Objective: We report two siblings from a Tunisian family with juvenile Parkinsonism associated with tonic-clonic seizures and good response to levodopa therapy carrying a novel compound heterozygous mutation in SYNJ1 gene.

Background: SYNJ1 gene is located on chromosome21 encodes for the synaptojanin1, a polyphosphoinositide phosphatase concentrated at the synapse, required for clathrin-coated pit and synaptic vesicle dynamics. Until now, ten early-onset atypical Parkinson disease patients with SYNJ1 mutations from five families with two affected siblings each were identified in Iran, Italy, silicy, Indian and German respectively.

Methods: Patients were screened for 23 PD-related genes by target sequencing: ATP13A2, DCTN1, DNAJC13, DNAJC6, SPG11, EIF4G1, POLG, FBXO7, GBA, GCH1, LRRK2, PANK2, PARK2, DJ-1, PINK1, PLA2G6, POLG, SNCA, VPS35, TH, UCHL1, VPS13C and SYNJ. We designed a complete set of probes for NGS target enrichment using NimbleDesign1 software. The custom Design KAPPA Library Preparation Kit (Roche) was used to hybridize and double capture all exons, intron–exon boundaries, 5′- and 3′-UTR sequences of the corresponding DNA sequences of index cases. Multiplexed-DNA sample library pools were directly sequenced in the MiSeqIlluminasequencer.

Results: Two siblings from a consanguineous Tunisian family had presented to our neurology department with an early-onset parkinsonism: The first patient, a 23YO man, had generalized tonic-clonic seizures since the age of 7years. He consulted at the age of 16years for dizziness and motor dysfunction of the right arm, hypomimia, generalized bradykinesia and mild dystonic posturing of the left arm. His sister, 28YO women, without any medical history, consulted at the age of 21years for a unilateral rest tremor of her right arm associated with rigidity, a slow shuffling, unsteady gait, global rigidity, axial stiffness and vertical gaze palsy. The two siblings had a normal Brain MRI and appropriate testing excluded other causes of Parkinsonism. Their symptoms responded well to dopamine agonist. Molecular analysis revealed that both PD patients carried a novel compound heterozygous mutation C-terminal SYNJ1 gene (p. Leu1406Phefs*42 and Leu1406*).

Conclusions: We confirm the implication of C-terminal SYNJ1 gene mutation in autosomal recessive juvenile parkinsonism with generalized seizures. We also suggest that compound heterozygous mutations in SYNJ1 gene are more likely to cause milder phenotype with good response to levodopa therapy and lower progression especially in late age.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-onset-parkinsonism-and-epilepsy-a-tunisian-family-carrying-a-novel-synj1-mutation/