Chronic ataxias with onset after the age of 50 differ significantly from ataxias with childhood or early adulthood onset. This article focuses on late-onset hereditary ataxias, particularly on new subtypes such as CANVAS (Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome) and SCA27B (Spinocerebellar Ataxia type 27B). It describes their clinical manifestations and diagnostic methods, including genetic testing and differential diagnosis against other sporadic ataxias, such as Multiple system atrophy type C. We present the main principles of diagnosing hereditary ataxias and the diagnostic approach used at the Center of Hereditary Ataxias at the Motol University Hospital, which includes a combination of laboratory, imaging, and genetic tests that allow for the exclusion of acquired causes and a pragmatic diagnosis of hereditary diseases.

• Keywords
• CANVAS, FXTAS,
• MeSH
• Ataxia * diagnosis   genetics   classification   MeSH
• Diagnosis, Differential MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple System Atrophy diagnosis   genetics   MeSH
• Aged MeSH
• Spinocerebellar Ataxias * diagnosis   genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• MeSH
• alpha-Synuclein metabolism   MeSH
• Autoantibodies MeSH
• Genome-Wide Association Study MeSH
• Humans MeSH
• Multiple System Atrophy * genetics   pathology   MeSH
• Olivopontocerebellar Atrophies * MeSH
• Autopsy MeSH
• Nerve Tissue Proteins genetics   MeSH
• Striatonigral Degeneration * MeSH
• Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Atypické parkinsonské syndromy tvoří pestrou škálu fenotypů charakterizovaných přítomností parkinsonského syndromu s měnlivou akcentací jednotlivých symptomů, motorických, kognitivních i behaviorálních, a s velmi variabilním průběhem. Klasifikace těchto onemocnění prochází rychlým vývojem, a to hlavně díky molekulární genetice a klinicko-patologické korelaci.

Atypical parkinsonian syndromes include a diverse range of phenotypes characterized by the presence of the parkinsonian syndrome with variable accentuation of the different symptoms, motor, cognitive and behavioural, and with very variable course. Classification of these diseases is rapidly evolving, mainly owing to molecular genetics and clinical-pathological correlation.

• Keywords
• Perryho syndrom, autozomálně dominantní spinocerebelární ataxie, atypické parkinsonské syndromy,
• MeSH
• Lewy Body Disease genetics   MeSH
• Frontotemporal Dementia genetics   MeSH
• Humans MeSH
• Multiple System Atrophy genetics   MeSH
• Parkinson Disease genetics   MeSH
• Parkinsonian Disorders * genetics   MeSH
• Spinocerebellar Ataxias MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

OBJECTIVE: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. METHODS: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. RESULTS: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. CONCLUSIONS: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

• MeSH
• alpha-Synuclein genetics   MeSH
• Lewy Body Disease diagnosis   genetics   MeSH
• Adult MeSH
• Genetic Predisposition to Disease epidemiology   MeSH
• Genetic Variation genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Multiple System Atrophy diagnosis   genetics   MeSH
• Parkinson Disease diagnosis   genetics   MeSH
• tau Proteins genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH