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Parkin gene related neuronal multisystem disorder
  1. MWIM Horstink1,
  2. BPC van de Warrenburg1,
  3. M Lammens2,
  4. A Brice3
  1. 1Department of Neurology, University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  2. 2Department of Pathology, University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  3. 3Hôpital de la Salpetriére, Paris, France
  1. Correspondence to;
 Dr MWIM Horstink;
  1. Y Kuroda4,
  2. T Mitsui4
  1. 4The First Department of Internal Medicine, School of Medicine, University of Tokushima, 3–18–15 Kuramoto, Tokushima 770–8503, Japan

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    We read with much interest the article on Japanese patients with parkin gene related autosomal recessive juvenile parkinsonism (ARJP) complicated by cerebellar and pyramidal tract dysfunction.1 Recently, we described a Dutch family with parkin gene related ARJP showing typical levodopa responsive parkinsonism. The proband clinically had additional mild gait ataxia and pathologically showed—besides classic parkin gene related ARJP findings—neuronal loss in parts of the spinocerebellar system—namely, Purkinje cell layer, dentate nucleus, and gracile fascicles.2 Just as our Japanese colleagues, we suspected some kind of hereditary multiple system degeneration with predominant parkinsonism until genetic analysis indicated parkin gene related ARJP. Although the non-extrapyramidal abnormalities in the Japanese and in our patients could have been coincidental, the recent Japanese findings seem to confirm that the spinocerebellar and probably also other systems can be affected in parkin gene related ARJP. The fact that the Japanese patients did not respond to levodopa may have very important clinical consequences because it suggests that neurologists have to request an analysis of the parkin gene in patients with autosomal recessive levodopa non-responsive parkinsonism accompanied by a multisystem disorder.

    The authors found identical parkin gene mutations in two unrelated families—namely, deletions extending from exons 3 to 4. Although it is very striking that two unrelated Japanese families showed identical genetic abnormalities, the degeneration of non-extrapyramidal systems is not exclusively related to these particular genetic abnormalities because our compound heterozygous patients showed clearly different mutations—that is, a heterozygous transversion Lys211Asn in exon 6 and a heterozygous deletion of exon 3. Furthermore, as Kuroda et al1 remarked themselves, other patients with similar parkin gene mutations to Kuroda's patients did not show non-extrapyramidal abnormalities, so the genotype-phenotype relation in parkin gene related ARJP remains to be elucidated. However, taken together the findings of Kuroda et al1 and of our own, it seems very probable that the symptoms of parkin gene related ARJP are not necessarily restricted to parkinsonism but can also include signs and symptoms of a neuronal multisystem disorder.


    Authors' reply

    Since the first report of autosomal recessive juvenile parkinsonism (ARJP),1 it has been established as a clinical entity on the basis of age at onset (usually before the age of 40), clinical features and neuropathological findings. The clinical symptoms include homogeneous features such as typical signs of parkinsonism (rigidity, tremor, akinesia), foot dystonia, diurnal fluctuations, sleep benefit, hyperreflexia, a striking response to levodopa, and early susceptibility to levodopa induced dyskinesia.2,3 Levodopa responsive parkinsonism is recognised as one of the most important features of ARJP. However, in 1994 we reported on two Japanese patients from a family with autosomal recessive parkinsonism complicated with multiple system degeneration.4 The patients exhibited symptoms corresponding to cerebellar and pyramidal tract dysfunctions as well as nigrostriatal dysfunction, and the most prominent feature in the patients was parkinsonism not responsive to levodopa, indicating dysfunction in both nigral dopaminergic neurons and the striatum. The clinical features were sharply contrastive to those in patients with ARJP; however, an in frame deletion mutation of the parkin gene extending from exons 3 to 4 was unexpectedly detected in our patients. Furthermore, it is notable that the deletion of this region is not specific in the Japanese family and is occasionally found in patients with ARJP in Japan as well as in Europe,5 although parkin mRNA has been analyzed in only a few studies and it is not well known whether large deletions are in frame or out of frame.

    We are very interested in the study by van de Warrenburg et al showing that the spinocerebellar system was involved in a patient with parkin mutations who exhibited cerebellar ataxia, because ARJP has been neuropathologically characterised by selective degeneration without Lewy bodies in the substantia nigra compacta and locus ceruleus. Their observation is concordant with our assumption that the parkin protein potentially functions not only in the substantia nigra but also in extranigral regions. It seems unlikely that the non-extrapyramidal involvement in ARJP specifically depends on some mutations or deletions of the parkin gene, as Horstink et al suggested. Patients with parkin gene mutations, even those in single families, have generally shown a wide range of clinical signs.5 These findings suggest that additional factors contribute to the phenotype. Because patients with ARJP have been considered to exhibit homogeneous clinical symptoms, patients with atypical parkinsonism and/or with non-extrapyramidal symptoms have remained to be examined for parkin gene mutations. Further extensive study in these patients will revitalise the insights into pathophysiology of the parkin gene related disorder.