Phenotypic variability in a large kindred (Family LA) with deletions in the <i>parkin</i> gene

Pramstaller, Peter P.; Kis, Bernhard; Eskelson, Cordula; Hedrich, Katja; Scherer, Monika; Schwinger, E.; Breakefield, Xandra O.; Kramer, Patricia L.; Ozelius, Laurie J.; Klein, Christine

doi:10.1002/mds.10071

Cited by 19 publications

(11 citation statements)

References 10 publications

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“…[18F]Fluorodopa uptake by positron emission tomography was reduced in heterozygous carriers without symptoms 28 29. In addition, heterozygous carriers of PRKN mutations have been reported to have either minor motor signs or present with late onset parkinsonism, suggesting a link between heterozygous mutations and disease pathogenesis 27 30 31. On the other hand, screening for PRKN mutations in late onset PD and healthy controls revealed similar frequencies of genetic variants 32 33…”

Section: Hereditary Pdmentioning

confidence: 99%

Molecular pathogenesis of Parkinson's disease: update

Saiki

Sato

2011

J Neurol Neurosurg Psychiatry

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Parkinson disease (PD) is a neurodegenerative disease characterised by progressive disturbances in motor, autonomic and psychiatric functions. Much has been learnt since the disease entity was established in 1817. Although there are well established treatments that can alleviate the symptoms of PD, a pressing need exists to improve our understanding of the pathogenesis to enable development of disease modifying treatments. Ten responsible genes for PD have been identified and recent progress in molecular research on the protein functions of the genes provides new insights into the pathogenesis of hereditary as well as sporadic PD. Also, genome wide association studies, a powerful approach to identify weak effects of common genetic variants in common diseases, have identified a number of new possible PD associated genes, including PD genes previously detected. However, there is still much to learn about the interactions of the gene products, and important insights may come from chemical and genetic screens. In this review, an overview is provided of the molecular pathogenesis and genetics of PD, focusing particularly on the functions of the PD related gene products with marked research progress.

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Section: Hereditary Pdmentioning

confidence: 99%

Molecular pathogenesis of Parkinson's disease: update

Saiki

Sato

2011

J Neurol Neurosurg Psychiatry

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“…We studied 13 subjects (mean age 38.9 Ϯ 5.8 years, seven men) carrying a single heterozygous mutation in the Parkin gene, either a deletion of exon seven (n ϭ 7) or a single base-pair deletion in exon nine (c.del1072T) (n ϭ 6). 13 Nine other subjects (mean age 41.9 Ϯ 5.7 years, seven men) carried a heterozygous c.1366CϾT nonsense mutation of the PINK1 gene.…”

mentioning

confidence: 99%

“…14 Three of the Parkin 13,15 and five of the PINK1 14,16 mutation carriers had minor motor signs upon careful clinical examination, but were not aware of the motor signs and motor signs did not interfere with their daily activities. None of these subjects had a Unified Parkinson's Disease Rating Scale score of more than 4 or met the international accepted diagnostic criteria of probable PD.…”

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confidence: 99%

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

Nuenen¹,

Weiss²,

Bloem³

et al. 2009

Neurology

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Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements. Methods:Nonmanifesting individuals carrying a single heterozygous Parkin (n ϭ 13) or PINK1 (n ϭ 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation. Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease areassociated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit. Neurology ® 2009;72:1041-1047 GLOSSARY BOLD ϭ blood oxygen level-dependent; CMA ϭ cingulate motor area; FDR ϭ false discovery rate; fMRI ϭ functional MRI; HRF ϭ hemodynamic response function; IPS ϭ intraparietal sulcus; M1 HAND ϭ primary motor hand area; PD ϭ Parkinson disease; PMd ϭ dorsal premotor cortex; SMA ϭ supplementary motor area; SPM ϭ statistical parametric mapping; SVC ϭ small volume correction; TE ϭ echo time; TMS ϭ transcranial magnetic stimulation; TR ϭ repetition time; VOI ϭ volumes of interest.Several genes have been identified that can lead to Parkinson disease (PD), including four recessively inherited forms caused by mutations in the Parkin (PARK2), DJ-1 (PARK7), PINK1 (PARK6), and ATP13A2 (PARK9) genes.1-3 These familial forms of PD show a substantial clinical overlap with sporadic PD. Nonmanifesting individuals who carry a single heterozygous mutation in the Parkin and PINK1 gene associated with recessively inherited PD

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“…ParkScreen was applied to five families (A to E). Family E was the only one in which a Parkin mutation for PD was known (Pramstaller et al 2002). ParkScreen was able to narrow linkage to the Parkin gene within the PARK2 locus in family E. The primary use of ParkScreen is as an exclusion panel; however, it also has utility in detecting linkage.…”

Section: Discussionmentioning

confidence: 96%

ParkScreen: A Low-Cost Rapid Linkage Marker Panel for Parkinson’s Disease

et al. 2009

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A genetic marker screening panel, ParkScreen, optimized for simultaneous marker amplification, was constructed to test or exclude linkage in families with parkinsonism or Parkinson's disease, using only a few affected individuals per family. ParkScreen functionality was proven by detection of linkage to PARK2 in a family with known Parkin mutations, exclusion of linkage to several of the known loci, and detection of suggestive linkage to PARK8, PARK3, and PARK11 in some families. In a novel approach, we also tested the ability of ParkScreen to screen patients originating from isolated populations. Using apparently sporadic patients from geographically isolated Alpine villages, suggestive linkage to PARK11 was found in one village. ParkScreen is a useful and inexpensive tool that allows the rapid screening of patients in families suitable for clinical follow-up and further characterization in order to identify specific mutations or novel genes.

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Phenotypic variability in a large kindred (Family LA) with deletions in the parkin gene

Cited by 19 publications

References 10 publications

Molecular pathogenesis of Parkinson's disease: update

Molecular pathogenesis of Parkinson's disease: update

Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype

ParkScreen: A Low-Cost Rapid Linkage Marker Panel for Parkinson’s Disease

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