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Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

ABSTRACT: Background:Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (PDYN). The frequency of PDYN variants is reportedly very low (~?0.1%) in several ataxia cohorts screened to date. Case presentations:We found five cases of SCA23 in two families (mean age at onset: 37.8?±?5.5?years; mean age at examination: 64.2?±?12.3?years) with a novel PDYN variant (c.644G?>?A:p.R215H). We identified marked heterogeneity in the clinical features in Family 1: the proband showed clinical and neuroimaging features suggestive of multiple system atrophy with predominant parkinsonism (MSA-P). Conversely, the proband's mother with the PDYN p.R215H variant had no subjective symptoms; she had not come to medical attention before our survey, although she showed apparent cerebellar atrophy on brain magnetic resonance imaging (MRI). The other two patients in Family 1 and a patient in Family 2 showed slowly progressive cerebellar ataxia. Conclusions:We here report two Japanese families with SCA23, one of which showed considerable phenotypic variation in affected members. Our findings support that SCA23 can phenotypically overlap with MSA.

SUBMITTER: Satoh S

PROVIDER: S-EPMC7310450 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

Satoh Shunichi S Kondo Yasufumi Y Ohara Shinji S Yamaguchi Tomomi T Nakamura Katsuya K Yoshida Kunihiro K

Cerebellum & ataxias 20200623

<h4>Background</h4>Spinocerebellar ataxia type 23 (SCA23) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the prodynorphin gene (<i>PDYN</i>). The frequency of <i>PDYN</i> variants is reportedly very low (~ 0.1%) in several ataxia cohorts screened to date.<h4>Case presentations</h4>We found five cases of SCA23 in two families (mean age at onset: 37.8 ± 5.5 years; mean age at examination: 64.2 ± 12.3 years) with a novel <i>PDYN</i> variant (c.644G > A:p.R215H). We iden ...[more]

PMID: 32587707

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Project description:Spinocerebellar ataxia type 23 (SCA23) is a late-onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α-neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress-induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYNR212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non-cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYNR212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein-a marker for PF-PC synapses-indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYNR212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.

Dataset Information

Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

Publications

Intrafamilial phenotypic variation in spinocerebellar ataxia type 23.

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