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Aim:
To report the clinical variability of the affected sisters and to discuss the role of heterozygous gene mutation carriers in a family with autosomal recessive parkinsonism due to compound heterozygous mutation in the parkin gene (PARK 2).
Case Presentations:
Case 1: This 32 year old woman reported a three years history of progressive bilateral tremor of the hands. She presented with a jerky tremor of both hands resembling myoclonus-dystonia phenotype. There were no clear cut signs of parkinsonism, normal gait and full eye movements. The Levodopa challenge test (200mg) was negative. She reported gait problems in her younger sister (case2).
Case 2: This 23 years old sister reported a 4 years history of progressive gait problems. The clinical examination revealed dystonia with tremor and bradykinesia pronounced on the left side with worsening of leg dystonia when walking.
Further investigations showed a negative Levodopa challenge test (200mg), severe bilateral pre-synaptic dopaminergic deficit in the DaTSCANTM, confirming degenerative parkinsonism. As she presented with the most characteristic picture of a PARK-2- associated parkinsonism genetic testing was performed and revealed a compound heterozygous mutation in the PARK-2 Gene: A point-mutation c.714C>G; pC238W and a deletion in Exon 3.
Case 3: At the age of 45 the father of case 1 + 2 developed tremor in his left arm with only mild progression over the past years. At the age of 62 he presents with mild left sided parkinsonism with tremor and bradykinesia. He is likely either to be the carrier of the deletion or the point mutation.
Discussion:
Some points in this family with PARKIN disease are interesting and merit attention:
- Dystonia is a common symptom in PARKIN disease but the myoclonus-dystonia phenotype of the older sister is unusual. The clue to the diagnosis was the younger sister, who presented with a more classical young onset PD.
- Even though PARKIN disease is known to have an excellent response to Levodopa, the Levodopa challenge test was negative in both sisters. This underlines the lack of sensitivity of this test.
- It is an on-going discussion whether heterozygous carriers of one parkin mutation develop subtle parkinsonism. Case 3 presented here is a good example favouring this hypothesis. Further support comes from a F-Dopa PET study in parkin gene mutation carriers, which showed that in these cases mean striatal uptake is lower than in healthy controls. [Khan et al]