Intrafamilial variability of Parkinson phenotype in SCAs: Novel cases due to SCA2 and SCA3 expansions

Socal, Mariana P.; Emmel, V.E.; Rieder, Carlos Roberto de Mello; Hilbig, Arlete; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach

doi:10.1016/j.parkreldis.2008.09.005

Cited by 47 publications

(28 citation statements)

References 30 publications

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“…In SCA2, expansions over 36 repeats are generally composed of pure CAG stretches; nevertheless, there are reports of intermediate size SCA2 alleles with CAG repeats interspersed by CAA in patients manifesting with Parkinson disease. [23][24][25][26] Although there were no absolute conclusions about the exact acceptable margins of error, the consensus was that this could be different for each SCA, as well as for normal alleles (±1) and most larger expansions ( ± 3); outside or close to the boundary of normal and pathogenic alleles, precision should be to the repeat unit, as this may have clinical consequences (together with the exact sequence, if interruptions are possible).…”

Section: Methodologiesmentioning

confidence: 99%

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Sequeiros

Seneca²,

Martindale

2010

Eur J Hum Genet

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Many laboratories worldwide are offering molecular genetic testing for spinocerebellar ataxias (SCAs). This is essential for differential diagnosis and adequate genetic counselling. The European Molecular Genetics Quality Network (EMQN) started an SCA external quality assessment scheme in 2004. There was a clear need for updated laboratory guidelines. EMQN and EuroGentest organized a Best Practice (BP) meeting to discuss current practices and achieve consensus. A pre-meeting survey showed that 36 laboratories (20 countries) conducted nearly 18 000 SCA tests the year before, and identified issues to discuss. Draft guidelines were produced immediately after the meeting and discussed online for several months. The final version was endorsed by EMQN, and harmonized with guidelines from other oligonucleotide repeat disorders. We present the procedures taken to organize the survey, BP meeting, as well as drafting and approval of BP guidelines. We emphasize the most important recommendations on (1) pre-test requirements, (2) appropriate methodologies and (3) interpretation and reporting, and focus on the discussion of controversial issues not included in the final document. In addition, after an extensive review of scientific literature, and responding to recommendations made, we now produce information that we hope will facilitate the activities of diagnostic laboratories and foster quality SCA testing. For the main loci, this includes (1) a list of repeat sequences, as originally published; (2) primers in use; and (3) an evidence-based description of the normal and pathogenic repeat-size ranges, including those of reduced penetrance and those in which there is still some uncertainty. This information will be maintained and updated in http://www.scabase.eu.

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Section: Methodologiesmentioning

confidence: 99%

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Sequeiros

Seneca²,

Martindale

2010

Eur J Hum Genet

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“…Whereas uninterrupted CAG repeat expansions are associated with ataxia, shorter expansions interrupted by CAA triplets are associated with parkinsonism [ 75 , 78 ]. More rarely, repeat expansions in SCA3 have also been associated with a phenotype resembling pure parkinsonism without prominent ataxia [ 79 ].…”

Section: Sca / Ataxins Gba Gch1 C9orf72 : Risk Factors or Dominmentioning

confidence: 99%

Genetics of Mendelian Forms of Parkinson’s Disease

Lesage

2015

Movement Disorder Genetics

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Over the past decade, genetic causes of parkinsonism have been elucidated but in less than 10 % of the cases. Since the discovery of the fi rst gene responsible for Parkinson's disease (PD), SCNA encoding α-synuclein, linkage mapping, and positional cloning have identifi ed autosomal dominantly or recessively inherited PD-causing mutations in the genes encoding Parkin , PTEN-induced kinase 1 ( PINK1 ), DJ -1 , leucine-rich repeat kinase 2 ( LRRK2 ), and ATP13A2 , indicating that PD has a highly heterogeneous etiology. With the introduction of next-generation sequencing, rare mutations in DNAJC6 , SYNJ1 , VPS35 , and DNAJC13 were then discovered to cause inherited parkinsonism. In addition, polymorphic variants in SNCA and LRRK2 and heterozygous mutations in the genes encoding β-glucocerebrosidase ( GBA ) and guanosine triphosphate cyclohydrolase 1 ( GCH1 ) appear to contribute to sporadic PD in several populations. These mutations have been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance, defective recycling of synaptic vesicles, and oxidative stress. Identifi cation of other Mendelian forms of PD will be the main challenge for the next decade.

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“…We thought that this dysfunction could be responsive to high-dose thiamine. Furthermore, PD has also been related to mutations associated with SCA2 4. Some reports have shown trinucleotide repeat expansions in the SCA2 gene in patients with levodopa-responsive parkinsonism.…”

Section: Introductionmentioning

confidence: 99%

High-dose thiamine as initial treatment for Parkinson's disease

Costantini¹,

Pala

Compagnoni

et al. 2013

BMJ Case Reports

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Parkinson's disease (PD) is a systemic disease with motor and non-motor deficits. We recruited three patients with newly diagnosed PD. They were not under anti-Parkinson's therapy. Plasmatic thiamine was within healthy reference range. We performed the Unified Parkinson's Disease Rating Scale (UPDRS) and started a parenteral therapy with high doses of thiamine. The therapy led to a considerable improvement in the motor part of the UPDRS ranging from 31.3% to 77.3%. From this clinical observation, it is reasonable to infer that a focal, severe thiamine deficiency due to a dysfunction of thiamine metabolism could cause a selective neuronal damage in the centres that are typically hit in this disease. Injection of high doses of thiamine was effective in reversing the symptoms, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations.

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Intrafamilial variability of Parkinson phenotype in SCAs: Novel cases due to SCA2 and SCA3 expansions

Cited by 47 publications

References 30 publications

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Genetics of Mendelian Forms of Parkinson’s Disease

High-dose thiamine as initial treatment for Parkinson's disease

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