Clinical characterization of a new individual with mild SC4MOL deficiency: diagnostic and therapeutic implications

Sterol C4-methyloxidase-like (SC4MOL) deficiency is an autosomal recessive condition caused by biallelic pathogenic variants in MSMO1, resulting in the accumulation of 4-monomethyl and 4,4′-dimethyl sterols due to an enzymatic block in the cholesterol synthesis pathway. SC4MOL deficiency was first reported in 2011, with only seven additional cases from five unrelated families described in the literature since. Based on these reports, the most characteristic clinical features include the triad of microcephaly, congenital cataracts, and psoriatic dermatitis, followed by delayed growth and puberty, and neurodevelopmental problems. Herein, we describe an 8-year-old boy who presented with congenital cataracts and developmental delay at age 6 months and was found to have biallelic variants in MSMO1 by trio exome sequencing. Initial total methylsterol levels were elevated but responsive to statin therapy, while total cholesterol levels remained normal throughout. Available clinical and biochemical data suggest this individual could represent the mildest case of SC4MOL deficiency to date

Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis

Context: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10−20). Objective: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. Design: Retrospective cohort study. Setting: Academic research. Patients: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. Main outcome measures: DHEA, DHEA-S, and DHEA-S/DHEA ratio. Results: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10−13), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). Conclusions: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology