A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro‐Caribbean individual

Abstract

Background: SYNJ1 encodes Synaptojanin-1, a dual-function polyphosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy.Methods: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. Results:We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

“…To date, 34 patients originating from 20 families with biallelic SYNJ1 missense, nonsense, frameshift, or splicing mutations have been reported to constitute a heterogeneous multitude of phenotypes ranging from EOPD or atypical parkinsonism (13 families) up to severe epileptic encephalopathies without parkinsonism (seven families) [ 42 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 ].…”

“…Levodopa response was variable and a multitude of adverse effects including dyskinesia, dystonia, and postural hypotension have been reported. Among them, five families with various ethnicities carried the R258Q missense variant, which is therefore thought to be a possible mutational hotspot [ 42 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 ]. A single autoptic examination displayed neuronal loss in SN without LBD, neurofibrillary degeneration, and tau protein staining in cell bodies and axonal hillocks [ 212 ].…”