Hereditary Spastic Paraplegia: Clinicogenetic Lessons from a Well-Defined Cohort (4943)

Objective: To describe clinical, radiological, and genetic features of a well-defined cohort of hereditary spastic paraplegia (HSP) patients in Alberta, Canada. Background: HSP is a group of heterogeneous hereditary disorders that share the common core feature of leg spasticity leading to gait impairment with more than 60 identified genes. Previously, over 50% of HSP cases remained genetically unsolved. Design/Methods: Patients meeting the clinical criteria for HSP in Alberta were recruited through Neurogenetics clinics in Edmonton and Calgary between 2012 and 2019, and enrolled in an observational study. Clinical features were collected via a standardized inventory. Research whole exome sequencing was performed, and results confirmed in an accredited lab. For some patients, additional testing with commercial multi-gene panels was conducted. Disability was assessed using Spastic Paraplegia Rating Scale (SPRS). Results: A total of 105 HSP patients were enrolled and five patients were lost to follow up. Sixty-seven patients (67%) were found to have mutations in 21 genes. The majority of cases had complicated HSP (56%). Inheritance patterns were 32% autosomal dominant, 21% autosomal recessive, 4% X-linked, and 43% sporadic. Mutations were most frequent in SPAST (27%), SPG7 (22%), SACS (7%), SPG11 (6%), CAPN1 (4%), and SYNE1 (4%). Patients with SPG4 (SPAST) had an age of onset ranging from 1 to 38 years while SPG7 ranged from 13 to 55 years. Compared to SPG4, patients with SPG7 had a lower mean SPRS score (26.00 ± 12.2 vs.14.8 ± 5.9). Abnormalities of brain MRI were more frequently observed in patients SACS (80%, progressive cerebellar atrophy) and SPG11 (50%, thin corpus callosum). SPG7 was more associated with polyneuropathy. Conclusions: This study provides large-scale data on patients with HSP in Alberta. Genetic results of well-phenotyped cohorts are of relevance to practicing neurologists and researchers studying the natural history of HSP with aim of therapeutic interventions. Disclosure: Dr. Assaedi has nothing to disclose. Setareh Ashtiani, 3056 has nothing to disclose. Mehrdad A Estiar 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. Dr. McKenzie has nothing to disclose. Dr. Shetty has nothing to disclose. Dr. Rouleau has nothing to disclose. Dr. Suchowersky has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Syneos/Alexion. The institution of Dr. Suchowersky has received research support from Brain Canada. The institution of Dr. Suchowersky has received research support from Abbvie. The institution of Dr. Suchowersky has received research support from Vaccinex. The institution of Dr. Suchowersky has received research support from Roche. The institution of Dr. Suchowersky has received research support from Wave LifeSciences. The institution of Dr. Suchowersky has received research support from CHDI. Dr. Suchowersky has received publishing royalties from a publication relating to health care. Dr. Suchowersky has received publishing royalties from a publication relating to health care.