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At least 19 recordsLinked to original sources
PubMed1985

Bile acid abnormalities and the diagnosis of cerebro-hepato-renal syndrome (Zellweger syndrome).

The Zellweger or cerebro-hepato-renal syndrome (CHRS) is a congenital disorder characterized by cerebral dysfunction, craniofacial dysmorphic features, transient cholestasis and renal cysts. Patients fail to thrive, and usually die in their first year of life. In some cases, a definite diagnosis on purely clinical signs might not be possible. Several biochemical abnormalities have been observed in these patients and some of them have been tested as diagnostic markers. The aim of this study is to evaluate bile acid metabolites as biochemical markers of the CHRS. From a study of 20 CHRS patients, we conclude that screening for the presence of coprostanic acids and the C-29 dicarboxylic bile acid in serum or urine is for detection of CHRS and confirmation of the diagnosis.

Bile Acids and Salts↗
PubMed1992

Prenatal diagnosis in high risk pregnancies for Zellweger syndrome.

Zellweger syndrome is a lethal disorder. At present, no effective therapies are known for the patients of Zellweger syndrome. Recently a typical case of Zellweger syndrome in Japan was observed. In spite of intensive care, the patient died at the age of 3 months. Following this, the parents requested prenatal diagnosis for their following two pregnancies. We investigated levels of very long chain fatty acids (VLCFA), levels of bile acids in amniotic fluid and immunoblotting of peroxisomal beta-oxidation enzymes in cultured amniocytes. We report that immunoblotting using cultured amniocytes is an effective method for prenatal diagnosis of Zellweger syndrome. Furthermore, if we use immunoblotting for prenatal diagnosis, we can discriminate pseudoZellweger syndrome from pseudoneonatal adrenoleucodystrophy. Following prenatal diagnosis, two healthy babies were delivered. After birth, no abnormal levels of VLCFA in either serum or red blood cell membranes were confirmed. In this paper, we report that we can diagnose a healthy fetus in a high risk pregnancy for Zellweger syndrome.

Amniocentesis↗
PubMed2006

Contribution of fetal MR imaging in the prenatal diagnosis of Zellweger syndrome.

Zellweger syndrome (ZS), or cerebrohepatorenal syndrome, was the first described peroxisomal biogenesis disorder. It represents the most severe phenotype, and some of its multiple congenital anomalies can manifest prenatally. Fetal hypokinesia, renal hyperechogenicity, and cerebral ventricular enlargement are the most common reported fetal features. Single and/or late detectable manifestations account for most of the difficulties of prenatal diagnosis, as well as the limitations of ultrasonography itself. Prenatal diagnosis, however, can be achieved through (1) assays of concentrations of peroxisomal metabolites (very-long-chain fatty acids, bile acids, intermediates, plasmalogens), (2) activities of peroxisomal enzymes (dihydroacetone-phosphate acyltransferase), or (3) molecular screening techniques, if available. We report on the contribution of MR imaging to the diagnosis of ZS in 2 unrelated fetuses. MR imaging was performed in the third trimester because of cerebral ventricular enlargement diagnosed on routine sonography examinations. In both cases, MR imaging revealed ZS-characteristic abnormal cortical gyral patterns, impaired myelination, and cerebral periventricular pseudocysts. In addition, MR imaging revealed renal microcysts and hepatosplenomegaly in one case. The high level of resolution of MR imaging, which allows analysis of cerebral gyration and myelination, facilitates the prenatal diagnosis of complex polymalformative syndromes such as ZS.

Abortion, Eugenic↗
PubMed1988

Molecular analysis of peroxisomal beta-oxidation enzymes in infants with Zellweger syndrome and Zellweger-like syndrome: further heterogeneity of the peroxisomal disorder.

