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Morales et al. J Transl Genet Genom 2022;6:257-65 https://dx.doi.org/10.20517/jtgg.2022.01 Page 259

Figure 1. Selected facial images of proband (Case 8). (A) At age 6 months. (B) At age 18 months.

During infancy, he exhibited signs of developmental delay with decreased head control and inability to sit
by 6 months of age. He was placed in physical, speech, and occupational therapy. Developmental milestones
included sitting independently at 10 months, standing with support at 12 months, walking independently by
18 months, and speaking his first word at 11 months. His speech was quite limited until after age 2 years
when he started to communicate by using multiple words.

While an infant, he also exhibited intermittent perianal redness that showed mild response to over-the-
counter topical ointments or prescribed topical steroids.

At 14 months, growth parameters included weight 8.90 kg (3rd centile), height 77.5 cm (46th centile) and
head circumference 45.7 cm (17th centile). Initial physical exam was remarkable for nystagmus, right-side
thoracic depression, prominent left-side rib margins, and bilateral fifth finger clinodactyly.

Comprehensive metabolic panel, creatine kinase, echocardiogram, acylcarnitine profile, and oligo-SNP
array were all normal.

At 27 months, trio exome sequencing revealed biallelic variants in MSMO1, consisting of a maternally
inherited VUS, c.536C>T (p.P179L), and a paternally inherited likely pathogenic variant, c.731A>G
(p.Y244C). Upon identification of these variants, plasma sterol analysis revealed a normal cholesterol level
and normal levels of proximal cholesterol precursors (desmosterol, 7-dehydrocholesterol, and lathosterol)
but increased levels of 4-monomethyl and 4,4′-dimethyl sterols in a pattern consistent with SC4MOL
deficiency [Figure 2]. He was started on simvastatin (0.25 mg/kg/d) to inhibit hydroxymethylglutaryl-CoA
(HMG-CoA) reductase and stimulate any residual SC4MOL enzyme activity, and coenzyme Q10 (CoQ10)
(50 mg/d), to reduce potential adverse effects from simvastatin intake. However, methylsterol levels after 3
months of statin therapy (30 months of age) remained increased [Figure 2], requiring a simvastatin dose
increase to 0.5 mg/kg/d.