👤 Eduardo E Benarroch

To report a clinical series of four patients diagnosed with early-onset Parkinson's disease (EOPD) who exhibit heterozygous pathogenic variants in the VPS13C gene. VPS13C encodes vacuolar protein sorting 13C, a lipid transport protein that localizes between the endoplasmic reticulum and endosomes-lysosomes, functioning as a bridge to allow phospholipids to traverse the cytosol. Mutations in this gene have been associated with early-onset PARK23 and dementia with Lewy bodies (DLB), highlighting its importance in mitochondrial and lysosomal homeostasis. Cases were identified through the Mayo Clinic Data Explorer. We included all subjects with a clinical diagnosis of PD who tested positive for a heterozygous VPS13C variant defined as pathogenic by the ACMG guidelines. DaT-SCAN imaging was consistent with PD diagnosis in three patients. Non-motor symptoms and cognitive impairment were prominent phenotypical characteristics in all cases: all the patients presented with insomnia, anxiety, depression, severe fatigue, and short-memory loss. The response to oral levodopa treatment was suboptimal, with an initial benefit followed by rapid decreased responsiveness. Additionally, two patients developed wearing-off episodes and one of them also exhibited treatment-induced dyskinesias. We hypothesize that VPS13C may confer an increased risk of EOPD in carriers of pathogenic variants, and may function as a phenotype modifier gene, contributing to significant non-motor symptoms development and suboptimal levodopa response. Specifically, we propose that the suboptimal treatment response is associated with a decrease level of dopamine L-type amino acid transporter 1 (LAT1). Show less

Fluoxetine is a selective serotonin reuptake inhibitor and long-lived open channel blocker of the acetylcholine receptor, often used in the treatment of slow-channel congenital myasthenic syndromes (CMS). We report a 42-year-old woman who had a history of episodic limb weakness that worsened after initiation of fluoxetine for treatment of depression. Genetic testing for CMS revealed a homozygous pathogenic mutation in the rapsyn (RAPSN) gene (p.Asn88Lys). Electrodiagnostic testing was performed before and 1 month after discontinuation of fluoxetine. The 2 Hz repetitive nerve stimulation of the fibular and spinal accessory nerves showed a baseline decrement of 36% and 14%, respectively. One month after discontinuing fluoxetine, the spinal accessory nerve decrement was no longer present, and the decrement in the fibular nerve was improved at 17%. This case demonstrates worsening of both clinical and electrophysiologic findings in a patient with CMS secondary to a RAPSN mutation treated with fluoxetine. Muscle Nerve 55: 131-135, 2017. Show less