Mutations of GBA(Glucocerebrosidase) and ATP13A2(P5-ATPase) genes are risk factors for Parkinson’s disease (PD). Homozygous mutations of these genes cause rare, early onset disorders: Gaucher disease (GD) and Kufor-Rakeb syndrome (KRS), respectively. We describe a patient with young onset PD and heterozygous mutations of these genes. 

A 28 year-old woman of Ashkenazi Jewish (AJ) ancestry developed left hand tremor at age 23 and was diagnosed with PD. DaTScan was consistent with the diagnosis. Brain MRI was normal. Levodopa response was satisfactory, but she soon developed motor fluctuations and dyskinesia. Early age of onset, despite a negative family history, prompted genetic testing. 

Metabolic/neurological genetic panel for disorders common in AJ population and a PD panel (testing for ATP13A2, DCTN1, DNAJC6, FBXO7, GCH1, LRRK2, PARK1, PARK7, PINK1, PRKR1, SLC6A3, SNCA, SPR, TH, VPS35) showed heterozygous pathogenic mutations of the GBA (p.Asn409Ser) and the ATP13A2(p.Tyr1020Thrfs*3) genes. Review of the literature confirmed that the age of onset of our patient was earlier compared to the average age of onset of heterozygous carriers of GBA and ATP13A2 mutations. 

A growing number of pathogenic genetic mutations have been identified in familial and sporadic forms of PD, some of which only represent risk factors, such as GBA and ATP13A2. Both these genes are important for membrane trafficking and for the endo-lysosomal compartment. In has been reported that in patients with PD there is an increase frequency of mutations in lysosomal genes (Roback et al., 2017). We suspect the ‘double hit’ to the same metabolic pathway is responsible for the phenotype of our patient. Screening for multiple genetic mutations should be considered, especially in early onset PD, to improve the understanding of pathogenic mechanisms of these forms, for a better description of phenotype-genotype correlations, and for genetic counseling implications.