projections from the cerebellar dentate nucleus to the inferior olivary nucleus.…”

Section: Introductionmentioning

confidence: 99%

An autopsy case of corticobasal degeneration with inferior olivary hypertrophy

et al. 2021

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We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-tomoderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tauimmunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentatoolivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

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“…Olivary hypertrophic degeneration was seen microscopically in a few patients with ALS, although there was no associated palatal tremor. 7,8 Through this case, we highlight the possibility of palatal tremor associated with ALS, which is an extremely rare phenomenon. This suggests that the neurodegeneration in ALS might not be restricted to motor neurons.…”

mentioning

confidence: 85%