Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism

Figures & data

Figure 1 Enzymatic stages in distal cholesterol metabolites and their associated clinical disorders. Syndromic disorders occur with mutations in 7 of the 9 post-lanosterol steps in late cholesterol synthesis (indicated by bold/italics). A prominent cutaneous phenotype (ichthyosis) occurs in 6 of these diseases (indicated by bold/italics & underline).

Figure 2 Pathogenesis-based therapy for disorders of distal cholesterol metabolites: Bases for improvement in clinical studies.

Table 1 Pathogenic mechanisms and potentially diagnostic features in disorders of distal cholesterol metabolism

Disorders	Keratohyalin/Keratins	Lamellar body formation/Contents	Lamellar body exocytosis	Post-secretary lipid processing	Lamellar bilayers	Cornified envelopes	Corneodesmosomes	Corneocyte lipid envelope
Cholesterol and Isoprenoid Metabolism
CHH/CHILD7,29	Normal/Normal	Abnormal contents	Impaired	Delayed	L/Non-L-PS	Normal	Normal	Normal
XLI17	Normal/Normal	Normal	Normal	Normal	L/Non-L-PS	Normal	Persist	Normal

*Bolded and italicized features are particularly helpful in differential diagnosis.

Table 2 Pathogenesis and pathway-based therapy of inherited disorders of distal cholesterol metabolism

Metabolic category	Inheritance pattern (Incidence)	Affected protein (gene)	Normal function	Amenable to Pathogenesis-based treatment	Proposed therapy
CHH (CDPX2)	x-linked dominant (rare)	delta(8)-delta(7) sterol isomerase emopamil-binding protein (EBP)	Distal cholesterol synthesis	Very Likely (but can be self-resolving)	HMGCoA reductase inhibitor + cholesterol
CHILD syndrome	x-linked dominant (very rare)	NAD(P)H steroid dehydrogenase-like protein (NSDHL)	Same	Yes (Shown)	Same (cholesterol alone ineffective)
SLOS	Recessive (fairly common)	7-dehydroreductase (DHCR7)	Same	Very Likely	Same
SC4MOL	Recessive (very rare)	Sterol-C4-methyl oxidase (SC4MOL)	Same	Very Likely	Same
Lathosterolosis (No known US cases)	Recessive (very rare)	Lathosterol-5-desaturase (Sc5d)	Same	Very likely	Same
Desmosterolosis	Recessive (very rare)	24-dehydroreductase (DHCR24)	Same	Very likely	Same
X-linked ichthyosis	X-linked recessive (fairly common)	Steroid sulfatase (STS)	Desulfation of cholesterol sulfate	Very Likely	HMGCoA reductase or SULT2B inhibitor + cholesterol

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