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Arch Neurol. 2006 Jun;63(6):833-8.

Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit?

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1
Department of Neurology, University of Lübeck, Germany.

Abstract

BACKGROUND:

Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear.

OBJECTIVE:

To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W).

DESIGN:

Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating.

SETTINGS:

University of Lübeck.

PARTICIPANTS:

Twenty family members.

MAIN OUTCOME MEASURES:

The PINK1 genotype and PD status of all family members.

RESULTS:

The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers.

CONCLUSIONS:

Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.

PMID:
16769864
DOI:
10.1001/archneur.63.6.833
[Indexed for MEDLINE]
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