Brain malformation and white matter abnormalities associated with LSS-related neuroectodermal syndrome

Abstract

Background: Disorders of cholesterol biosynthesis encompass a broad range of phenotypes with overlapping features, including intellectual disability, brain and limb malformations, and ectodermal defects. Bi-allelic mutations in LSS, encoding lanosterol synthase, recently were found to cause a spectrum of abnormalities beyond cataract, including hypotrichosis and a severe neuroectodermal syndrome (MIM#618840) with some genotype-phenotype correlation. This phenotype has been recapitulated in a murine model with lanosterol synthase deficiency in affected tissue. Aim: To describe the neuroimaging abnormalities in patients with the LSS-associated alopecia and intellectual disability syndrome. Methods: Individuals with bi-allelic mutations in LSS and abnormal CNS neuroimaging were identified via international neurogenetic research collaborations. Previous reports of LSS-associated alopecia and intellectual disability syndrome were reviewed for neuroimaging abnormalities. Results: Four unrelated individuals were identified. CNS abnormalities in these individuals and previous reports include holoprosencephaly, cortical malformations, periventricular nodular heterotopia, cerebral atrophy, open opercula, cerebellar dysplasia, abnormal myelination, and corpus callosum dysgenesis. All four patients had congenital alopecia and epilepsy, and additional malformations included cleft palate, polydactyly, and genital hypoplasia. Sterol analysis identified an increased level of desmosterol in one individual, consistent with in vitro studies that show inhibition of desmosterol reductase by oxidosqualene as a feature of partial deficiency of LSS. Conclusion: LSS-associated neuroectodermal syndrome causes a spectrum of clinical features characterized by hypotrichosis and intellectual disability with or without epilepsy, brain malformation, and white matter abnormality. The cholesterol metabolism pathway is a potential target to modify the developmental and epileptic phenotype and warrants further investigation.L6371734722022-02-10 <br />