Clinical characterization of a new individual with mild SC4MOL deficiency: diagnostic and therapeutic implications

Abstract

Sterol C4-methyloxidase-like (SC4MOL) deficiency is an autosomal recessive condition caused by biallelic pathogenic variants in MSMO1, resulting in the accumulation of 4-monomethyl and 4,4′-dimethyl sterols due to an enzymatic block in the cholesterol synthesis pathway. SC4MOL deficiency was first reported in 2011, with only seven additional cases from five unrelated families described in the literature since. Based on these reports, the most characteristic clinical features include the triad of microcephaly, congenital cataracts, and psoriatic dermatitis, followed by delayed growth and puberty, and neurodevelopmental problems. Herein, we describe an 8-year-old boy who presented with congenital cataracts and developmental delay at age 6 months and was found to have biallelic variants in MSMO1 by trio exome sequencing. Initial total methylsterol levels were elevated but responsive to statin therapy, while total cholesterol levels remained normal throughout. Available clinical and biochemical data suggest this individual could represent the mildest case of SC4MOL deficiency to date.

Keywords

SC4MOL deficiency / microcephaly / cataract / psoriasiform dermatitis / MSMO1

References

[1] Luo J,Song BL.Mechanisms and regulation of cholesterol homeostasis.Nat Rev Mol Cell Biol2020;21:225-45

[2] Schade DS,Eaton RP.Cholesterol review: a metabolically important molecule.Endocr Pract2020;26:1514-23

[3] Repa JJ.The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.Annu Rev Cell Dev Biol2000;16:459-81

[4] Porter FD.Malformation syndromes caused by disorders of cholesterol synthesis.J Lipid Res2011;52:6-34 PMCID:PMC2999931

[5] Herman GE.Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome.Am J Med Genet C Semin Med Genet2012;160C:301-21

[6] He M,Chang R,Vockley J.The role of sterol-C4-methyl oxidase in epidermal biology.Biochim Biophys Acta2014;1841:331-5 PMCID:PMC3943829

[7] He M,Michel JJ.Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay.J Clin Invest2011;121:976-84 PMCID:PMC3049385

[8] Byskov AG,Nordholm L.Chemical structure of sterols that activate oocyte meiosis.Nature1995;374:559-62

[9] Xie H,Byskov AG,Bo S.Roles of gonadotropins and meiosis-activating sterols in meiotic resumption of cultured follicle-enclosed mouse oocytes.Mol Cell Endocrinol2004;218:155-63

[10] Frisso G,Procopio E.A rare case of sterol-C4-methyl oxidase deficiency in a young Italian male: biochemical and molecular characterization.Mol Genet Metab2017;121:329-35

[11] Kalay Yildizhan I,Onoufriadis A.New homozygous missense MSMO1 mutation in two siblings with SC4MOL deficiency presenting with psoriasiform dermatitis.Cytogenet Genome Res2020;160:523-30

[12] Elias PM,Paller A,Williams ML.Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: therapeutic implications for topical treatment of these disorders.Dermatoendocrinology2011;3:100-6 PMCID:PMC3117009

[13] Sirtori CR.The pharmacology of statins.Pharmacol Res2014;88:3-11

[14] Kanungo S,He M.Sterol metabolism disorders and neurodevelopment-an update.Dev Disabil Res Rev2013;17:197-210

[15] Zambrano T,Hirata MH,Salazar LA.Statins differentially modulate microRNAs expression in peripheral cells of hyperlipidemic subjects: a pilot study.Eur J Pharm Sci2018;117:55-61

[16] Mohammadzadeh N,Carbone F,Al-Rasadi K.Statins: epidrugs with effects on endothelial health?.Eur J Clin Invest2020;50:e13388

[17] Qu H,Chai H,Gao ZY.Effects of coenzyme Q10 on statin-induced myopathy: an updated meta-analysis of randomized controlled trials.J Am Heart Assoc2018;7:e009835 PMCID:PMC6404871

[18] Sirtori CR,Triolo M.Clinical response to statins: mechanism(s) of variable activity and adverse effects.Ann Med2012;44:419-32