Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families

Istituto di Neurologia, Università Cattolica, Roma, Italy.
Movement Disorders (Impact Factor: 5.63). 12/2001; 16(6):999-1006.
Source: PubMed

ABSTRACT The clinical features of nine patients (three women and six men) affected by PARK6-linked parkinsonism, belonging to three unrelated Italian families, are reported. The occurrence of affected men and women within one generation suggested an autosomal recessive mode of inheritance in all three families. Mean age at disease onset was 36 +/- 4.6 years; all cases except one presented with asymmetrical signs, consisting of tremor and akinesia of one upper limb or unilateral short step gait. Affected individuals had a mean age of 57 +/- 8.5 years, and average disease duration was 21 +/- 7.8 years. Parkinsonian features included benign course, early onset of drug-induced dyskinesias, and a good and persistent response to levodopa. There were no other associated features (i.e., pyramidal or cerebellar signs, dysautonomia, or diurnal fluctuations unrelated to drug treatment). Cognition was unaffected. The clinical picture was remarkably similar in all patients; no relevant family-related differences were found. PARK6 disease is a new form of early-onset parkinsonism without other atypical clinical features.

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Available from: Anna Rita Bentivoglio, Aug 10, 2015
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    • "We used the PINK1 − / − mice model of PD to determine whether juvenile (P14–P21) motor cortex networks are hypersynchronized and typify the effect of parkinsonian treatments on this signature. The PINK1 − / − mice is a model of the autosomal recessive PARK6-linked Parkinsonism, an early-onset variant of familial PD caused by loss-of-function mutations in the mitochondrial protein PINK1 (Bentivoglio et al., 2001). PINK1 − / − mice show electrophysiological signs of dopaminergic dysfunction already at the age of 3–6 months and a reduction of locomotor activity 10 months later (Kitada et al., 2007; Dehorter et al., 2012). "
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    ABSTRACT: In Parkinson's disease (PD), cortical networks show enhanced synchronized activity but whether this precedes motor signs is unknown. We investigated this question in PINK1(-)/(-) mice, a genetic rodent model of the PARK6 variant of familial PD which shows impaired spontaneous locomotion at 16 months. We used two-photon calcium imaging and whole-cell patch clamp in slices from juvenile (P14-P21) wild-type or PINK1(-)/(-) mice. We designed a horizontal tilted cortico-subthalamic slice where the only connection between cortex and subthalamic nucleus (STN) is the hyperdirect cortico-subthalamic pathway. We report excessive correlation and synchronization in PINK1(-)/(-) M1 cortical networks 15 months before motor impairment. The percentage of correlated pairs of neurons and their strength of correlation were higher in the PINK1(-)/(-) M1 than in the wild type network and the synchronized network events involved a higher percentage of neurons. Both features were independent of thalamo-cortical pathways, insensitive to chronic levodopa treatment of pups, but totally reversed by antidromic invasion of M1 pyramidal neurons by axonal spikes evoked by high frequency stimulation (HFS) of the STN. Our study describes an early excess of synchronization in the PINK1(-)/(-) cortex and suggests a potential role of antidromic activation of cortical interneurons in network desynchronization. Such backward effect on interneurons activity may be of importance for HFS-induced network desynchronization.
    Frontiers in Systems Neuroscience 05/2014; 8:95. DOI:10.3389/fnsys.2014.00095
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    • "Among the 40 or more PINK1 mutations identified in symptomatic individuals, 15 segregate with disease in pedigrees of early onset Parkinsonism. Even though some of the clinical hallmarks of sporadic PD are observed in PD sufferers with PINK1 gene mutations, the underlying mechanism of pathogenesis appears to be a distinct form of familial neurodegeneration (Bentivoglio et al. 2001; Valente et al. 2001, 2004a,b). Atypical clinical features have been observed in PINK1 Parkinsonism, including psychiatric disturbances, dystonia at onset, and sleep benefit (Hatano et al. 2004; Valente et al. 2004a; Tan and Dawson 2006). "
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    ABSTRACT: Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism. To decipher the role of PINK1 in pathogenesis of Parkinson's disease (PD), researchers need to identify protein substrates of PINK1 kinase activity that govern neuronal survival, and establish whether aberrant regulation and inactivation of PINK1 contribute to both familial Parkinsonism and idiopathic PD. These studies should take into account the several unique structural and functional features of PINK1. First PINK1 is a rare example of a protein kinase with a predicted mitochondrial-targeting sequence and a possible resident mitochondrial function. Second, bioinformatic analysis reveals unique insert regions within the kinase domain that are potentially involved in regulation of kinase activity, substrate selectivity and stability of PINK1. Third, the C-terminal region contains functional motifs governing kinase activity and substrate selectivity. Fourth, accumulating evidence suggests that PINK1 interacts with other signaling proteins implicated in PD pathogenesis and mitochondrial dysfunction. The most prominent examples are the E3 ubiquitin ligase Parkin, the mitochondrial protease high temperature requirement serine protease 2 and the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1. How PINK1 may regulate these proteins to maintain neuronal survival is unclear. This review describes the unique structural features of PINK1 and their possible roles in governing mitochondrial import, processing, kinase activity, substrate selectivity and stability of PINK1. Based upon the findings of previous studies of PINK1 function in cell lines and animal models, we propose a model on the neuroprotective mechanism of PINK1. This model may serve as a conceptual framework for future investigation into the molecular basis of PD pathogenesis.
    Journal of Neurochemistry 05/2008; 105(1):18-33. DOI:10.1111/j.1471-4159.2008.05249.x · 4.24 Impact Factor
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    ABSTRACT: Im Mittelpunkt steht der genetische Hintergrund von Morbus Parkinson (MP), insbesondere der häufigen Late-Onset Form der Erkrankung. Eine Mutationsanalyse der Gene Parkin und PINK1 wurde in zwei großen europäischen MP Patientenkohorten durchgeführt. In einer deutschen MP Kohorte erfolgte eine Analyse des zuletzt beschriebenen Kandidatengens LRRK2. Im Parkin Gen wurden 3 verschiedene Mutationen (T240M, R402C und R256C) bei insgesamt 4 Late-Onset Patienten identifiziert. Die Analyse des LRRK2 Gens zeigte insgesamt 3 Patienten (2,5%) mit putativ pathogenen Mutationen (G2019S, A1151T), einschließlich der erstmals beschriebenen Mutation A1151T. Bei der Analyse des PINK1 Gens wurden keine pathogene Mutationen gefunden. Mit der vorliegenden Arbeit konnte gezeigt werden, dass ein - wenn auch kleiner - Anteil von Patienten mit MP Mutationen in den bisher bekannten Kandidatengenen Parkin und LRRK2 vorweist. Das PINK1 Gen scheint keine Rolle bei der Pathogenese der Late-Onset Form zu spielen.
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