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Page 258 Morales et al. J Transl Genet Genom 2022;6:257-65 https://dx.doi.org/10.20517/jtgg.2022.01

INTRODUCTION
Cholesterol is a complex sterol molecule that participates in multiple cellular processes, including cell wall
[1,2]
permeability/stability, mitosis and meiosis, Hedgehog signaling, and ultimately embryonic development .
Dietary intake of cholesterol is responsible for approximately 25% of serum cholesterol, with the remainder
[3]
synthesized de novo from acetyl-CoA primarily in the liver . The de novo cholesterol biosynthesis pathway
requires more than 20 enzymes and is generally divided into two components: pre-squalene and post-
squalene cholesterol synthesis . Pre-squalene synthesis leads to the production of squalene, used by post-
[4]
[4]
squalene synthesis for sterol and vitamin D production . To date, 17 separate genetic diseases have been
described due to single enzyme deficiencies in the de novo cholesterol synthesis pathway, with 10 of the 17
[5]
representing a disorder of post-squalene synthesis .
The sterol C4-methyloxidase like (SC4MOL) or methylsterol monooxygenase 1 (MSMO1) enzyme
functions within the sterol demethylation complex of the post-squalene synthesis pathway, catalyzing the
first step in demethylation of 4,4′-dimethylsterols . SC4MOL deficiency (OMIM #616834) is an autosomal
[5]
recessive genetic condition caused by biallelic pathogenic variants in the gene, MSMO1, resulting in the
[6,7]
accumulation of 4-monomethyl and 4,4′-dimethyl sterols . These methylsterols are also referred to as
meiosis-activating sterols (MASs) based on their role in mammalian meiosis . Although there is no clear
[8,9]
evidence of their effect on mitosis and cell cycle regulation, there is documentation of skin cell
hyperproliferation in individuals with this disorder, suggesting a higher rate of cell division . Other effects
[7]
of MASs accumulation include immune dysregulation such as overactivation of CD16+ and toll-like
receptor (TLR)-2+ granulocytes (potentially leading to an abnormal response in presence of bacterial
infections), reduced endothelial-growth factor receptor signal transduction, and impaired intracellular
[6]
vesicular trafficking .

The first individual with SC4MOL deficiency was described in 2011; only seven additional cases from five
unrelated families have been reported since [6,7,10,11] . Based on these reports, the most characteristic clinical
features of SC4MOL deficiency include the triad of microcephaly, congenital cataracts, and psoriatic
dermatitis (MCCPD), followed by delayed growth and puberty, developmental delay, and intellectual
disability. Reported biochemical abnormalities consist of increased levels of 4-monomethyl and
4,4′-dimethyl sterols in plasma from all five patients from whom cholesterol precursor levels were evaluated,
in addition to decreased total cholesterol level in two cases [6,10] .

Herein, we describe an 8-year-old boy who presented with congenital cataracts and moderate
developmental delay at 6 months of age, who was found to have a likely pathogenic variant and a variant of
uncertain significance (VUS) in MSMO1 by trio exome sequencing. Initial total methylsterol levels were
elevated, but decreased as statin therapy was implemented with a positive impact on his clinical status.

CASE REPORT
A 6-month-old Caucasian boy presented for evaluation by medical genetics due to a concern for congenital
cataracts and developmental delay [Figure 1]. There were no prenatal complications other than advanced
maternal age. He was born at 39 weeks of gestation by C-section due to failure to progress to a 35-year-old
mother and father. His birth growth parameters were weight 3.5 kg (48th centile), length 51 cm (65th
centile), and head circumference 35.4 cm (41st centile). Shortly after birth, he was identified with left
lacrimal obstruction requiring observation. As he grew older, his parents noticed eye misalignment, which
by 6 months raised the concern for bilateral congenital cataracts due to absent red reflexes. Cataracts were
confirmed and lens removal was performed at 7 months of age. Family history consisted of Italian, German,
and Basque ancestry, but was otherwise non-contributory.