Objective: To study the phenotype and subtypes of familial Parkinson’s disease (PD) in Ireland, establish the genetic background in a cohort of Irish PD patients and to identify pedigrees without known PD genes mutations for identification of novel PD genes (linkage analysis and next generation sequencing-NGS).

Background: 10 % of PD patients have a PD family history. Familial studies have led to the identification of causative gene mutations at 7 chromosome loci in either autosomal dominant (SNCA, LRRK2, VPS 35), or recessive (Parkin, DJ1, PINK1, ATP13A2) fashion.

Methods: We expanded upon a 12-year familial PD study (Gosal D, Wiley J, McCarthy A) and identified a further 158 familial cases. 98 of the 158 patients were partially studied previously (McCarthy A, Ross O) including detailed genetic testing of the known PD genes. We identified 3 Parkin positive patients among the 98 patients. 85% of pedigrees have autosomal dominant inheritance pattern. 60 new probands have been recruited and we expanded the promising pedigrees in 6 of the original 98 families and 16 of the 60 new families using a family study method.

Results: In 98 genetically-tested families we failed to find any LRRK2 mutations. We are doing genetic analysis of the 60 new probands at present. One kindred has 6 affected members with PD (3 were assessed). In analysis of the 60 new pedigrees male to female ratio was 1.6, mean age of PD onset was 55.2 (range 29-79). Young onset PD (<age 50) occurred in 26.6% (16/60). Mean disease duration from the symptom onset up to our assessment was 7.78 years (1-31). Average motor UPDRS was 21. 70% of patients had tremor-predominant disease, 26.6% had postural instability and gait disorder and 3.33% mixed disease. We identified 2 families with overlapping PD/ET. PD dementia (MOCA<21) occurred in 8.3%, cognitive impairment (MOCA <26) in additional 20% and hallucinations in 10%. Motor complications occurred in 48% of patients (wearing off in 23.5%, dyskinesia in 21.6%, freezing of gait in 18.3%, all 3 in 8.3%, wearing off with freezing episodes in 1.6%, wearing off and dyskinesia in 1.6%) and falls in 28.3%.

Conclusions: Familial PD is common. We identified 3 Parkin mutations but surprisingly we did not find any LRRK2 mutations among the 98 pedigrees. LRRK2 mutations frequency varies geographically and is uncommon in Ireland. We will perform NGS to identify new PD genes in the expanded pedigrees.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/familial-parkinsons-disease-in-ireland/