Setchell KD, Heubi JE, Bove KE, et al. Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy

Johns Hopkins University, Baltimore, Maryland, United States
Gastroenterology (Impact Factor: 16.72). 01/2003; 124(1):217-32. DOI: 10.1053/gast.2003.50017
Source: PubMed


Inborn errors of bile acid metabolism may present as neonatal cholestasis and fat-soluble vitamin malabsorption or as late onset chronic liver disease. Our aim was to fully characterize a defect in bile acid synthesis in a 2-week-old African-American girl presenting with coagulopathy, vitamin D and E deficiencies, and mild cholestasis and in her sibling, whose liver had been used for orthotopic liver transplantation (OLT).
Bile acids were measured by mass spectrometry in urine, bile, serum, and feces of the patient and in urine from the unrelated recipient.
Liver biopsy specimens showed neonatal hepatitis with giant cell transformation and hepatocyte necrosis; peroxisomes were reduced in number. High concentrations of (25R)3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid in the urine, bile, and serum established a pattern similar to that of Zellweger syndrome and identical to the Alligator mississippiensis. Serum phytanic acid was normal, whereas pristanic acid was markedly elevated. Biochemical, MRI, and neurologic findings were inconsistent with a generalized defect of peroxisomal function and were unique. Analysis of the urine from the recipient of the deceased sibling's liver confirmed the same bile acid synthetic defect. A deficiency in 2-methylacyl-CoA racemase, which is essential for conversion of (25R)THCA to its 25S-isomer, the substrate to initiate peroxisomal beta-oxidation to primary bile acids, was confirmed by DNA analysis revealing a missense mutation (S52P) in the gene encoding this enzyme. Long-term treatment with cholic acid normalized liver enzymes and prevented progression of symptoms.
This genetic defect further highlights bile acid synthetic defects as a cause of neonatal cholestasis.

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    • "In a few patients with AMACR deficiency cholestatic liver disease developed in childhood with malabsorption of fat soluble vitamins [36]. Histological alterations were similar to those in patients with bile acid synthesis defects including giant cell transformation and subsequent necrosis [36]. In contrast, other AMACR patients, several of which even had the same genetic constellation, only exhibited nervous system pathologies in adulthood [37]. "
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    ABSTRACT: The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remain unclear.
    Full-text · Article · Oct 2015 · Biochimica et Biophysica Acta
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    • "Currently Amacr is widely regarded as a diagnostic marker in prostate cancer and it is also overexpressed in other types of tumors, including liver, kidney and colorectal cancers [12]. Amacr deficiency is a rare peroxisomal disorder with varying neurological symptoms in the late-onset form and bile acid deficiency in early-onset disease, although elevated levels of pristanic acid and bile acid intermediates are common to all patients [13] [14] [15] [16] [17] [18] [19]. "
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    ABSTRACT: Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolisms that allow these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse.
    Full-text · Article · May 2013 · Biochimica et Biophysica Acta
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    • "Alpha-methylacyl-coA racemase deficiency has also been reported in four infants although clinical presentation differed to that seen in adults with abnormal bile acid synthesis, coagulopathy and neonatal cholestasis [9,28,29]. In addition to the variability seen in patients with α-methylacyl-coA racemase deficiency, deficiency of SCPx, a downstream enzyme in the peroxisomal β-oxidation, causes similar clinical and MRI findings with increased pristanic acid in blood [15]. "
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    ABSTRACT: Background Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. Methods We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. Results A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. Conclusions Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset α-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.
    Full-text · Article · Jan 2013 · Orphanet Journal of Rare Diseases
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