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Parkin mutations and early onset parkinsonism

Karen E. Morrison
DOI: http://dx.doi.org/10.1093/brain/awg189 1250-1251 First published online: 1 June 2003

Several recent articles have considered novel therapies in Parkinson’s disease, ranging from controlled trials of cell transplantation techniques in patients through to experimental treatments with iron chelation therapy in animal models of the disease. Alongside such reports are frequent papers on the genetics of Parkinson’s disease, the disorder once considered to be a key example of a ‘non‐genetic disease’. This issue of Brain is no exception, containing two reports on parkin mutations in early onset parkinsonism.

Mutations in parkin were first identified in 1998, in Japanese patients with autosomal recessive juvenile parkinsonism (Kitada et al., 1998). Subsequently parkin mutations were detected in cases of autosomal recessive early onset (<45 years) parkinsonism, in isolated young onset cases presenting as fairly typical Parkinson’s disease and in familial cases with an age at onset of symptoms as late as 64 years (Abbas et al., 1999; Lucking et al., 2000; Klein et al., 2000). The paper by Khan et al. (2003) in this issue of Brain builds on this literature by providing detailed clinical information on 24 cases of parkin related Parkinson’s disease. These 24 cases were identified following screening of 115 cases with age at onset <50 years or ‘unusual features’. As with previous reports, mutations were identified in several exons, with the same mutation identified in seemingly isolated and familial cases. Mutations in both parkin alleles were seen in 14 cases, while only a single mutant allele was identified in the remaining 10 cases. The ethnic origin of the cases was wide, including patients of Japanese, Indian and European origin.

The key clinical features of parkin disease were broadly comparable to those previously described, including age at onset <40 years, foot dystonia, psychiatric symptoms, dramatic response to treatment and dose dependent motor and psychiatric complications of drug therapy. Three new phenotypes at presentation were reported: cervical dystonia, autonomic dysfunction and peripheral neuropathy, and pure exercise‐induced dystonia. As with other single gene disorders, clinical heterogeneity was evident, both between and within families sharing the same mutation. One interesting observation was that behavioural disorders such as anorexia nervosa, self‐harm and suicide attempts affected one‐quarter of the patients. The authors also emphasize the slow progression of clinical parkinsonism in parkin disease, even in the case of one particular parkin patient with a highly abnormal [18F]dopa PET scan .

The paper by Periquet et al. (2003) also in this issue, approaches the subject area from a different angle, considering 145 cases of isolated early onset (<45 years) cases of parkinsonism, and then screening to identify parkin mutations. It is not clear if any of the cases screened and described here are duplicated in the Khan et al. study. They report comparable results, identifying parkin mutations in 20 patients. Combining this data with their previous publication (Lucking et al., 2000), 15% (38 of 246) of early onset cases without family history screened harbour parkin mutations, with a negative correlation between age at onset and the presence of mutations. It is of interest that they did not identify parkin mutations in any of the eight patients with consanguinity. As in the study by Kahn et al., they also identified two mutations in parkin in roughly half of their cases, while detecting only a single mutation in the others. Again, parkin mutations were found in diverse ethnic groups (including Brazilian and North African cases) with similar relative frequency in different races.

In contrast to Khan et al. they could not identify any clear clinical differences between those with and without parkin mutations. Many of the features listed in Table 5 of Kahn et al. as ‘Key features of parkin disease’ were seen as frequently in those young onset Parkinson’s disease cases without parkin mutations. Do some of these ‘key features’ merely represent features of young onset disease? One bears in mind that the two studies considered different groups of patients: Periquet et al. investigated only isolated cases, whereas more than half of the cases studied by Kahn et al. were familial, with more than one affected individual from each family reported. Periquet et al. also do not give clinical details such as response to anticholinergics, behavioural disturbances or autonomic symptoms. It is interesting that while an ‘excellent response to l‐dopa’ is listed as a key feature in Khan et al., there was no difference in the daily dose of l‐dopa between cases with and without parkin mutations in the report by Periquet et al., nor were differences seen in the incidence of l‐dopa induced dyskinesias, fluctuations or dystonia.

In a further recent paper, the French Parkinson’s disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s disease report finding parkin mutations in 10 of 30 families screened with early onset autosomal recessive parkinsonism (Rawal et al., 2003). Although the sample size was small, there was a trend for earlier disease onset and slower progression in patients with parkin mutations. It is again stated in this paper that no individual clinical signs were found to help distinguish parkin mutation disease from other forms of early onset parkinsonism, although few clinical details of the cases are given.

In summary, it is clear from both reports in the current issue of Brain that parkin mutations are found in a substantial number of young onset Parkinson’s disease cases (‘15% of all isolated Parkinson’s disease cases with age at onset <45 years’). Mutations are found in only a single parkin allele in ∼50% of cases, suggesting that undetected intronic or promoter mutations are occurring or that other, as yet unidentified, genetic susceptibility factors are also important. Although one study lists ‘Key features of parkin related disease’ many of these features were found similarly in young onset Parkinson’s disease cases without parkin mutations in the other report. Finally, both studies detail cases with parkin mutations showing atypical features.

So what of the biology of parkin? Parkin is an E3 ubiquitin‐protein ligase that targets specific substrates for degradation via the ubiquitin‐proteasome pathway (Shimura et al., 2000). One of its substrates is a glycoslyated form of α‐synuclein, perhaps providing a link between parkin and idiopathic Parkinson’s disease (Hardy et al., 2003). Neuropathological examination has only been reported in a few parkin mutation cases and in only one were typical Lewy bodies detected in the substantia nigra and locus coeruleus (Farrer et al., 2001). Hardy et al. (2003) have recently speculated on a possible mechanism underlying the reported absence of typical highly ubiquitinated Lewy bodies in parkin disease. They suggest that complete loss of function of parkin, such as might occur due to deletion of an allele, leads to cell death in the absence of Lewy body formation, whereas incomplete loss of function of parkin, such as may occur due to point mutations in the gene, may result in parkinsonism with Lewy body formation. Further pathological studies of patients with parkin mutations are needed to see if this attractive hypothesis bears out.

To date nine loci (with four genes) for Parkinson’s disease have been reported and mutations in other genes that result in a parkinsonian phenotype, e.g. tau, ataxin‐2 and ataxin‐3, have been described (Hardy et al., 2003). The identification of loci, and then disease causing gene mutations, is the first step. Much further work is now required to define the function of the normal and abnormal gene products, to then translate understanding of disease pathogenesis into effective therapy. Unravelling the basis of discrete entities within the whole spectrum of parkinsonism, such as determining the clinical and genetic features of parkin mutations in young onset parkinsonism cases presented in this issue, is but one step along this path.

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