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SC4MOL Deficiency: 11th Reported Patient with Updates in Treatment Outcomes and Review of Reported Cases  

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction
Deficiency in sterol C4 methyl oxidase, encoded by SC4MOL (previously MSMOL1), is the first autosomal recessive disorder identified in the sterol demethylation complex. This complex includes 3 beta-hydroxysteroid C4-methyl oxidase (4-alpha-methylsterol oxidase) which converts dihydro-TMAS to cholestra-8(9)-en-3beta-ol in the cholesterol synthesis pathway. SC4MOL deficiency has been most consistently characterized by developmental delay, intellectual disability, congenital cataracts, and eczema to psoriasiform dermatitis. Other features include microcephaly, growth delay, and structural brain abnormalities. Ten patients from seven different families have been described in the literature since 2011.

 

Case Presentation
The patient is a 5-year-old female with history of congenital cataracts (s/p removal), sensitive skin/eczema, spasticity of lower extremities, and non-specific white matter changes on brain MRI who was born AGA at term to nonconsanguineous parents after an uncomplicated pregnancy. Gross motor and speech delays were noted at the age of 6 months which prompted further evaluation by genetics.

 

Diagnostic Workup
CMA and trio genome at age 1 year were non-diagnostic. Trio genome reanalysis at age 4 showed two variants of uncertain significance in MSMO1 not previously reported: c.405G>T (p.Trp135Cys) and c.801_804delinsATGA (p.Trp267Ter). Initial quantitative plasma sterol analysis showed elevation of 4 alpha-methyl- and 4, 4’-dimethylsterols with elevated methylsterol/cholesterol % ratio of 0.7 (ref <0.1). Clinical, genetic, and biochemical evidence was consistent with SC4MOL deficiency due to biallelic variants in MSMO1.

 

Treatment and Management
Cholesterol is an important part of oxysterols, bile acids, hormones, myelin, and cell membranes. Hypothetically, statin therapy blocks HMG-CoA reductase and decreases accumulated methylsterols prior to the enzyme deficiency. Some patients with SC4MOL deficiency treated with oral cholesterol supplementation and statin therapy showed improved weight gain, linear growth, and improved skin disease. The methylsterol to cholesterol ratio also decreased, which may be a measurable treatment target. The patient was started on Rosuvastatin 5 mg PO daily and increased dietary cholesterol supplementation.

 

Outcome and Follow-Up
Three months after initiation of treatment, her methylsterol/sterol ratio decreased from 0.7 to 0.2. Cholesterol levels were within the normal range. Parents reported significant interval developmental gains particularly in speech and gross motor (balance). The patient has been on treatment for eight months. Clinical and biochemical monitoring is ongoing.

 

Discussion
The patient had elevated plasma sterol levels and methylsterol/sterol ratio as well as normal cholesterol, consistent with prior patients with SC4MOL deficiency. In addition to global developmental delay and congenital cataracts, she exhibited more CNS involvement, but very mild skin pathology compared to previous reports.  

 

Conclusion
SC4MOL deficiency is an ultra-rare disorder of cholesterol biosynthesis amenable to treatment with HMG-coA reductase inhibitor and oral cholesterol supplementation. Additional reports, case series, and clinical trials are needed to better understand the phenotypic spectrum and develop consensus regarding optimal therapeutic treatment and biochemical monitoring targets.

 

Agenda

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