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.
"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 . 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       . "
[Show abstract][Hide abstract] 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.
"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 . "
[Show abstract][Hide abstract] 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.
We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.
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.
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.
"To date, 10 patients with AMACR deficiency have been described. Clinical features range from neonatal cholestasis and/ or giant cell hepatitis [Van Veldhoven et al., 2001; Setchell et al., 2003], recurrent rhabdomyolysis [Kapina et al., 2010], to late-onset neurological disease, including encephalopathy, sensory and motor neuropathy, seizures, cerebellar ataxia, and retinitis pigmentosa [Ferdinandusse et al., 2000; Clarke et al., 2004; Thompson et al., 2008; Smith et al., 2010; Dick et al., 2011]. There is considerable clinical overlap with other peroxisomal disorders, especially Refsum disease. "
Jihwa Chung, Kyoung Hwa Kim, Seok Cheol Lee, Shung Hyun An, Kihwan Kwon
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