Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: Hybrid Posters

Abstract

Background/Objectives: Spastic paraplegia type-64 (SPG64; OMIM615683) is an ultra-rare form of complicated hereditary spastic paraplegia. SPG64, caused by biallelic ENTPD1 mutations, is associated with impaired purinergic neurotransmission. Here, we report a novel ENTPD1 variant which adds novel dysmorphic findings, thalamus atrophy and sensorimotor polyneuropathy to phenotypic spectrum of SPG64. Methods: Clinical exome sequencing was conducted utilizing Illumina-TruSight-One panel and analyzed by SophiaDDM. Results: The previously unreported nonsense ENTPD1 variant NM-001776: c.1174C>T (p.Gln392Ter) is located in the extracellular loop domain and is linked to a severe SPG64 phenotype in the proband, associated with early age-of-onset (2 years) and total loss of ambulation at 6 years. Segregation was in accordance with autosomal recessive inheritance in the family. Conclusion: Only 9 individuals with SPG64 from 5 families have been described with clinical details and the full phenotypic spectrum remains inadequately characterized. Based on our comprehensive follow-up for 4 years and comparison with reported individuals, the clinical spectrum of SPG64 can include cognitive decline (9/10), speech abnormality (7/10), dystonia (3/ 10) and brain abnormalities (3/7). Additionally, presence of sensorimotor polyneuropathy in the proband, accompanied by thalamus atrophy possibly secondary to sensory neuropathy, suggests that the clinical spectrum of SPG64 is broader than previously reported. Early-stage neuropathy suspected in a previous individual with SPG64 supports that neuropathy may be an overlooked phenotypic component of SPG64. Moreover, neuropathy may also be associated with impaired purine metabolism since purines are acting as neurotransmitters in peripheral nervous system. Our study highlights the importance of evaluating all future patients for clues of neuropathy.