Genotype-Phenotype Correlations in Parkinson Disease

Mutations in four autosomal dominant genes (α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), vacuolar protein sorting 35 (VPS35), and eukaryotic translation initiation factor 4-gamma 1 (EIF4G1)) and three recessive genes (parkin (PARK2/PRKN), phosphatase and tensin homolog-induced putative kinase1 (PINK1), and oncogene DJ1 (PARK7/DJ1)) are known to cause Parkinson disease (PD). This chapter describes the clinical and pathologic phenotypes associated with mutations in these genes. We systematically reviewed the phenotypes associated with all known pathogenic mutations in the dominant genes. SNCA point mutations and genomic multiplications cause a disorder with akinetic-rigid parkinsonism, dysautonomia, cognitive decline, myoclonus, and pronounced α-synuclein pathology. LRRK2 mutations cause tremor-dominant or akinetic-rigid parkinsonism with variable pathology. Our knowledge about the newly described genes VPS35 and EIF4G1 is still limited. Homozygous or compound heterozygous mutations in the recessive PD genes cause parkinsonism with an early or very early onset, but many different mutations are found in these genes and genotype-phenotype correlations are based on low numbers of patients per mutation. Homozygous mutations in acid β-glucosidase (GBA) may cause parkinsonism, usually in patients who have Gaucher disease, whereas heterozygous GBA mutations are genetic risk factors for PD. The monogenic forms of PD represent distinct subtypes of this heterogeneous disorder.