Objective: To report a clinicopathological case of digenic PD with R1441G- LRRK2 and PRKN mutations.

Background: Digenic inheritance of R1441G-LRRK2 and PRKN mutation is extremely rare. Separately, both mutations typically confer a similar PD phenotype (tremor onset, good response to LD and a non-aggressive course), but generally differ in the age at onset (AAO) (≈63 and ≈ 34 years, respectively). Neuropathological findings are also similar with absence of Lewy bodies (LBs) as a hallmark in most cases. Only a few clinical cases with double-mutation R1441G-LRRK2 and PRKN have previously been reported and findings have been controversial. Although a synergistic effect has been suggested, none of the cases presented with an earlier AAO or faster disease progression. To our knowledge this is the first reported case with clinical, genetical and neuropathological correlation of PD associated with the double-mutation R1441G-LRRK2 and PRKN.

Method: Clinical assessment, genetical and neuropathological studies.

Results: A 44-year-old man originally from Gipuzkoa (Basque Country, Spain) presented with right leg tremor. On examination, he only exhibited mild rest tremor in the lower right limb. Tremor dominant PD (H&Y1) was diagnosed and LD was started, with a dramatic and maintained response. His mother and a brother of his mother had a clinically similar form of PD, at the age of 45 and 57 respectively. The former was not genetically tested and the latter carried the R1441G-LRRK2 mutation. Genetic analysis in the proband showed a deletion of exons 3 to 12 in heterozygosis (Del(X3-X12)) in PRKN gene and R1441G mutation in heterozygosis in exon 31 in LRRK2 gene. Parkinsonism showed a slow and benign progression. Except for a mild depression, the patient did not exhibit other NMS. Mild motor fluctuations and foot dystonia appeared 10 years after disease onset. He died at 69 due to a cerebral intravascular lymphoma. The neuropathological study disclosed severe neuronal loss in the SNpc with only a few isolated a-synuclein inclusions, but LBs and Lewy neurites were absent.

Conclusion: Digenic R1441G-LRRK2 and PRKN mutations in PD showed neuronal loss without LBs in SNpc and a benign clinical course. Comparing to single R1441G-LRRK2 or PRKN mutation carriers, there were no significant variations regarding AAO or severity of disease. Further studies are needed to elucidate a possible synergistic effect of both mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/digenic-r1441g-lrrk2-and-parkin-mutations-in-parkinsons-disease-first-clinicopathological-case-report/