Cholesterol 7α-hydroxylase
deficiency | 118455 | Hypercholesterolemia, hypertriglyceridemia,
gallstones | Disruption of the first step of the neutral pathway | Codominant | CYP7A1 mutation analysis | Powerful statin plus niacin |
CYP7A1 |
8q11-q12 |
3β-Hydroxy-Δ5-C27-steroid
dehydrogenase deficiency | 607764 | Neonatal cholestatic jaundice with normal γ-GT. | Conversion of 7α-hydroxy
cholesterol to 7α-hydroxycholest-4-en-3-one blocked.
7 α-HC converted to C24 bile acids containing 3 β,7α-dihydroxy-Δ5structure | AR | UBA: 469,485,526,542 | Chenodeoxycholic acid and/or cholic
acid |
3β-HSD defic. | Steatorrhea, fat-soluble vitamin deficiencies (eg, rickets, hypocalcemia, bruising/bleeding | C27-3BETA-HSD (=HSD3B7) | PBA: low CDCA and CA for cholestasis. Increased
3β-hydroxy-Δ5 bile acids |
Progressive cholestatic liver disease | 16p11.2-12 |
Δ4-3-Oxosteroid
5β-reductase deficiency | 604741 | Neonatal cholestatic jaundice with normal γ-GT. | Reduction of 3-oxo-Δ4 intermediates
to 5β(H) intermediates blocked. Synthesis of 3-oxo-Δ4bile
acids and 5α(H) (allo) bile acids | AR | UBA: 444,460,494,510 | Chenodeoxycholic acid + cholic acid
or cholic acid alone |
5β-reductase defic. | Fat-soluble vitamin deficiencies | SRD5B1 (=AKR1D1) | PBA: low CDCA and CA for cholestasis. Increased
3-oxo-Δ4 bile acids in infancy; increased
allo bile acids in childhood |
235555 ?different gene | Liver failure | 7q31 |
?other genes |
Sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) | 213700 | Neonatal cholestatic jaundice with normal γ-GT. | Impaired cholesterol metabolism in extrahepatic tissues leading to cholesterol and cholestanol accumulation | AR | UBA: 611,627,643 | Cholic acid in infancy, chenodeoxycholic acid in childhood/adult life or chenodeoxycholic acid plus cholic acid |
606530 | Diarrhea, cataracts in preschool child | Bile acid intermediates converted to 25-hydroxy
derivatives (eg, 5β-cholestane-3α,7α,12α,25-tetrol) and
excreted in urine as bile alcohol glucuronides | CYP27A1 | In infancy 3,7,12,24,25-pentol. In older children,
3,7,12,22,25-pentols and 3,7,12,23,25-pentols |
Dementia, motor dysfunction in teenager/young adult | 2q33-qter | PBA: 5β-cholestane-3α,7α,12α,25-tetrol and
bile acid precursors |
Tendon xanthomata, premature atherosclerosis |
α-Methyl-acyl-CoA racemase deficiency | 604489 | Neonatal cholestasis, vitamin K deficiency,
developmental delay, epilepsy, postictal encephalopathy, pigmentary retinopathy,
neuropathy | Failure to convert C27 bile acyl-CoAs to the isomer
that can be side-chain shortened by peroxisomal β-oxidation | AR | UBA: 556,572,588 | Cholic acid for cholestasis in infancy. |
AMACR | PBA: DHCA, THCA | Dietary phytanate restriction for high pristanate
levels - ? of benefit to neurological disease |
5p13.2-q11.1 | Other: Raised pristanate |
Normal VLCFA |
Peroxisomal D-bifunctional protein deficiency | 601860 | Neonatal hypotonia, seizures, severe developmental
delay death in first 2 years | Defective conversion of Δ24-THCA
via varanyl-CoA to 3α,7α,12α-trihydroxy-24-oxo-5β-cholestanoyl-CoA | AR | UBA: 570,572 in some cases | No specific treatment described |
261515 | Milder variants | HSD17B4 | PBA: Varanic acid in some, DHCA and THCA elevated
in 74% |
5q2 | Other: VLCFA elevated in 94% |
Peroxisomal sterol carrier protein X (thiolase) deficiency | 184755 | Torticollis, dystonia, ataxia, hyposmia, and
azoospermia (young adult) | Defective conversion of 3α,7α,12α-trihydroxy-24-oxo-5β-cholestanoyl-CoA
to choloyl-CoA | AR | UBA: 611,613,627,629 | No specific treatment. |
Leukoencephalopathy with dystonia and motor
neuropathy | SCP2 | PBA: slight elevation of DHCA and THCA | Dietary phytanate restriction for high pristanate
levels - ? of benefit to neurological disease |
1p32 | Other: pristanate markedly elevated |
Bile acid CoA: amino acid N-acyltransferase deficiency | 602938 | Neonatal onset cholestasis | Failure to convert bile acyl-CoA esters to amidated bile acids | AR | UBA: 407,471,487,567,583 | ?Ursodeoxycholic acid |
BAAT defic. | Failure to thrive | Synthesis of nonamidated bile acids and their sulfates and
glucuronides | BAAT | PBA: increased nonamidated bile acids |
Amish hypercholanemia type 2 | Steatorrhea, fat-soluble vitamin deficiencies | 9q22.3 |
Bile acyl-CoA synthetase | 603314 | Neonatal onset cholestasis | Failure to synthesize CoA esters from unconjugated
bile acids | AR | UBA: 391,407, 471, 567, 583 | No specific treatment described |
BACS defic. | Failure to thrive | SLC27A5 | PBA: increased nonamidated bile acids |
Chr.19 |
Oxysterol 7α-hydroxylase deficiency | 603711 | Neonatal cholestasis leading to liver failure | Disruption of second step of “acidic” pathway.
Accumulation of 27-OH-cholesterol and 3β-OH-Δ5 bile acids
(hepatotoxic). | AR | UBA: 453,510 | Transplantation for liver failure |
270800 | Onset (1 to 40 years) of lower extremity weakness
and spasticity with sensory impairment | Deranged extrahepatic cholesterol catabolism and neurosteroid catabolism | CYP7B1 | PBA: Increased concentration of 3β-hydroxy-5-cholenoic
acid and 3β-hydroxy-5-cholestenoic acid |
8q21.3 | Other: raised plasma 27-hydroxycholesterol |
Peroxisome biogenesis disorders | | Neonatal hypotonia seizures, dysmorphic features,
liver disease | Failure to assemble peroxisomes (in which β-oxidation
of C27 bile acyl-CoA to C24 bile acyl-CoAs and amidation occur) | AR | UBA: 572 | Phytanate restriction, DHA supplementation.
No treatment has any significant impact on the severe forms of the
disease. |
Zellweger syndrome | 214100 | Failure to thrive | PEX genes: 1-3, 5,6,10,12-14, 16,19,26 | PBA: DHCA, THCA, C29-dicarboxylic acid |
202370 | Developmental delay | Other: increased VLCFA, phytanate and/or
pristanate, low erythrocyte plasmalogens, low DHA |
Neonatal adrenoleukodystrophy | 266510 | Retinopathy, deafness |
Infantile Refsum’s disease | Spastic paraparesis, ataxia |