Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls

Table 1 Inherited defects of cholesterol biosynthesis in humans

Disorder	OMIM#	Frequency	Enzyme (blood biomarkers)	Primary site of expression	Treatable	Ref.
SLOS	270400	1:20000/1:50000	7-dehydrocholesterol reductase (7-dehydrocholesterol, 8-dehydrocholesterol)	Multisystemic	Yes	[28,36]
					Mild cases
Desmosterolosis	602398	9 cases	3β-hydroxysterol-∆24-reductase (desmosterol)	Multisystemic	No	[25,37]
CDPX21	302960	≤ 1:400000	3β-hydroxysteroid-∆8,∆7-sterol isomerase [8-dehydrocholesterol, cholesta-8(9)-en-3β-ol]	Skin and skeletal systems	No	[25,38]
CHILD syndrome	308050	< 1:1000000	3β-hydroxysteroid dehydrogenase [4α-carboxymethylcholest-8(9)-en-3β-ol, 4α-monomethyl-and 4,4’-dimethylsterols]2	Skin and skeletal systems	No	[25,39]
Lathosterolosis	607330	4 cases	3β-hydroxysteroid-∆5-desaturase (lathosterol)	Multisystemic	Yes	[40-43]
					Two cases
Antley-Bixler syndrome3	201750	> 100 cases	Lanosterol 14α-demethylase (lanosterol, dihydrolanosterol)2	Skin and genital systems	No	[44,45]
Greenberg dysplasia	215140	11 cases	Sterol-∆14-reductase (cholesta-8,14-dien-3β-ol, cholesta-8,14,24-trien-3β-ol)2	Skeletal system	No	[25,46]
CK syndrome	300831	13 cases	3β-hydroxysteroid dehydrogenase (4α-monomethyl- and 4,4’-dimethylsterols)2	Nervous system	No	[25,47,48]
SC4MOL deficiency	616834	5 cases	Sterol-C4-methyl oxidase (4α-monomethyl- and 4,4’-dimethylsterols)	Skin and eye	Yes	[49,50,88]
				Systems	One case

¹An hypomorphic variant (#300960) has been reported in 10 male patients[25,51];

²Presence of biomarkers in tissue and/or cultured cells only;

³A variant form (#613571) due to deficiency of cytochrome P450 oxidoreductase has been reported 9 subjects[45,52]. CDPX2: X-linked dominant disorder chondrodysplasia punctata-2; CHILD: Congenital hemidysplasia with ichthyosiformerythroderma and limb defects; CK: Eponym derived from the first case; SC4MOL: Sterol-C4-methyl oxidase; SLOS: Smith-Lemli-Opitz syndrome.

Table 2 Inherited defects of bile acids biosynthesis in humans

Disorder	OMIM#	Frequency	Enzyme (urine biomarkers)1	Primary site of expression	Treatable	Ref.
CTX	213700	1:50000	Sterol 27-hydroxylase (tetrahydroxy-, pentahydroxy- and hexahydroxy-bile alcohols)2	Eye, central and peripheral nervous systems	Yes	[26,30,35]
CBAS1	607765	73 cases	3β-hydroxy-∆5-C27-steroid oxidoreductase (3β-hydroxy-∆5 bile acids)	Liver	Yes	[26,35,57,58]
CBAS2	235555	41 cases	∆4-3-oxosteroid 5β-reductase (∆4-3-oxo bile acids)	Liver	Yes	[35,59-65]
SPG5A	270800	31 cases	Oxysterol 7α-hydroxylase (27-hydroxycholesterol)3	Central and peripheral nervous systems	No	[66-69]
FHCA	607748	15 cases	BAAT4 (unconjugated cholic acid)3	Liver and intestine	Yes	[35,70,71]
CBAS4	214950	6 cases	α-methylacyl-CoA racemase (THCA)5	Liver, intestine and peripheral nervous systems	Yes	[35,72,73]
CBAS3	613812	3 cases	oxysterol 7α-hydroxylase (3β-hydroxy-5-cholenoic and 3β-hydroxy-5-cholestenoic acids)	Liver	No	[35,74,75]
BACL deficiency	NR	8 cases	Bile acid-CoA ligase (unconjugated cholic acid)3	Liver and intestine	No	[76]
CYP7A1 deficiency	NR	< 1:1000000	CYP7A1 (3β-hydroxy-5-cholenoic and 3β-hydroxy-5-cholestenoic acids, 27-hydroxycholesterol)6	Cardiovascular system	No	[35,77]

¹Conjugated form unless otherwise noted;

²Plasma and tissue accumulation of cholestanol and cholesterol precursors;

³Presence also in serum;

⁴FHCA can be due also to mutations in Tight junction protein-2 and Microsomal epoxide hydrolase-1 genes;

⁵Plasma and tissue accumulation of phytanic and pristanic acids;

⁶High plasma levels of total and LDL-cholesterol, and 27-hydroxycholesterol. BAAT: Bile acids-CoA aminoacid N-acyltransferase; CTX: Cerebrotendinous xanthomatosis; CYP7A1: Cholesterol 7α-hydroxylase; FHCA: Familial hypercholanemia; NR: Not reported; SPG5A: Spastic paraplegia-5A; THCA: 3α,7α,12α-trihydroxy-5β-cholestan-26-oic acid.

Table 3 Clinical and laboratory findings shared by some treatable defects of cholesterol and bile acid biosynthesis

Clinical features	SLOS1	LATHO	SC4MOL	CTX	CBAS1	CBAS2	CBAS4	Shared findings
Microcephaly	Yes	Yes	Yes	No	No	No	No	3/7
Congenital cataracts	Yes	Yes	Yes	Yes	No	No	No	4/7
Intellectual disability	Yes	Yes	Yes	Yes	No	No	No	4/7
Neurological disease	No	No	No	Yes	No	No	Yes	2/7
Developmental delay	Yes	Yes	Yes	No	No	No	No	3/7
Cholestasis	No	Yes	No	Yes	Yes	Yes	Yes	5/7
Steatosis	No	Yes	No	No	No	Yes	No	2/7
AST	Normal	High	Normal	High	High	High	Normal	4/7
ALT	Normal	High	Normal	High	High	High	Normal	4/7
γGT	Normal	High	Normal	Normal	Normal	High	Normal	2/7
Conjugated bilirubin	Normal	High	Normal	High	High	High	Normal	4/7
Total cholesterol	Very low to normal	Low to normal	Low to normal	Normal to high	Normal	Normal	Normal	n.a.
Fat-soluble vitamin	Normal	Low	Normal	Normal	Low	Low	Low	4/7
Diagnostic method
GC-MS	Sterols (p)	Sterols (p)	Sterols (p)	Sterols (p)
LC-MS/MS				HBA (u)	BA (u)	BA (u, p)	BA (u, p)
Treatment	Cholesterol plus statins	Statins or LT	Cholesterol plus statins and bile acids	CDCA plus statins	Cholic acid	UDCA or cholic acid	Cholic acid2

¹Mild phenotypes;

²Associated with a phytanic/pristanic acid-restricted diet. BA: Bile acids; CDCA: Chenodeoxycholic acid; HBA: Hydroxy bile alcohols; LATHO: Lathosterolosis; LT: Liver transplant; n.a.: Not applicable; (p): Plasma; (u): Urine; UDCA: Ursodeoxycholic acid. GC-MS: Gas chromatography coupled to mass spectrometry; LC-MS/MS: Liquid chromatography coupled to tandem mass spectrometry.