Genetic and Phenotypic Characterisation of Autosomal Recessive Parkinson's Disease in a Large Multicentre Cohort

2019 ◽  
Author(s):  
Suzanne Lesage ◽  
Ariane Lunati ◽  
Marion Houot ◽  
Sawssan Benromdhan ◽  
Fabienne Clot ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Phenotypic Characterisation ◽  
Multicentre Cohort

scholarly journals Therapeutic Potential of α-Synuclein Evolvability for Autosomal Recessive Parkinson’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jianshe Wei ◽  
Gilbert Ho ◽  
Yoshiki Takamatsu ◽  
Eliezer Masliah ◽  
Makoto Hashimoto
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Gene Mutations ◽  
Mitochondrial Alteration ◽  
Rational Therapy ◽  
Ubiquitin Proteasome ◽  
Dominant Genes

The majority of Parkinson’s disease (PD) is sporadic in elderly and is characterized by α-synuclein (αS) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage. Since no radical therapies are available for PD, the objective of this paper is to discuss a mechanistic role for amyloidogenic evolvability, a putative physiological function of αS, among PD subtypes, and the potential relevance to therapy. Presumably, αS evolvability might benefit familial PD due to autosomal dominant genes and also sporadic PD during reproduction, which may manifest as neurodegenerative diseases through antagonistic pleiotropy mechanism in aging. Indeed, there are some reports describing that αS prevents apoptosis and mitochondrial alteration under the oxidative stress conditions, notwithstanding myriads of papers on the neuropathology of αS. Importantly, β-synuclein (βS), the nonamyloidogenic homologue of αS, might buffer against evolvability of αS protofibrils associated with neurotoxicity. Finally, it is intriguing to predict that increased αS evolvability through suppression of βS expression might protect against autosomal recessive PD. Collectively, further studies are warranted to better understand αS evolvability in PD pathogenesis, leading to rational therapy development.

scholarly journals The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2220-2234 ◽  
Author(s):  
Yuwen Zhao ◽  
Lixia Qin ◽  
Hongxu Pan ◽  
Zhenhua Liu ◽  
Li Jiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Chinese Population ◽  
Autosomal Recessive ◽  
Age At Onset ◽  
Mainland China ◽  
Mainland Chinese ◽  
Pathogenic Variants ◽  
Disease Associated Genes ◽  
Mainland Chinese Population

Abstract This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

scholarly journals Familial Subsets in Idiopathic Parkinson’s Disease

1984 ◽  
Vol 11 (S1) ◽  
pp. 144-150 ◽  
Author(s):  
André Barbeau ◽  
Madeleine Roy
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Essential Tremor ◽  
Autosomal Recessive ◽  
Biochemical Analysis ◽  
Great Part ◽  
Autosomal Dominant Disorder ◽  
Genetic Characteristics ◽  
Susceptibility Factors ◽  
Hla Haplotypes

ABSTRACTIn the present paper we explore in some detail the hypothesis that the presence of familial aggregations in 10–15% of Parkinson’s disease cases is due in great part to the existence of well-defined familial subsets, rather than to chance occurrences. We describe the clinical and genetic characteristics of the two main subsets: “Essential tremor-related Parkinsonism” and the “Familial akineto-rigid Syndrome” previously identified.The former type of Parkinsonism is associated at random, but with increased frequency, to an autosomal dominant disorder, usually essential tremor but occasionally OPCA. Two possible susceptibility factors were uncovered in this entity: an increased incidence of familial hyperthyroidism (augmentor factor) and a decreased incidence of the generally frequent HLA Haplotypes A1B8or A2B5(Protective factors).The other presentation, the “familial akineto-rigid syndrome”, appears to be a definite disease entity with an autosomal recessive mode of inheritance (normal parents, increased incidence of identical parkinsonism in sibs, increased consanguinity rate in parents). This newly defined disorder deserves much further genetic and biochemical analysis.

Sign in / Sign up

Export Citation Format

Share Document