PARK7-Related Early Onset Parkinson Disease in the Setting of Complete Uniparental Isodisomy of Chromosome 1

AbstractBackground:Several studies have compared early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD) but most are not based on autopsy confirmed cases.Methods:We compared clinical and pharmacological profiles, time to reach irreversible Hoehn and Yahr (H&Y) Stage 3 and levodopa motor complications in autopsy confirmed EOPD and LOPD cases.Results:At first clinic visit EOPD cases were younger but had longer disease duration and they died at a younger age (all p<0.0001). Anti-Parkinsonian drug use, including levodopa, was significantly delayed in EOPD. Lifetime use of amantadine (p<0.05) and dopamine agonists (p<0.01) were higher in EOPD. While lifetime use of levodopa was similar in the two groups, levodopa was used for a significantly longer period by EOPD (p< 0.0001). EOPD had a higher cumulative incidence of dyskinesias (p<0.01), wearing-off (p<0.01), and on-off (p<0.01). However, the time to dyskinesia onset was similar in the two groups. The threshold to wearing-off was much longer in EOPD (p<0.01). H&Y stage profile at first visit was similar in the two groups. The duration from disease onset to reach irreversible H&Y stage 3 was significantly longer in EOPD.Conclusions:Our observations indicate that progression of PD is slower in EOPD and suggest that the pre-clinical interval in this group is longer. These findings can be used for case selection for drug trials and studies of the pathogenesis of PD.

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Early-Onset Parkinson Disease Screening in Patients From Nigeria

Frontiers in Neurology ◽

10.3389/fneur.2020.594927 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lukasz M. Milanowski ◽

Olajumoke Oshinaike ◽

Benjamin J. Broadway ◽

Jennifer A. Lindemann ◽

Alexandra I. Soto-Beasley ◽

...

Keyword(s):

Functional Analysis ◽

Parkinson Disease ◽

Neurodegenerative Diseases ◽

Early Onset ◽

Local Population ◽

Age At Onset ◽

Compound Heterozygous ◽

Loss Of Function ◽

African Countries ◽

Age Related

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

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3.023 FREQUENCY OF THE MUTATIONS IN THE PARK2, PINK1 AND DJ-1 GENES IN POLISH PATIENTS WITH THE EARLY-ONSET PARKINSON DISEASE

Parkinsonism & Related Disorders ◽

10.1016/s1353-8020(11)70759-3 ◽

2012 ◽

Vol 18 ◽

pp. S174-S175

Author(s):

D. Koziorowski ◽

D. Hoffman-Zacharska ◽

J. Sławek ◽

P. Górka ◽

J. Bal ◽

...

Keyword(s):

Parkinson Disease ◽

Early Onset

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A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice.

Journal of Experimental Medicine ◽

10.1084/jem.159.1.1 ◽

1984 ◽

Vol 159 (1) ◽

pp. 1-20 ◽

Cited By ~ 206

Author(s):

J B Roths ◽

E D Murphy ◽

E M Eicher

Keyword(s):

Lymph Node ◽

Early Onset ◽

Lymphoid Hyperplasia ◽

Peripheral Blood Lymphocytes ◽

Lymphoproliferative Disease ◽

Chromosome 1 ◽

Recessive Mutation ◽

New Mutation ◽

Antinuclear Autoantibodies ◽

Lymph Node Enlargement

A newly discovered autosomal recessive mutation, generalized lymphoproliferative disease (gld), in the C3H/HeJ strain of mice, determines the development of early onset massive lymphoid hyperplasia with autoimmunity. Significant lymph node enlargement is apparent as early as 12 wk of age. By 20 wk, lymph nodes are 50-fold heavier than those of coisogenic C3H/HeJ-+/+ mice. There is a concomitant increase in the numbers of peripheral blood lymphocytes. Analysis of C3H-gld lymph node lymphocyte subsets by immunofluorescence indicates an increase in numbers of B cells, T cells, and null (Thy-1-, sIg-) lymphocytes by 6-, 15-, and 33-fold compared with congeneic control mice. Serologically, gld/gld mice develop antinuclear antibodies (including anti-dsDNA), thymocyte-binding autoantibody, and hypergammaglobulinemia with major increases in several immunoglobulin isotypes. Mutant gld mice live only one-half as long as normal controls (12 and 23 mo, respectively). Interstitial pneumonitis was found in virtually all C3H-gld mice autopsied when moribund. Although immune complexes were detected in the glomerulus by immunofluorescence techniques, only 14% of the autopsied mice had significant lupus-like nephritis. Vascular disease was not found. The pattern of early onset massive lymph node enlargement, hypergammaglobulinemia, and production of antinuclear autoantibodies resembles the basic abnormal phenotype induced by the lpr (lymphoproliferation) mutation. The mutations gld and lpr are not allelic. Linkage studies indicate that gld is located between Pep-3 and Lp on chromosome 1. This new mutation adds another genetically well-defined model to the list of murine lymphoproliferative/autoimmune disorders that may be exploited to gain a clearer understanding of immunoregulatory defects and for identifying common pathogenetic factors involved in systemic autoimmune diseases.

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