Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single
            <i>parkin</i>
            mutation

Khan, Naheed L.; Scherfler, Christoph; Graham, Elizabeth; Bhatia, Kailash P.; Quinn, Niall; Lees, Andrew J.; Brooks, David J.; Wood, Nicholas W.; Piccini, Paola

doi:10.1212/01.wnl.0000148725.48740.6d

Cited by 129 publications

(96 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is mostly supported by neurophysiological and functional neuroimaging studies, that showed significant albeit subclinical signs of dopaminergic dysfunction in healthy carriers of Parkin and PINK1 single mutations (reviewed in Klein et al, 2007). A role for these variants as PD susceptibility factors would justify their higher frequency among our patients with positive family history of unclear inheritance (6.5%), and their occurrence also in healthy subjects and in individuals with very mild parkinsonian signs (Khan et al, 2005;Hedrich et al, 2006). Yet, it is presently unknown whether the subclinical abnormalities found in healthy heterozygotes are going to remain stable or to evolve towards a clinically manifest phenotype.…”

Section: Discussionmentioning

confidence: 57%

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

View full text Add to dashboard Cite

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

show abstract

Section: Discussionmentioning

confidence: 57%

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The pattern of dopaminergic deficit in symptomatic parkin patients mimics that of idiopathic PD, putamen being targeted, but the caudate and midbrain are relatively more involved (59). Asymptomatic heterozygote parkin gene carriers also show a mild but significant reduction in putamen 18 F-dopa uptake (60). This dopaminergic deficit could conceivably make heterozygote carriers more susceptible to late-onset PD.…”

Section: Detection Of Preclinical Pdmentioning

confidence: 97%

Imaging Approaches to Parkinson Disease

Brooks¹

2010

J Nucl Med

187

109

View full text Add to dashboard Cite

Parkinson disease (PD) is associated with nigral degeneration and striatal dopamine deficiency. Demonstrating midbrain structural abnormalities with transcranial sonography or diffusionweighted MRI or showing striatal dopamine terminal dysfunction with PET or SPECT supports the diagnosis and rationalizes the use of dopaminergic medications. In atypical PD variants, transcranial sonography can detect striatal hyperechogenicity, and diffusion-weighted imaging can detect increased putamen water diffusion, whereas 18 F-FDG PET reveals reduced lentiform nucleus glucose metabolism. PET and SPECT can detect changes in striatal dopamine levels after levodopa administration and relate these to motor responses. Loss of cortical dopaminergic and cholinergic function is present in demented PD and, on occasion, amyloid deposits can be detected. Loss of cardiac sympathetic innervation can be sensitively detected in PD with 18 F-dopamine PET or 123 I-metaiodobenzylguanidine SPECT. Finally, PET can detect widespread brain inflammation in PD. This review discusses the role of structural and functional imaging for diagnosing and managing different parkinsonian syndromes.

show abstract

“…These parkin mutations include exonic deletion, duplication, and triplication as well as several missense/ nonsense substitutions. Although initially described as a recessive disorder, emerging evidence suggest that heterozygous parkin mutations may confer increased susceptibility to PD (Hilker et al, 2001(Hilker et al, , 2002Oliveira et al, 2003;Khan et al, 2005;L. N. Clark et al, 2006;Sun et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

Cheng¹,

Lu²,

Ouyang³

et al. 2007

J. Neurosci.

123

View full text Add to dashboard Cite

Mutations in the parkin gene are a predominant cause of familial parkinsonism. Although initially described as a recessive disorder, emerging evidence suggest that single parkin mutations alone may confer increased susceptibility to Parkinson's disease. To better understand the effects of parkin mutations in vivo, we generated transgenic Drosophila overexpressing two human parkin missense mutants, R275W and G328E. Transgenic flies that overexpress R275W, but not wild-type or G328E, human parkin display an agedependent degeneration of specific dopaminergic neuronal clusters and concomitant locomotor deficits that accelerate with age or in response to rotenone treatment. Furthermore, R275W mutant flies also exhibit prominent mitochondrial abnormalities in their flight muscles. Interestingly, these defects caused by the expression of human R275W parkin are highly similar to those triggered by the loss of endogenous parkin in parkin null flies. Together, our results provide the first in vivo evidence demonstrating that parkin R275W mutant expression mediates pathogenic outcomes and suggest the interesting possibility that select parkin mutations may directly exert neurotoxicity in vivo.

show abstract

Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation

Cited by 129 publications

References 10 publications

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

Imaging Approaches to Parkinson Disease

DrosophilaOverexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities

Contact Info

Product

Resources

About