Genetic Identification in Early Onset Parkinsonism among Norwegian Patients

Emil K. Gustavsson; Joanne Trinh; Marna McKenzie; Stephanie Bortnick; Maria Skaalum Petersen; Matthew J. Farrer; Jan O. Aasly

doi:10.1002/mdc3.12501

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients

Emil K. Gustavsson^*, Joanne Trinh, Marna McKenzie, Stephanie Bortnick, Maria Skaalum Petersen, Matthew J. Farrer, Jan O. Aasly

^*Corresponding author for this work

Institute of Neurogenetics

22 Citations (Scopus)

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.

Original language	English
Journal	Movement Disorders Clinical Practice
Volume	4
Issue number	4
Pages (from-to)	499-508
Number of pages	10
DOIs	https://doi.org/10.1002/mdc3.12501
Publication status	Published - 01.07.2017

Funding

Ethical Compliance Statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: This research was supported in part by funds from St. Olav’s hospital (E.K.G.), Reberg’s Legacy (J.O.A.), and Sør-Trøndelag Parkin-sonforening (J.O.A.); the Canada Excellence Research Chairs program (M.J.F.); Leading Edge Endowment Funds provided by the Province of British Columbia (M.J.F.); LifeLabs (M.J.F.) and Genome BC support the Dr. Donald Rix BC Leadership Chair (M.J.F.), and the Peter Cundill Foundation (M.J.F.), and Canadian Institutes of Health Research (J.T.). The Faroese project has been supported by the Faroese Research Council and the Faroese and Danish Parkinson Associations. The authors report no other sources of funding and no conflicts of interest. Financial Disclosures for the previous 12 months: Matthew J. Farrer serves on the scientific advisory boards of Parkinson’s Society Canada, Parkinson’s UK, and the Michael J. Fox Foundation. The remaining authors report no sources of funding and no conflicts of interest.

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Research Area: Medical Genetics

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10.1002/mdc3.12501

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@article{f714e7559319420293ffda07cb8748b6,

title = "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.",

author = "Gustavsson, \{Emil K.\} and Joanne Trinh and Marna McKenzie and Stephanie Bortnick and Petersen, \{Maria Skaalum\} and Farrer, \{Matthew J.\} and Aasly, \{Jan O.\}",

year = "2017",

month = jul,

day = "1",

doi = "10.1002/mdc3.12501",

language = "English",

volume = "4",

pages = "499--508",

journal = "Movement Disorders Clinical Practice",

issn = "2330-1619",

publisher = "John Wiley and Sons Ltd",

number = "4",

}

TY - JOUR

T1 - Genetic Identification in Early Onset Parkinsonism among Norwegian Patients

AU - Gustavsson, Emil K.

AU - Trinh, Joanne

AU - McKenzie, Marna

AU - Bortnick, Stephanie

AU - Petersen, Maria Skaalum

AU - Farrer, Matthew J.

AU - Aasly, Jan O.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85061896412

U2 - 10.1002/mdc3.12501

DO - 10.1002/mdc3.12501

M3 - Journal articles

AN - SCOPUS:85061896412

SN - 2330-1619

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EP - 508

JO - Movement Disorders Clinical Practice

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ER -

Genetic Identification in Early Onset Parkinsonism among Norwegian Patients

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