Characterization of cholesterol biosynthesis defects: a new case of sterol-C4-methyl oxidase deficiency in Italy

Inborn defects of cholesterol biosynthesis are metabolic disorders presenting with multi-organ and tissues anomalies. Recently, a new autosomal recessive defect in 4 patients involving the demethylating enzyme C4-methylsterols (SC4MOL) has been described. In infancy, all showed congenital cataracts, growth delay, microcephaly,psoriasiform dermatitis, immune dysfunction, and intellectual disability (1). Here, we describe a new case of SC4MOL deficiency, showing bilateral congenital cataracts, psychomotor and development delay and learning disabilities in the early life. At 15 years, he showed small stature and behavioral disorder. His skin never demonstrated a marked psoriasiform rash, but only abundant dandruff of scalp. Despite numerous biochemical and genetic examinations, the diagnosis was missed until 19 years. Based on clinical evidences, such as congenital cataracts and developmental delay, a cholesterol biosynthesis defect was suspected. Blood C4-monomethyland C4-dimethylsterols levels, analyzed by gas-chromatography and mass spectrometry, were significantly higher than controls, suggesting a deficiency of SC4MOL. Sequencing analysis of SC4MOL gene showed mutations in both alleles (1st variant: c.731A>G, p.Y244C, already known; 2nd one: c.605G>A, p.G202E, new variant). Both mutations were absent in both EXAC database and healthy controls. His parents were found heterozygous. Finally, integrating clinical, metabolic, and genetic tests, we diagnosed the SC4MOL deficiency definitively. Notably, the interactions of multifield skills are fruitful to diagnose a new defect of cholesterol biosynthesis. Therefore, we suggest that plasma sterol profile should be taken early into account for all undiagnosed patients showing clinical signs overlapping that of patient presented here. (Reference: 1. He et al., 2014, BBA 1841:331)