Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kufor-Rakeb syndrome is an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration. The onset is in the teenage years with clinical features of Parkinson's disease plus spasticity, supranuclear upgaze paresis, and dementia. Brain scans show atrophy of the globus pallidus and pyramids and, later, widespread cerebral atrophy. We report linkage in Kufor-Rakeb syndrome to a 9 cM region of chromosome 1p36 delineated by the markers D1S436 and D1S2843, with a maximum multipoint lod score of 3.6.
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PMID:Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. 1158 46

Four chromosomal loci ( PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson's disease.
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PMID:DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism. 1459 65

Studies of familial forms of Parkinson's disease (PD) have identified a growing number of genes that derive from the loci given the nomenclature PARK1-PARK13 (OMIM 168600). The alpha-synuclein gene has been implicated in rare autosomal dominant PD because of either mis-sense mutations (PARK1) or gene multiplications (PARK4). Moreover, UCHL1 (PARK5), LRRK2 (PARK8) and HTRA2 (PARK13) have been identified as causative genes for autosomal dominant PD, whereas parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and ATP13A2 (PARK9) have been identified as causative genes for autosomal recessive PD. Neuropathological examination of the kindreds of PARK1/4 showed Lewy body pathology ranging from classic PD to diffuse Lewy body disease. The pathological findings of PARK3 are similar to those of classic PD. In contrast, autopsies of patients with PARK2 showed nigral cell loss without Lewy bodies, although exceptions have been reported. Several kindreds of PARK8 included cases with Lewy body pathology, tau pathology, or with nigral cell loss in the absence of obvious protein deposition. Ubiquitin-positive inclusions that are negative for alpha-synuclein and tau are also seen in some cases. Moreover, widespread Lewy body pathology was also reported in several cases of familial Alzheimer's disease with presenilin-1 mutations.
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PMID:[Pathology of familial Parkinson's disease]. 1771 21

Studies of specific populations have provided invaluable knowledge about Parkinson's disease (PD), especially in the field of genetics. The present report systematically reviews the medical literature on PD in Arabs. Medline and Embase were searched, and 24 article were identified: genetic (n = 17), epidemiological (n = 3), and clinical series (n = 5). Both autosomal dominant and recessive forms of inherited PD are described, associated with four genes (Parkin, PINK1, LRRK2, and PARK9). The G2019S LRRK2 mutation is more common in both familial (37-42%) and apparently sporadic PD (41%) in North African Arabs than in Europeans and North Americans (2-3%). The incidence of PD is reported at 4.5 per 100,000 person-years and reported prevalence at 27 to 43 per 100,000 persons. Hospital-based clinical series suggest that parkinsonism is the commonest movement disorder. Clinical features of PD in Arabs are not significantly different from those reported elsewhere. PD was reported as the cause of dementia in around 7% of Arabs. The majority of studies relate to the role of genes in the etiology of PD in North African Arabs. Further genetic, epidemiological and clinical studies from the majority of Arabic countries may enhance our understanding of PD.
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PMID:Parkinson's disease in Arabs: a systematic review. 1844 38

Recessively inherited mutations in ATP13A2 result in Kufor-Rakeb syndrome (KRS), whereas genetic variability and elevated ATP13A2 expression have been implicated in Parkinson disease (PD). Given this background, ATP13A2 was comprehensively assessed to support or refute its contribution to PD. Sequencing of ATP13A2 exons and intron-exon boundaries was performed in 89 probands with familial parkinsonism from Tunisia. The segregation of mutations with parkinsonism was subsequently assessed within pedigrees. The frequency of genetic variants and evidence for association was also examined in 240 patients with nonfamilial PD and 372 healthy controls. ATP13A2 mRNA expression was also quantified in brain tissues from 38 patients with nonfamilial PD and 38 healthy subjects from the United States. Sequencing analysis revealed 37 new variants; seven missense, six silent, and 24 that were noncoding. However, no single ATP13A2 mutation segregated with familial parkinsonism in either a dominant or recessive manner. Four markers showed marginal association with nonfamilial PD, prior to correction for multiple testing. ATP13A2 mRNA expression was marginally decreased in PD brains compared with tissue from control subjects. In conclusion, neither ATP13A2 genetic variability nor quantitative gene expression in brain appears to contribute to familial parkinsonism or nonfamilial PD.
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PMID:ATP13A2 variability in Parkinson disease. 1908 12

Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.
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PMID:Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. 1918 5

Four genes responsible for recessively inherited forms of Parkinson's disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exons of the ATP13A2 coding region in 112 patients with early-onset PD (EOPD; <40 years) of mostly European ethnic origin and of 55 controls. We identified four carriers (3.6%) of novel single heterozygous ATP13A2 missense changes that were absent in controls. Interestingly, the carrier of one of these variants also harbored two mutations in the Parkin gene. None of the carriers had atypical features previously described in patients with two mutated ATP13A2 alleles (Kufor-Rakeb syndrome). Our data suggest that two mutated ATP13A2 alleles are not a common cause of PD. Although heterozygous variants are present in a considerable number of patients, they are-based on this relatively small sample-not significantly more frequent in patients compared to controls.
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PMID:ATP13A2 variants in early-onset Parkinson's disease patients and controls. 1970 61

ATP13A2 (PARK9) mutations are related to Kufor-Rakeb syndrome (KRS). We performed genetic analysis of the Ala746Thr variant in an independent cohort of the patients with PD and healthy controls from mainland China. The Ala746Thr variant was present in 1/532 (0.19%) of PD compared with 1/480 (0.21%) of healthy controls (odds ratio=0.90, 95% CI 0.06, 14.39, P=1.00). The two subjects carried the heterozygous genotype. Subset analysis in the group </=50 years of age revealed a prevalence of 0.7% in PD compared with 0% in healthy controls and in the group >50 years of age showed 0% in PD versus 0.3% in healthy controls. We did not observe a significant association between Ala746Thr and Parkinson's disease in Han Chinese population, even after stratification by age at onset. The results suggested that Ala746Thr variant was not a major susceptible factor for PD in Han Chinese people.
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PMID:Lack of association between ATP13A2 Ala746Thr variant and Parkinson's disease in Han population of mainland China. 2022 61

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome.
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PMID:Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. 2066 27

There is no unique way to define Parkinson's disease (PD) clinically. "Classical parkinsonian features" can be found not only in sporadic idiopathic PD patients, but also in other parkinsonian disorders, such as genetic forms associated with mutations in PARK or in other genes. The present review will describe the parkinsonian phenotypes emerging from the new Mendelian genes which have been linked to PD (such as PARK9 and PARK14), the associated dystonia-parkinsonism disorders (such as the syndromes of neurodegeneration with brain iron accumulation) and the emerging data on heterozygous variants of genes which could influence the risk to develop PD and the PD phenotypes (like PD associated with glucose cerebrosidase mutations).
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PMID:Emerging parkinsonian phenotypes. 2081 31


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