The cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects

Kelley, Richard I.

doi:10.1002/ajmg.1320160409

Cited by 170 publications

(52 citation statements)

References 72 publications

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“…Diagnosis of ALD was based on neurological findings and was confirmed by increased C2(,0 fatty acid levels in leukocytes and fibroblasts (1 5). Patients with NCL were diagnosed by the typical clinical and ultrastructural findings (16) and the patient with CHRS was recognized by the typical clinical characteristics (2) and by the presence of hyperpipecolic acidemia.…”

Section: Materials a N D Methodsmentioning

confidence: 99%

The Cerebrohepatorenal (Zellweger) Syndrome: An Improved Method for the Biochemical Diagnosis and its Potential Value for Prenatal Detection

et al. 1985

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Section: Materials a N D Methodsmentioning

confidence: 99%

The Cerebrohepatorenal (Zellweger) Syndrome: An Improved Method for the Biochemical Diagnosis and its Potential Value for Prenatal Detection

et al. 1985

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“…The importance ofperoxisomes in man can be gauged from the existence of a group of genetic diseases caused by an impairment in one or more peroxisomal functions (5)(6)(7)(8). Goldfischer and co-workers (9) were the first to observe that morphologically distinguishable peroxisomes are absent in liver and kidney tubules from patients with the cerebro-hepato-renal (Zellweger) syndrome, the prototype of this newly recognized group of peroxisomal disorders.…”

Section: Introductionmentioning

confidence: 99%

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Wanders¹,

Roermund²,

Wijland³

et al. 1987

J. Clin. Invest.

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The peroxisomal oxidation of the long chain fatty acid palmitate (C16:0) and the very long chain fatty acids lignocerate (C24:0) and cerotate (C26:0) was studied in freshly prepared homogenates of cultured skin fibroblasts from control individuals and patients with peroxisomal disorders. The peroxisomal oxidation of the fatty acids is almost completely dependent on the addition of ATP, coenzyme A (CoA), Mg2+ and NAD'.However, the dependency of the oxidation of palmitate on the concentration of the cofactors differs markedly from that of the oxidation of lignocerate and cerotate.The peroxisomal oxidation of all three fatty acid substrates is markedly deficient in fibroblasts from patients with the Zellweger syndrome, the neonatal form of adrenoleukodystrophy and the infantile form of Refsum disease, in accordance with the deficiency of peroxisomes in these patients. In fibroblasts from patients with X-linked adrenoleukodystrophy the peroxisomal oxidation of lignocerate and cerotate is impaired, but not that of palmitate. Competition experiments indicate that in fibroblasts, as in rat liver, distinct enzyme systems are responsible for the oxidation of palmitate on the one hand and lignocerate and cerotate on the other hand. Fractionation studies indicate that in rat liver activation of cerotate and lignocerate to cerotoyl-CoA and lignoceroyl-CoA, respectively, occurs in two subcellular fractions, the endoplasmic reticulum and the peroxisomes but not in the mitochondria. In homogenates of fibroblasts from patients lacking peroxisomes there is a small (25%) but significant deficiency of the ability to activate very long chain fatty acids. This deficient activity of very long chain fatty acyl-CoA synthetase is also observed in fibroblast homogenates from patients with X-linked adrenoleukodystrophy. We conclude that X-linked adrenoleukodystrophy is caused by a deficiency of peroxisomal very long chain fatty acyl-CoA synthetase.

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“…2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty acids, bile acid intermediates and pipecolic acid, and a severe depletion of ether phospholipids and docosahexaenoic acid. 2…”

mentioning

confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

et al. 2005

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Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

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The cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects

Cited by 170 publications

References 72 publications

The Cerebrohepatorenal (Zellweger) Syndrome: An Improved Method for the Biochemical Diagnosis and its Potential Value for Prenatal Detection

The Cerebrohepatorenal (Zellweger) Syndrome: An Improved Method for the Biochemical Diagnosis and its Potential Value for Prenatal Detection

Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders.

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

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