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.
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.
Authors: Anne Grünewald; Guido J Breedveld; Katja Lohmann-Hedrich; Christan F Rohé; Inke R König; Johann Hagenah; Nicola Vanacore; Giuseppe Meco; Angelo Antonini; Stefano Goldwurm; Suzanne Lesage; Alexandra Dürr; Ferdinand Binkofski; Hartwig Siebner; Alexander Münchau; Alexis Brice; Ben A Oostra; Christine Klein; Vincenzo Bonifati Journal: Neurogenetics Date: 2007-01-12 Impact factor: 2.660
Authors: Mirta Fiorio; Enza Maria Valente; Mattia Gambarin; Anna Rita Bentivoglio; Tamara Ialongo; Alberto Albanese; Paolo Barone; Maria Teresa Pellecchia; Francesco Brancati; Giuseppe Moretto; Antonio Fiaschi; Michele Tinazzi Journal: J Neurol Date: 2008-07-03 Impact factor: 4.849
Authors: Jung Mi Choi; Myoung Soo Woo; Hyeo-Il Ma; Suk Yun Kang; Young-Hee Sung; Seok Woo Yong; Sun Ju Chung; Joong-Seok Kim; Hae-won Shin; Chul Hyoung Lyoo; Phil Hyu Lee; Jong Sam Baik; Sang-Jin Kim; Mee Young Park; Young Ho Sohn; Jin-Ho Kim; Jae Woo Kim; Myung Sik Lee; Myoung Chong Lee; Dong-Hyun Kim; Yun Joong Kim Journal: Neurogenetics Date: 2008-08-15 Impact factor: 2.660