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BRIEF COMMUNICATIONS: N. L. Khan, C. Scherfler, E. Graham, K. P. Bhatia, N. Quinn, A. J. Lees, D. J. Brooks, N. W. Wood, and P. Piccini Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation Neurology 2005; 64: 134-136 [Abstract] [Full text] [PDF]

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Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation

Rivka Inzelberg, Rivka Inzelberg, Nobutaka Hattori, Yoshikuni Mizuno   (7 June 2005)

Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation 7 June 2005
Rivka Inzelberg, Hilllel Yaffe Medical Center Department of Neurology, Hillel Yaffe Medical Center, Hadera, 38100, Israel, Rivka Inzelberg, Nobutaka Hattori, Yoshikuni Mizuno Send Correspondence to journal: Re: Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation irivka{at}tx.technion.ac.il Rivka Inzelberg, et al.	We read with interest the article by Khan et al. [1] The authors studied asymptomatic parkin heterozygotes by 18F-dopa PET and found a significant reduction of uptake in putamen, caudate, dorsal and ventral midbrain. An interesting observation relates to the subtle extrapyramidal symptoms in four of these “asymptomatic” carriers. The authors recommended follow-up to verify whether they develop parkin disease. One of our patients with a single parkin mutation developed parkin disease 23 years after the manifestation of tremor as the only symptom. This 56 year-old man is the only child of non- consanguineous parents of European Jewish origin. At age 13, left hand tremor was noticed. Tremor severity remained unchanged for 23 years (without treatment), until the age of 36, when he experienced prominent rest tremor and bradykinesia of the left limbs. Five years later, L-dopa was initiated with excellent response. Dyskinesias occurred 3 years after L-dopa onset, necessitating a left pallidotomy 18 years later. Brain MRI was normal. Genetic testing revealed a heterozygous C to T transition at nucleotide position 1197 of parkin gene (exon 10). Parkin disease presents as slowly progressive parkinsonism. [2,3] Even if significant dopaminergic dysfunction appears in PET studies of single parkin mutation carriers, other mechanisms and the amount of intact dopamine store at a young age might be compensatory to prevent early clinical expression. [1] However, this explanation may only relate to some patients. Others might develop parkin disease earlier, as occurred in another of our sporadic patients who carries a single parkin mutation. This 36 year-old woman is the only child of non- consanguineous parents of European Jewish origin. At the age of 31, she experienced left foot dystonia, slowing of her left hand accompanied with rest tremor, which later progressed to bilateral parkinsonism. Response to L-dopa given 5 years after disease onset, was excellent. Brain MRI was normal. A heterozygous deletion of exon 7 of parkin was found. [4] Haploinsufficiency (reduction in normal protein function) and dominant negative effects (nonfunctional polypeptide physically interferes with normal protein) proposed as causes of dopaminergic cell dysfunction [1] or the inhibition of parkin’s ubiquitin 3 ligase activity by S- nitrosylation [5] are probably not the only explanations. Other genetic or environmental factors might predispose carriers of a single parkin mutation not only for late-onset but also for young-onset PD. We have no conflicts of interest. References 1) Khan NL, Scherfler C, Graham E, et al. Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 2005;64:134-136. 2) Nisipeanu P, Inzelberg R, Abo Mouch S, et al. Parkin gene causing benign autosomal recessive juvenile parkinsonsim. Neurology 2001;56:1573- 1576. 3) Inzelberg R, Hattori N, Nisipeanu P, et al. Camptocormia, axial dystonia, and parkinsonism: phenotypic heterogeneity of a parkin mutation. Neurology 2003;60: 1393-1394. 4) Inzelberg R, Nisipeanu P, Carasso RL, Blumen SC, Hattori N, Mizuno Y. Early-onset parkinsonism in heterozygous parkin mutation carriers. Ann Neurol 2004; 56, Suppl 8, S28. 5) Choung KKK,Thomas B, Li X, et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 2004; 304: 1328-1331. The authors had the opportunity to respond to this Correspondence but declined.