PINK1 Mutations Are Associated with Sporadic Early-Onset Parkinsonism Enza Maria Valente, MD, PhD, 1 Sergio Salvi, BSc, 1 Tamara Ialongo, MD, 2 Roberta Marongiu, BSc, 1 Antonio Emanuele Elia, MD, 2 Viviana Caputo, BSc, 1,3 Luigi Romito, MD, 4 Alberto Albanese, MD, 2,4 Bruno Dallapiccola, MD, 1,3 and Anna Rita Bentivoglio, MD, PhD 2 We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype–phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37– 47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified. Ann Neurol 2004;56:336 –341 Parkinson’s disease (PD) is one of the commonest neu- rodegenerative diseases, with age-related prevalence reaching 2% in subjects older than 65 years of age. The clinical phenotypic core (resting tremor, rigidity, bradykinesia, and postural instability) is caused by stri- atal denervation consequent to massive loss of dopami- nergic neurons in the pars compacta of the substantia nigra. The identification of several genes responsible for mendelian forms of PD has brought important in- sights into the molecular mechanisms leading to neu- rodegeneration. Whereas dominant forms of PD are rare, autosomal recessive inheritance is relatively fre- quent especially among patients with early-onset par- kinsonism (EOP). 1 The phenotype of EOP can be in- distinguishable from sporadic, late-onset classic PD, yet peculiar features can be present, such as dystonia at on- set, hyperreflexia, psychiatric disturbances, and long- lasting excellent response to L-dopa with early occur- rence of L-dopa–induced dyskinesias. 2 The Parkin gene is estimated to be responsible for up to 50% of familial cases and 10 to 15% of sporadic cases of EOP. 3 Many distinct mutations have been re- ported in diverse ethnic groups, with a clear negative correlation between mutation frequency and age of on- set. 3–9 A second autosomal recessive gene, DJ-1, is less important than Parkin in terms of prevalence, because only eight mutations were identified in more than 500 patients with familial and sporadic EOP, with muta- tion frequency not exceeding 1%. 10 –15 In a considerable number of Parkin-positive and DJ- 1–positive cases, only a single mutation in heterozy- gous state could be found despite extensive mutation screening. Although the existence of a second undetec- ted mutation cannot be confidently ruled out, these findings suggest that haploinsufficiency of one of these genes could represent a risk factor to develop the dis- ease, possibly in conjunction with other, as yet uniden- tified genetic or environmental factors. We have recently identified PINK1, a third gene re- sponsible for autosomal recessive EOP in three consan- guineous families. 16 The clinical presentation in af- fected family members was closely overlapping that of From 1 IRCCS Casa Solliero della Sofferenza, Mendel Institute; 2 In- stitute of Neurology, Catholic University; 3 Department of Experi- mental Medicine and Pathology, La Sapienza University, Rome; and 4 National Neurologic Institute Carlo Besta, Milan, Italy. Received May 14, 2004, and in revised form Jul 29. Accepted for publication Jul 16, 2004. Published online Aug 31, 2004, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.20256 Address correspondence to Dr Valente, IRCCS CSS, Mendel Insti- tute, viale Regina Margherita 261, I-00198 Rome, Italy. E-mail: e.valente@css-mendel.it 336 © 2004 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services