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[1].

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[2] 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: [1] 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).
[2] 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.
[3] 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.
[4] 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.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-profile-of-fifteen-patients-with-park-prkn-a-largest-single-center-cohort-from-india/