Category: Parkinson's Disease: Genetics
Objective: To study the clinico-genetic profile of patients with genetically proven parkinsonism secondary to biallelic variants in PRKN gene (PARK-PRKN).
Background: PARK-PRKN is the most common recessively inherited PD worldwide and has clinical and pathological differences compared to idiopathic PD.
Method: Retrospective analysis of patients with PARK-PRKN from a single centre.
Results: Fifteen patients (10 males, 13 families) of PARK-PRKN were included. The median (range) age at onset (AAO) was 29 years (10-46), age at examination was 38 years (19-73), and duration of illness was 6 years (0.5-36) respectively. Early onset (21-49 years) was noted in 80% and juvenile onset in 20%. Consanguineous parentage was noted in 8/13 families and recessive family history in 6/13. Tremor (9 patients, 60%) was the most common symptom at onset followed by slowness (3, 20%), dystonia (2, 13.3%) and walking difficulty (1, 6.7%). Non-motor symptoms were noted in 10 patients (66.7%, historical RBD in 4). On examination, cognition was normal in all 9 patients who underwent cognitive assessment, 10 (66.7%) had dysarthria, 15 (100%) had parkinsonism, 14 (93.3%) had tremor, 9 (60%) had dystonia (leg in 5, LL>UL in 2, generalized in 2), 6 (40%) had hyperreflexia, 3 (20%) had extensor plantar, 6 (40%) had freezing and 8 (53.3%) had postural instability. These values are similar to the findings noted in MDSgene review on PARK-PRKN after excluding missing data (median AAO-31 years, parkinsonsim-100%, tremor-91.9%, dystonia-65.3%, dyskinesia-78.9%, hyperreflexia-49.1%, and postural instability-76.1%). The median (range) UPDRS-III OFF score (14 patients) was 37 (13-55), ON score (10 patients) 7 (3-32) with levodopa (LD) response of 74% (18-94). LD induced dyskinesia was noted in all 8 patients who received LD for more than 1 year. Sixteen pathogenic/likely pathogenic variants were identified through exome sequencing from 13 families [figure1]. Ten were exon deletions, 3 splice-site, 1 stop gain and 2 missense variants. Homozygous variants were identified in 10 families and compound heterozygous in 3. 5/6 single nucleotide variants were novel.
Conclusion: The study, a largest cohort of PARK-PRKN from India [3, 4], highlights the clinical and genetic spectrum of PARK-PRKN. Tremor and dystonia were frequent additional extrapyramidal signs. Truncating variants was seen in 85% (Exon deletion 69%) of the studied families.
References:  E.J. Vollstedt, S. Schaake, K. Lohmann, S. Padmanabhan, A. Brice, S. Lesage, C. Tesson, M. Vidailhet, I. Wurster, F. Hentati, Embracing Monogenic Parkinson’s Disease: The MJFF Global Genetic PD Cohort, Movement Disorders (2023).
 M. Kasten, C. Hartmann, J. Hampf, S. Schaake, A. Westenberger, E.J. Vollstedt, A. Balck, A. Domingo, F. Vulinovic, M. Dulovic, I. Zorn, H. Madoev, H. Zehnle, C.M. Lembeck, L. Schawe, J. Reginold, J. Huang, I.R. König, L. Bertram, C. Marras, K. Lohmann, C.M. Lill, C. Klein, Genotype-Phenotype Relations for the Parkinson’s Disease Genes Parkin, PINK1, DJ1: MDSGene Systematic Review, Mov Disord 33(5) (2018) 730-741.
 P.L. Kukkle, T.S. Geetha, R. Chaudhary, J.F. Sathirapongsasuti, V. Goyal, R.M. Kandadai, H. Kumar, R. Borgohain, A. Mukherjee, M. Oliver, M. Sunil, M.F.E. Mootor, S. Kapil, N. Mandloi, P.M. Wadia, R. Yadav, S. Desai, N. Kumar, A. Biswas, P.K. Pal, U.B. Muthane, S.K. Das, S.M. Sakthivel Murugan, A.S. Peterson, E.W. Stawiski, S. Seshagiri, R. Gupta, V.L. Ramprasad, P. Prai, Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson’s Disease Patients from India, Adv Biol (Weinh) 6(11) (2022) e2101326.
 S. Pandey, L.R. Tomar, S. Kumar, S. Dinesh, B.K. Thelma, Expanding the canvas of PRKN mutations in familial and early-onset Parkinson disease, Parkinsonism Relat Disord 66 (2019) 216-219.
To cite this abstract in AMA style:V. Holla, S. Kamath, P. Phulpagar, N. Kamble, B. Muthusamy, R. Yadav, P. Pal. Clinical and genetic profile of fifteen patients with PARK-PRKN: A largest single-center cohort from India. [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/clinical-and-genetic-profile-of-fifteen-patients-with-park-prkn-a-largest-single-center-cohort-from-india/. Accessed September 28, 2023.
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