GCH1 Mutations in Hereditary Spastic Paraplegia (2100)

Objective: NA Background: Mutations in GCH1 have been associated with dopa-responsive dystonia (DRD), Parkinson’s disease (PD), and hyperphenylalaninemia B. More recently, these mutations have been reported in patients diagnosed with hereditary spastic paraplegia (HSP). Design/Methods: Whole exome sequencing (WES) was carried out in 400 HSP patients from 291 families. Results: Three HSP patients were identified to have GCH1 mutations: one patient with a p.(Val205Glu) mutation, and monozygotic twins with a p.(Ser77_Leu82del) mutation. All patients presented with spasticity of the lower limbs at childhood, abnormal plantar responses, and hyperreflexia. None of the patients had dystonia or parkinsonism, and only one had diurnal fluctuation of symptoms. The monozygotic twins showed clinical differences, and they had a significant response to levodopa treatment. Conclusions: GCH1 mutations could cause HSP; thus, including GCH1 in the HSP genes screening panels may be of benefit. Phenotypic differences between the monozygotic twins suggest the role that environmental factors could play in the presentation of the disease. Disclosure: Parizad Varghaei has nothing to disclose. Dr. Yoon has nothing to disclose. Mehrdad A Estiar has nothing to disclose. Dr. Dupre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Akcea Therapeutics Canada. The institution of Dr. Dupre has received research support from ARSACS Foundation. The institution of Dr. Dupre has received research support from CHUdeQuebec Foundation. Dr. Rouleau has nothing to disclose. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Idorsia. Dr. Gan-Or has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Inception Sciences. Dr. Gan-Or has received personal compensation in the range of $0-$499 for serving as a Consultant for Lighthouse. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prevail Therapeutics. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Therapeutics. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Deerfield. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Handl Therapeutics.