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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 261

individuals include early-childhood onset of psoriasiform dermatitis or dry skin (n = 6),
neurodevelopmental problems (n = 5), microcephaly (n = 4), growth delay (n = 4), congenital cataracts
(n = 3) and other ocular findings (n = 2) [Table 1].

Our patient did not present with the characteristic SC4MOL deficiency clinical triad (MCCPD), but did
exhibit congenital cataracts and developmental delay, both of which have improved with surgical and
medical intervention, respectively. While growth delay does not appear to be a feature in our patient, there
was early evidence of poor weight gain at 14 months of age (3rd centile). It is possible that the use of statin
therapy in childhood has mitigated and prevented growth delay in our patient; however, he has yet to
experience puberty and reach his adult height.

Psoriasiform dermatitis and congenital cataracts (or other ocular findings) may be considered characteristic
findings in SC4MOL deficiency based on the higher frequency presented in this cohort [Table 1]. The
presence of these features in an individual with neurodevelopmental impairment could raise the question of
a cholesterol synthesis disorder. However, as other conditions have a similar presentation, some affected
individuals were diagnosed only after an extensive work-up that eventually included plasma sterol analysis
and MSMO1 sequencing to confirm the diagnosis [Table 1].

Of the variants identified in our proband, the paternally inherited likely pathogenic variant p.Y244C has
been reported in trans in two non-consanguineous cases [7,10] . Interestingly, one of the other affected patients
Case 5, [Table 1] carrying the p.Y244C variant is of Caucasian descent , particularly from Italian origin, a
[10]
similar ethnic background to our patient based on the reported paternal ethnicity [Table 1]. In comparison,
the p.P179L variant has not been reported in other affected individuals. However, its absence from healthy
cohorts (NHLBI Exome Sequencing Project, 1000 Genomes Project), alteration of highly conserved amino
acid, and deleterious predictions by in-silico models (Polyphen, SIFT), along with the biochemical evidence
of SC4MOL dysfunction, support its pathogenicity.

[12]
Due to the enzyme’s proximal location and function in the post-squalene pathway , accumulation of
methylsterols occurs . This was evident in our patient, as well as five other reported individuals who also
[6,7]
had elevated levels of methylsterols at diagnosis [Table 1]. Based on this deficiency, it is also expected that
the distal end-product of this pathway (cholesterol) would show reduced concentrations. However, unlike
[7]
the first case reported , our patient’s total cholesterol levels remained normal both before and after onset of
therapy [Figure 2]. Furthermore, our review indicates that only 25% (n = 2) of affected individuals had low
cholesterol levels at some point after diagnosis , suggesting the presence of residual enzymatic activity or
[6]
possibly increased absorption of dietary cholesterol.

The molecular and biochemical evidence available is not sufficient to make detailed genotype-phenotype
correlations or predictions of outcome at this point. Based on the limited number of cases reported, it
appears that patients with homozygous variants tend to have a “classic” phenotype entailing psoriasiform
dermatitis/dry skin, microcephaly, ocular findings and developmental delay/intellectual disability [6,11] . The
variant p.N27T appears to have a severe presentation when homozygous, in comparison to the p.G115R
variant [6,11] . The first case identified with the p.Y244C had a severe presentation compared to Case 5 and our
patient [Table 1]. Therefore, individuals harboring the p.Y244C variant may vary in severity according to
the second variant in trans.

The therapeutic goal of treating individuals with SC4MOL deficiency is to reduce methylsterol levels with
statin therapy and provide the possibly deficient end-product, cholesterol, through dietary supplementation.