Biochemical and genetic characterization of a cholesterol biosynthesis defect: a new case of sterol-C4-methyl oxidase defect in a young Italian male

Cholesterol plays a pivotal role in cell membrane physiology and in the biosynthesis of steroids, bile acids, and vitamin D. Inborn defects of cholesterol biosynthesis are a group of metabolic disorders presenting with multiple congenital anomalies, growth delay, and psychomotor disabilities. Recently, a new defect of cholesterol biosynthesis, involving the sterol-C-4-methyl oxidase (SC4MOL) enzyme, has been described in four patients as an autosomal recessive disease due to the defect of demethylation of C4-methylsterols (1). Herein, we describe a new case of SC4MOL deficiency. His clinical history reported bilateral congenital cataracts at the age of 8 months; at 4 years old, he showed psychomotor development delay and learning disabilities; at the age of 15 years, he showed small stature, microcephaly, cerebellum hypoplasia, obesity, and behavioural disorder. Despite numerous clinical, biochemical, and genetic examinations, such as array-CGH, X-fragile test, mitochondrial DNA sequencing, amino acids and organic acids in plasma and urine, the diagnosis was missed until the age of 19 years. Based on these evidences, a cholesterol biosynthesis defect was suspected. Sterol analysis by GC-FID and GC-MS showed higher levels of C4-monomethyl- and C4-dimethylsterols in plasma and red blood cell membranes, suggesting a defect of SC4MOL enzyme. Sequencing of the SC4MOL gene showed that the patient is compound heterozygote for two mutations: c.731A>G (p.Y244C), a known mutation, which substitutes an amino acid within highly conserved metal-binding domain; c.605G>A (p.G202E), not previously described, occuring in a trans-membrane site of fatty acid hydroxylase region. It is absent in EXAC database and in 250 healthy Caucasian individuals. Bioinformatics analysis suggests that this substitution may have a pathogenic role. Both his parents are found heterozygous. Therefore, genetic result supports the diagnosis of SC4MOL deficiency. In conclusion, integration between plasma and red blood cell membranes sterol analysis and genetic analysis allows to reach the definitive diagnosis. In addition, genetic result allows to differentiate among overlapping phenotype, and to establish the exact reproductive risk. Reference: 1) He et al 2014, BBA 1841:331