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.
Keywords: Autosomal recessive; Epilepsy; Juvenile Parkinson’s disease; SYNJ1 gene; Tonic-clonic.