Parkin disease: a phenotypic study of a large case series

Abstract

Mutations in the parkin gene, PARK2, are a common cause of parkinsonism in familial as well as isolated cases with an age of onset <40 years and should be considered in the diagnostic work up of young-onset parkinsonism. We report a detailed clinical evaluation of a personal series of 24 patients with mutations in the parkin gene. The clinical presentation of most cases was broadly comparable to that of previous descriptions of autosomal recessive early-onset or juvenile parkinsonism and young-onset Parkinson's disease and also had similarities with phenotypes of dopa-responsive dystonia. However, our only case with consanguineous parents had an age of onset of 54 years. We report three new phenotypes at presentation: cervical dystonia; autonomic dysfunction and peripheral neuropathy; and pure exercise-induced dystonia. We emphasize a number of clinical features that can be seen in parkin disease: focal dystonia; early instability; freezing; festination or retropulsion; concurrent autonomic failure; dramatic response to anticholinergics; early or atypical L-dopa-induced dyskinesias; exquisite sensitivity to small doses of L-dopa; and recurrent psychosis, even taking L-dopa alone. We also report behavioural disorder prior to the onset of parkinsonism. Some relatives carrying a single parkin mutation without extrapyramidal symptoms or signs also had psychiatric symptoms that might be related to their carrier status.

Clinical and molecular neuroimaging characteristics of Brazilian patients with Parkinson's disease and mutations in PARK2 or PARK8 genes

“…While many patients have family history of PD, as seen in our study, sporadic cases have been also reported developing at the age of 40 years [12][13][14] . Their clinical presentation can be similar to idiopathic PD but they remarkably have dystonia in lower limbs, which was not seen in our group.…”

“…The gene locus for this form of parkinsonism was mapped in 6q25.2-27 chromosome 12 . PARK2 patients develop EOPD around the age of 20-30 and show distinct clinical characteristics compared to idiopathic PD (slow progress, dystonia at onset involving lower limbs, and dyskinesia after low-dose L-DOPA) 13 . Interestingly, pathologically, these patients do not have Lewy bodies 12 .…”

“…Their clinical presentation can be similar to idiopathic PD but they remarkably have dystonia in lower limbs, which was not seen in our group. Disease progression is often slower than in idiopathic PD but they tend to develop early-onset dyskinesia after low-dose L-DOPA [12][13][14] . The rate of dyskinesia (66%) found in our study is more characteristically seen in LOPD patients.…”

N-myc Regulates Parkin Expression

“…Another gene down-regulated by N-myc with a similar expression profile to parkin, NDRG1 (N-myc down-regulated gene 1), is involved in growth arrest and cell differentiation and is mutated in hereditary motor and sensory neuropathy-Lom (27). The involvement of autosomal-recessive loss of function mutations in NDRG1 in human peripheral neuropathy may be all the more relevant to parkin-linked disease, in that loss-offunction parkin mutations have also been identified in human patients with peripheral and sensory neuropathy (28,29). It is conceivable that the mechanisms of neurodegeneration resulting from mutations in the parkin or NDRG1 gene overlap, at least in the peripheral nervous system.…”

Parkin-deficient mice are not a robust model of parkinsonism

“…The age-related and progressive signs of PD classically include resting tremor, muscular rigidity, abnormal gait, and slow movement; however, other signs and symptoms associated with parkinsonism can include somatosensory deficits, impaired cognitive function, and psychiatric disturbances (2)(3)(4). Many PD signs result from the degeneration of dopaminergic neurons in the substantia nigra pars compacta.…”