Dataset Information

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients.

ABSTRACT:

Background

An initial diagnosis of Parkinson's disease (PD) is challenging, especially in patients who have early onset and atypical disease. A genetic etiology for parkinsonism, when established, ends that diagnostic odyssey and may inform prognosis and therapy. The objective of this study was to elucidate the genetic etiology of parkinsonism in patients with early onset disease (age at onset <45 years).

Methods

Whole-exome sequencing, copy number variability, and short tandem repeat analyses were performed. The analyses were focused on genes previously implicated in parkinsonism and dystonia in patients with early onset parkinsonism. Genotype-phenotype correlations were assessed using regression models.

Results

The patient cohort was characterized by early onset, slowly progressive parkinsonism with a mean age at onset of 39.2 ± 5.0 years (n = 108). By 10 years of disease duration, the mean Hoehn & Yahr stage was 2.6 ± 0.8, the mean Unified Parkinson's Disease Rating Scale, part III (motor part) score was 24.9 ± 12.1 (n = 83), and 30 patients were cognitively impaired at the last examination (Montreal Cognitive Assessment score ? 26). Ten patients with typical early onset PD harbored homozygous or compound heterozygous mutations phosphatase and tensin homolog-induced putative kinase 1 (PINK1) (n = 4), parkin (PRKN) (n = 3), or the leucine-rich repeat kinase 2 (LRRK2) c.6055 G to A transition (n = 3). In addition, 5 patients with more atypical disease were compound heterozygotes for the glucocerebrosidase gene (GBA) (n = 3) 1 was heterozygous for solute carrier family 2, member 1 (SLC2A1) and another carried a novel ataxin 2 (ATXN2) exon 1 duplication. In most patients, the cumulative mutational burden did not appear to contribute to age at onset or progression.

Conclusion

In this clinical series, 15 patients (14%) carried mutations that were linked to monogenic parkinsonism. GBA carriers were most likely to suffer an earlier cognitive demise. Nevertheless, the etiology for most patients with early onset PD remains to be determined.

SUBMITTER: Gustavsson EK

PROVIDER: S-EPMC6174458 | biostudies-literature | 2017 Jul-Aug

REPOSITORIES: biostudies-literature

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Publications

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients.

Gustavsson Emil K EK Trinh Joanne J McKenzie Marna M Bortnick Stephanie S Petersen Maria Skaalum MS Farrer Matthew J MJ Aasly Jan O JO

Movement disorders clinical practice 20170523 4

<h4>Background</h4>An initial diagnosis of Parkinson's disease (PD) is challenging, especially in patients who have early onset and atypical disease. A genetic etiology for parkinsonism, when established, ends that diagnostic odyssey and may inform prognosis and therapy. The objective of this study was to elucidate the genetic etiology of parkinsonism in patients with early onset disease (age at onset <45 years).<h4>Methods</h4>Whole-exome sequencing, copy number variability, and short tandem re ...[more]

PMID: 30363439

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Project description:The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Dataset Information

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients.

Background

Methods

Results

Conclusion

Publications

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients.

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