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Page 260 Morales et al. J Transl Genet Genom 2022;6:257-65 https://dx.doi.org/10.20517/jtgg.2022.01

Figure 2. Total cholesterol and methylsterol/total sterol ratio through proband’s life. (A) Simvastatin and CoQ10 were initiated at time
of diagnosis. (B) Pravastatin added at 6.4 years of age, after an increase in methylsterol levels. Purple line: methylsterol/total sterol
ratios. Blue line:total cholesterol levels. Red dotted line normal methylsterol/total sterol ratio (< 0.1%). Green dotted line: lower normal
limit of total cholesterol (< 140 mg/dL).

Six months after initiating statin therapy (age 34 months), marked improvements in his language were
noted, including the ability to say 25-50 words and communicate in three-word sentences. A follow-up
methysterol level analysis at 37 months showed a decrease in total methylsterol levels with a reduced
methylsterol/total sterol ratio of 0.15 [Figure 2].

Clinical adverse events to simvastatin therapy have been limited to myalgia. Statin-related monitoring of
transaminases, creatine kinase, and renal function has remained stable and within normal limits to date.
Total cholesterol, high-density lipoprotein (HDL), triglycerides, and low-density lipoprotein (LDL)
surveillance were initiated at 53 months of age, with no major alterations except for elevated triglycerides
(104 mg/dL) at 6 years 5 months of age. This, along with rising methylsterol levels, prompted the addition of
pravastatin to his statin regimen [Figure 2]. Triglycerides normalized (49 mg/dl) by age 8 years.

At age 7 years, the proband was diagnosed with autism spectrum disorder, obsessive-compulsive disorder,
and anxiety, requiring dexmethylphenidate. He exhibited a severe perianal rash with excoriation and other
ichthyotic skin changes that responded only to a topical combination of cholesterol 10% and simvastatin
2%. He was also diagnosed with mild bilateral genu valgum, requiring orthotics.

Currently, at the age of 8 years 2 months, his growth parameters are in the normal range, with height 129
cm (48th centile), weight 35.3 kg (93rd centile) and head circumference 52.5 cm (47th centile). His physical
exam continues to be unremarkable with resolution of his severe prior perianal inflammation. He attends
elementary school where he receives special education in addition to physical and occupational therapy. His
most recent sterol studies continue to show a normal cholesterol level, but there has been a slight upward
trend in the methylsterol/total sterol ratio [Figure 2]. His current therapeutic regimen consists of
simvastatin 10 mg/day (0.3 mg/kg/d), pravastatin 4 mg/day, and CoQ10 50 mg/day. He is followed by
endocrinology because of the risk of potential cholesterol-dependent hormone deficiencies. His last
evaluation by ophthalmology did not show evidence of additional complications, and there are plans for
lens implantation between ages 10 to 12 years.

DISCUSSION
SC4MOL deficiency is considered to be one of the rarest cholesterol synthesis disorders with only seven
cases from five unrelated families described to date [6,7,10,11] . The most common clinical findings in affected