Early Onset Parkinson’s Disease and Mutations in the Parkin Gene
August 1, 2000 3 minutes read
Early Onset Parkinson’s Disease and Mutations in the Parkin Gene
Abstract & Commentary
Source: Lucking CB, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560-1567.
The last five years have witnessed major advances in understanding the genetics of Parkinson’s disease (PD). Four genetic loci have been linked to autosomal dominant PD and two genes have been discovered—a-synuclein and ubiquitin carboxy-terminal hydrolase L1. Nevertheless, the vast majority of patients who present with PD do not have a family history of autosomal dominant inheritance.
Family members of patients with PD often ask the treating neurologist to comment on their risk of developing the disorder. Facts indicate such. An increased risk of PD among first-degree relatives of affected patients exists, and the risk increases with the number of diseased family members. Lack of an autosomal dominant inheritance, however, does not ensure that a patient does not have a genetic form of PD. Recently, mutations in a gene called parkin have been reported in several families with autosomal recessive PD. Affected persons have been reported in a variety of ethnic groups. Their clinical and pathologic profiles are similar to those of idiopathic PD, with dopa-responsive parkinsonism accompanied with selective loss of dopaminergic neurons in the substantia nigra and locus ceruleus. Unlike idiopathic PD, however, Lewy bodies are absent.
Lucking and associates report a colossal effort by a consortium of European investigators to determine the relative role of parkin mutations in patients with early PD. Seventy-three families with autosomal recessive levodopa-responsive PD with onset before the age of 45 were studied. Families originated from Italy, France, England, the Netherlands, Germany, Portugal, Spain, North Africa, and Vietnam. One hundred patients with sporadic PD beginning before age 45 were studied as controls. Patients were examined and had their blood drawn to screen for point mutations, deletions, and rearrangements in the parkin gene.
Mutations in the parkin gene were found in 36 of the 73 families with autosomal recessive PD. Among the 100 patients with sporadic early-onset PD, 18 had mutations in parkin. Compared to patients with sporadic PD, parkin patients had an earlier age of onset (32 vs 42 years) along with an equal male to female ratio, and more commonly presented with lower extremity dystonia, hyperreflexia, and symmetrical rigidity. They responded excellently to levodopa, but frequently developed dyskinesias within five years of starting the drug. While most patients with parkin mutations developed the disease in their early 30s, their age ranged widely from 7 to 58 years. Genetic analysis of the parkin gene revealed a high proportion of rearrangements in exons 2, 3, and 4, implying that these regions of the protein may be particularly important.
Commentary
This study answers several important questions facing neurologists and their patients. The lack of a known family history of PD does not exclude the possibility that an individual may have genetic Parkinson’s, especially when symptoms begin before the fourth decade. Among rare families with autosomal recessive parkinsonism, parkin mutations are surprisingly frequent. In the long run, they may be responsible for the majority of these cases. Patients with parkin mutations are too similar to idiopathic PD patients to be distinguished on clinical grounds alone, although the presence of hyperreflexia or lower extremity dystonia may help. Finally, patients who are diagnosed with parkin mutations can be reassured that their illness, while progressive, usually proceeds extremely slowly and is responsive to treatment with levodopa. —steven frucht
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