Park6‐linked parkinsonism occurs in several european families

Abstract

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson's disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.

Molecular Pathophysiology of Parkinson's Disease

“…Additional unrelated families with positive linkage to this region were described (Valente et al 2002), and mutations in the PINK1 gene were identified (Valente et al 2004a). Initial screens for PINK1 mutations in early-onset familial cases revealed a number of novel mutations; however, these mutations are less common than are alterations in the parkin gene in early-onset PD cases (Hatano et al 2004, Valente et al 2004b.…”

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

“…PARK6 (gene PINK1, PTEN-induced putative kinase 1): It is characterized by early onset in most patients (mean age at onset in the 30s, ranging from childhood until the seventh decade of life), dystonia at onset or symptom symmetry in some cases, slow disease progression, excellent levodopa responsiveness, early peak-dose dyskinesias; hyperreflexia has been described; rare cases with very early onset display sleep benefit and diurnal fluctuations (Valente et al 2001(Valente et al , 2002Bonifati 2005;Ibáñez et al 2006;Leutenegger et al 2006). Psychiatric disturbances such as depression, anxiety, and psychosis are a frequent finding (Bonifati 2005;Ibáñez et al 2006;Steinlechner et al 2007).…”

Clinical features and neuroimaging of PARK7‐linked parkinsonism

“…9 In PARK6-linked parkinsonism, symptoms often reported in patients with early-onset autosomal-recessive parkinsonism, such as early dystonia and sleep benefit, were not observed. 10 We recently mapped a third locus (PARK7) in a consanguineous pedigree with early-onset autosomal recessive parkinsonism. 11 The PARK7 critical region lies on chromosome 1p36, and is clearly separated from PARK6 by 25 cM.…”