Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia

Abstract

Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. Conclusion: ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.

Keywords: ABHD16A; hereditary spastic paraplegia; lipid metabolism; next-generation sequencing; phosphatidylserine; targeted-metabolomics.

Figure 1

The pedigrees of families F37 and F69 and patient F37-314 brain MRI. The family pedigrees of family F37 (left) and F69 (right) show consanguinity in the two families. Axial T2 TIRM dark fluid brain MRI of patient F37-314 shows periventricular and subcortical white matter hyperintensities (left image: arrow heads), whereas sagittal T1 image shows thin corpus callosum (right image: arrow).

Figure 2

Lysophosphatidylserine molecular species in fibroblasts derived from patients F37-314, F37-315, and F69-508. LPS 18:1, 20:0, 20:1, and 20:4 are lower in the patients than in the healthy controls. AU, arbitrary units; LPS, lysophosphatidylserine.

Figure 3

The reactions and the disorders across the ABHD16A-ABHD12 pathway. HSP, hereditary spastic paraplegia; PHARC syndrome, syndrome of polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract; PS, phosphatidylserine; LPS, lysophosphatidylserine; FFA, free fatty acid; GPS, glycerophosphoserine.