Objective: To describe and discuss genetic considerations regarding a kindred with PD cases with similar clinical characteristics, some with identified mutations in the LRRK2 gene and other siblings with negative results but with the same phenotype.

Background: PD due to LRRK2 gene mutations is a common cause of genetic PD. Its clinical phenotype can be relatively similar to idiopathic PD. Although it is inherited in an autosomal dominant way, it has a low penetrance.

Method: Analysis of clinical, imagiological and genetic data of a family with parkinsonism.

Results: A 68-year-old male presents with a predominantly akinetic-rigid syndrome since his 65 years, associated with REM sleep behavior disorder, substantial benefit with levodopa therapy and more recently with left lower limb dyskinesias. DaT-Scan showed an asymmetric deficit of dopamine presynaptic transporters in the striatum.  

He has a family history of no known consanguinity. His mother died at 92 years old and had upper limb “tremor” complaints, without a diagnosis of PD. He has 8 siblings, 4 with typical PD starting in their 60s. One sister with PD was initially tested for LRRK2 mutations and an heterozygous pathogenic variant c.6055G>A (p.Gly2019Ser) was detected. Another brother with PD underwent Sanger Sequencing for this variant and was positive as well. Our patient underwent the same test and was negative. Genetic testing was expanded through a Parkinson’s Disease Next Generation Sequencing (NGS) Panel (29 genes, including GBA) but was negative as well. The remaining siblings remain untested.

Conclusion: We present the case of a kindred with a high frequency of PD, in which a pathogenic variant in the LRRK2 gene was identified in all but one of the tested affected siblings, despite no discernable clinical differences. Also, no other genes frequently involved in genetic parkinsonian syndromes were identified in the negative. We could argue that it is purely a case of idiopathic PD, although it would be highly unlikely, given the family history. Also we cannot exclude the presence of other unknown genetic variants increasing PD risk. Another hypothesis is the possibility of mosaicism, even though limited, and to our knowledge never reported in the literature in LRRK2 cases. Testing through a mouth swab is underway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/caveats-regarding-a-family-with-pd-and-lrrk2-mutations/