A Novel SYNJ1 Mutation in a Tunisian Family with Juvenile Parkinson’s Disease Associated with Epilepsy

Sawssan Ben Romdhan, Salma Sakka, Nouha Farhat, Siwar Triki, Mariem Dammak, Chokri Mhiri

Mutations in SYNJ1 gene have been described in few families with juvenile atypical Parkinson disease (PD). This gene encodes for "Synaptojanin 1," an enzyme playing a major role in the phosphorylation and the recycling of synaptic vesicles. In this study, we report two siblings, from a consanguineous Tunisian family, presenting juvenile PD. Both siblings developed mild Parkinsonism at 16 and 21 years old respectively. One patient had generalized tonic-clonic seizures since the age of 7 years. There was no evidence of sleep or autonomic dysfunctions and psychiatric disorders in both cases, but they developed a moderate cognitive impairment. They kept a good respond to low doses of levodopa treatment with no dyskinesia or motor fluctuations. We designed an NGS-based screening of 22 currently most prevalent parkinsonism-associated genes. Genetic study revealed a novel compound heterozygous mutation (p.Leu1406Phefs*42 and p.Lys1321Glu) in SYNJ1 gene. The p.Lys1321Glu mutation is located in the proline-rich domain and leads to a significant change in the 3D structure of the protein (RMS = 12.58 Å). The p.Leu1406Phefs*42 mutation disrupt the AP2 binding sites and subsequently disable synaptic and vesicle endocytic recycling in neurons. This is the first report of mutation in the C-terminal domain of Synaptojanin 1 protein causing mild juvenile PD with generalized seizures, cognitive impairment, and good respond to levodopa treatment.