Objective: To report two cases and a clinical course of a young-onset Parkinson’s disease presumably caused by a duplication of 22q11.2 region.

Background: 22q11.2 duplication syndrome is a rare genetic disorder with variable clinical presentations, ranging from normal phenotype to intellectual disability and behavioral abnormalities. While 22q11.2 deletion syndrome and its phenotype are thoroughly described and may include, among other features, an early-onset Parkinson’s disease, there have been no reports on Parkinson’s disease in association with 22q11.2 duplication.

A 44-year-old male patient was referred to a neurologist with a history of bradykinesia and resting tremor in his right hand for 1 year. He had previously been diagnosed with moderate intellectual disability. His older brother had been diagnosed with an idiopathic Parkinson’s disease at the age of 48. His brother had a normal neurodevelopment.

Method: Next generation sequencing (NGS) using Illumina TruSight One Expanded Panel and a chromosomal microarray analysis were performed.

Results: The proband was identified with a pathogenic hemizygous mutation in RAB39B gene as well as 1.6 Mb duplication of 22q11.22 region. His brother was identified with a 22q11.22 duplication but no RAB39B mutation or other changes on NGS. The proband had rapid disease progression over the next 5 years, developing motor fluctuations which were somewhat alleviated by increasing levodopa dosage and adding dopamine agonist and opicapone, with a total levodopa equivalent daily dose (LEDD) of over 1600mg. His brother’s condition remained stable over the years with a total LEDD of 1000mg without motor fluctuations despite a longer disease duration.

Conclusion: RAB39B mutations are known to cause X-linked intellectual disability and early-onset Parkinson’s disease (Waisman syndrome, OMIM #311510). However, since only one of the brothers had the mutation in RAB39B, we suggest that 22q11.22 duplication might contribute to an early-onset Parkinson’s disease which was observed in both siblings. The more severe phenotype of the proband is probably caused by a concomitant mutation in RAB39B gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-clinical-spectrum-of-22q11-2-duplication-syndrome-a-5-year-follow-up-of-two-siblings-with-young-onset-parkinsons-disease/