The biosynthesis of enzymes of peroxisomal beta-oxidation was investigated in an attempt to elucidate the mechanism of deficiencies of proteins of these enzymes in 3 infants with Zellweger syndrome and in a baby with Zellweger-like syndrome with clinical and biochemical findings consistent with Zellweger syndrome except that the peroxisomes were detected electronmicroscopically. Enzyme proteins of peroxisomal beta-oxidation, acyl-CoA oxidase, bifunctional protein and 3-ketoacyl-CoA thiolase were hardly detectable, in both syndromes. Total hepatic RNA extracted from the liver of one patient with each syndrome and three controls was translated in a rabbit reticulocyte lysate protein-synthesizing system in the presence of [35S]methionine. Translatable mRNAs for all of the peroxisomal beta-oxidation enzymes were detected in both patients at much the same levels seen in the controls. Pulse labelling and chase experiments of fibroblasts from the control revealed that the 72 kDa subunit of acyl-CoA oxidase was first synthesized, after which the 52 kDa and 21 kDa subunits were processed from the 72 kDa subunit. In the patient with Zellweger syndrome, little of the 52 kDa and 21 kDa subunits of acyl-CoA oxidase were synthesized. The mature form of peroxisomal 3-ketoacyl-CoA thiolase was also not processed from its precursor form, in this patient. We consider that Zellweger-like syndrome is a new variant form of a peroxisomal disorder in which biogenesis of peroxisomes is intact, while in contrast, the biogenesis of peroxisome is considered to be defective in those with Zellweger syndrome. Multiple defects of enzymes of beta-oxidation in Zellweger-like syndrome are assumed to be caused by a defect of transport or localization of these enzymes. Our molecular analyses indicate that the enzymes of peroxisomal beta-oxidation are synthesized in patients with Zellweger and Zellweger-like syndrome but that these enzymes are not processed normally and are degraded rapidly.

Abnormalities, Multiple↗
PubMed1983

Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome (Zellweger's syndrome) and its relationship to neonatal adrenoleukodystrophy.

The eyes of three infants with cerebrohepatorenal disease (Zellweger's syndrome) who died demonstrated ganglion cell loss, gliosis of the nerve fiber layer and optic nerve, optic atrophy, and changes resembling those of retinitis pigmentosa in the retina and pigment epithelium. Ultrastructural examination showed bileaflet inclusions identical to those seen in neonatal adrenoleukodystrophy in the pigment epithelium and in pigmented macrophages, but these were absent in the cornea. Biochemical analysis of tissues demonstrated an excessive amount of very-long-chain fatty acids in the ocular tissues, an abnormality also found in adrenoleukodystrophy. These histopathologic and biochemical results demonstrated that the cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy are similar in regard to ocular abnormalities and the presence of saturated very-long-chain fatty acids.

Adrenoleukodystrophy↗
PubMed1976

Neuropathological considerations in cerebro-hepato-renal syndrome (Zellweger's syndrome).

The nervous system in patients with cerebro-hepato-renal syndrome appeared to be affected at various tissue levels. There was evidence of a migrational disorder manifested by polymicrogyria and lack of normal neuronal maturation. There was dysmyelination of the white matter associated with accumulation of neutral fat in astrocytes. Within the peripheral nerves, masses of tangled neurofilaments producing dystrophic axons were demonstrated by electron microscopy. These findings could be explained on the basis of a genetic metabolic defect, one that involved particularly the amino acids. The defect may have interfered with the normal intercellular reaction during embryogenesis resulting in the malformation of multiple organs. The same metabolic abnormality could have caused the hepatic damage and disturbance in normal myelination during the neonatal period.

Abnormalities, Multiple↗
PubMed1999

Identification of a common PEX1 mutation in Zellweger syndrome.

The Zellweger spectrum of disease, encompassing Zellweger syndrome and the progressively milder phenotypes of neonatal adrenoleukodystrophy and infantile Refsum disease, is due to a failure to form functional peroxisomes. Cell fusion complementation studies demonstrated that these diseases are genetically heterogeneous, with two-thirds of all patients lying within a single complementation group, CG1. Molecular genetic and cell biology studies have shown that PEX1 is deficient in many CG1 patients. However, previous studies have focused on mildly affected patients and there is still no report of two mutant PEX1 alleles in any Zellweger syndrome patient. Furthermore, mutations in the PMP70 gene have also been identified in two Zellweger syndrome patients from CG1, raising the possibility that CG1 patients may represent a mixture of PEX1-deficient and PMP70-deficient individuals. To address the molecular basis of disease in Zellweger syndrome patients from CG1, we examined all 24 PEX1 exons in four patients, including both patients that have mutations in PMP70. PEX1 mutations were detected in all four patients, including a 1-bp insertion (c.2097insT) in exon 13 that was present in three of the four patients. Subsequent studies demonstrated that this mutation is present in one-half of all CG1 patients and correlates with the Zellweger syndrome phenotype. As this mutation leads to a loss of protein function its frequency makes it the most common cause of Zellweger syndrome, helping to explain the high percentage of patients that belong to CG1.

