There is a substantial lack of data describing the link between the genetic mutations identified as inheritable causes of Parkinson’s — those that affect the SNCA, LRRK2, and VPS35 genes — and patient symptoms, a review study has found.
Despite this missing information, the researchers conducting the review were still able to make some determinations, including findings indicating that SNCA mutation carriers are younger in age at disease onset and have additional psychiatric symptoms, while VPS35 mutation carriers have a good response to levodopa therapy.
The study, “Genotype‐phenotype relations for the Parkinson’s disease genes SNCA, LRRK2, VPS35: MDSGene systematic review,” was published in Movement Disorders.
Parkinson’s disease, the second most prevalent neurodegenerative disease in the elderly after Alzheimer’s disease, is a complex, multifactorial disorder characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits.
Previous studies have estimated that genetic factors may account for up to 34 percent of all Parkinson’s cases. More specifically, genetic mutations in the SNCA, LRRK2, and VPS35 autosomal genes (genes located on any chromosome other than sex chromosomes) are considered a cause of disease in up to 30 percent of all patients with Parkinson’s, depending on family history, age at onset, and population background.
“The International Parkinson and Movement Disorder Society Genetic mutation database (MDSGene) aims to systematically collect clinical and genetic information for movement disorder patients who have pathogenic mutations. In this study, we present a systematic MDSGene review and devote it to autosomal-dominant PD [Parkinson’s disease] across the three disorders, PARK-SNCA, PARK-LRRK2, and PARK-VPS35,” the researchers wrote.
The comprehensive, systematic review gathered information from 199 studies (54 on SNCA, 133 on LRRK2, and 12 on VPS35) involving a total of 937 patients (146 SNCA, 724 LRRK2, and 67 VPS35 mutation carriers) with inherited Parkinson’s disease attributed to 44 different mutations in these three genes.
“A major challenge for this systematic review was the degree of missingness of phenotypic [disease symptoms] data. Missing data not only affected non-motor signs and symptoms (NMS) of all patients, but specific information was even often unavailable for basic demographic information such as age at onset or sex or cardinal motor signs,” the authors said.
Despite the lack of data, the review managed to validate findings from previous studies showing that patients carrying mutations in the SNCA gene were more likely to develop Parkinson’s disease at an earlier age than those carrying mutations in LRRK2 and VPS35.
Pooled data also revealed that SNCA mutation carriers more frequently experienced psychiatric symptoms, while LRRK2 mutation carriers rarely had atypical symptoms of Parkinson’s disease. The researchers also found that VPS35 mutation carriers responded rather well to levodopa therapy.
“The most significant finding is the proportion of missing phenotypic data. … We propose to utilize MDSGene as the basis for the systematic collection of curated clinical and genetic information on inherited movement disorders as a solution to increase reporting of phenotypes for better genetic counseling and future gene-specific therapies,” the researchers wrote.
“To this end, the MDS Task Force on Genetic Nomenclature in Movement Disorders is drafting checklists that we propose should become the standard for clinical data reporting of individuals with movement disorders. Standard reporting of core features could improve the situation considerably,” they concluded.