Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report.

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM #611105) is a genetic disease of the central nervous system characterized by lower limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far. CASE PRESENTATION: Two siblings, aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters. CONCLUSION: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. This may have implications for the detection of mutation carriers in LBSL.

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

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.