Objective: (1) To identify the genetic basis of young-onset or familial Parkinson’s disease in South Africa; (2) to clinically characterize the phenotypes observed.

Background: Mutations in monogenic Parkinson’s disease (PD) genes only account for a small percentage of cases. Oligogenic inheritance is likely to be more common [1]. Mutations in the GBA gene, which causes the recessive lysosomal storage disorder (LSD) Gaucher’s disease, are the most common genetic risk factor for PD. Bi-allelic mutations in the Parkin gene cause recessive young-onset PD, whilst mono-allelic variants may increase PD risk.

Methods: Whole exome sequencing was conducted on 14 South African PD patients with a strong family history or an age-of-onset below 45 years. We report the clinical presentation of two Parkin heterozygotes that also carry a pathogenic mutation in a LSD gene.

Results: Pathogenic Parkin variants were identified in 2 patients. Patient 1 is heterozygous for Parkin p.R275W and GBA p.N370S. He had an age-of-onset of unilateral tremor at 18 years, which has progressed to severe bilateral tremor, mild rigidity and mild balance impairment over 33 years. He is of Afrikaner ancestry with no family history of PD. Patient 2 has heterozygous Parkin p.P437L, SNCAIP p.E709Q and a rare loss-of-function CLN5 p.W224X mutations. He has an age-of-onset of 55 years and a slow progression of akinetic-rigid PD over 12 years. He is of English South African ancestry. Multiple members of his family had PD and his sister had both young-onset PD and Charcot-Marie-Tooth neuropathy.

Conclusions: Clinically divergent phenotypes are observed in our heterozygous Parkin carriers which may be influenced by concomitant LSD pathology and other confounding PD-associated genes. Parkin ubiquitinates both mutant glucocerebrosidase and the α-synuclein interacting protein synphillin-1 (SNCAIP). CLN5 mutations cause neuronal ceroid lipofuscinosis, a rare recessive LSD. The CLN5 gene has not been linked to PD. However, both GBA and CLN5 mutations disrupt lysosomal function and ceramide synthesis pathways, which are linked to the pathology of Lewy body diseases [2]. While further work is needed to elucidate the cause of disease in these cases, multiple pathogenic mechanisms may underlie the PD pathology in these patients. References: 1. Escott-Price, V., et al. Ann. Neur. 77.4 (2015): 582-591. 2. Bras, J., et al. FEBS J. 275.23 (2008): 5767-5773.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-presentations-of-2-parkin-lysosomal-storage-disorder-heterozygotes-with-parkinsons-disease/