ATP-Binding Cassette Transporters↗
PubMed1991

Importance of peroxisomes in the formation of chenodeoxycholic acid in human liver. Metabolism of 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid in Zellweger syndrome.

Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered [3H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 3H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of [3H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid.

Bile↗
PubMed2003

Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype.

Zellweger syndrome is the archetypical peroxisome biogenesis disorder and is characterized by defective import of proteins into the peroxisome, leading to peroxisomal metabolic dysfunction and widespread tissue pathology. In humans, mutations in the PEX13 gene, which encodes a peroxisomal membrane protein necessary for peroxisomal protein import, can lead to a Zellweger phenotype. To develop mouse models for this disorder, we have generated a targeted mouse with a loxP-modified Pex13 gene to enable conditional Cre recombinase-mediated inactivation of Pex13. In the studies reported here, we crossed these mice with transgenic mice that express Cre recombinase in all cells to generate progeny with ubiquitous disruption of Pex13. The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death. These animals lacked morphologically intact peroxisomes and showed deficient import of matrix proteins containing either type 1 or type 2 targeting signals. Biochemical analyses of tissue and cultured skin fibroblasts from these animals indicated severe impairment of peroxisomal fatty acid oxidation and plasmalogen synthesis. The brains of these animals showed disordered lamination in the cerebral cortex, consistent with a neuronal migration defect. Thus, Pex13(-/-) mice reproduce many of the features of Zellweger syndrome and PEX13 deficiency in humans.

Animals↗
PubMedDate not supplied

A case of pseudo-Zellweger syndrome with a possible bifunctional enzyme deficiency but detectable enzyme protein. Comparison of two cases of Zellweger syndrome.

Three infants with peroxisomal disorders were investigated clinicobiochemically and neuroradiologically. Two had classical Zellweger syndrome, and cranial CT scans showed typical disproportionate enlargement of the occipital horns of the lateral ventricles (colpocephaly) with marked hypodensity of the white matter. In one female infant, although the clinical findings were similar to those in Zellweger syndrome, some findings, such as elevated transaminase levels, liver fibrosis, the absence of renal cortical cysts and colpocephaly, were negative or milder. Biochemical analyses revealed increased very long-chain fatty acids, dicarboxylic aciduria and impaired beta-oxidation of lignoceric acid. However, peroxisomes were abundantly present in hepatocytes and cultured fibroblasts, and all peroxisomal beta-oxidation enzyme proteins were detected on immunoblot analysis. A cell fusion study suggested that the enzyme responsible for this case of 'pseudo-Zellweger syndrome' is bifunctional.

Cerebral Ventriculography↗
PubMed1986

Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy.

Patients with the cerebrohepatorenal syndrome of Zellweger lack peroxisomes and certain peroxisomal enzymes such as dihydroxyacetone phosphate acyltransferase in their tissues. Deficiency of this enzyme, which is necessary for glycerol ether lipid synthesis, provides a biochemical method for recognizing patients with subtle manifestations of Zellweger syndrome and suggests the utility of exogenous ether lipid precursors as a therapeutic strategy for these children. We describe the results of glycerol ether lipid supplementation to two children, one with classic Zellweger syndrome and 9% of control fibroblast dihydroxyacetone phosphate acyltransferase activity, and one with mild facial manifestations, wide sutures, hypotonia, developmental delay, hepatomegaly, peripheral retinal pigmentation, and 50% of control fibroblast dihydroxyacetone phosphate acyltransferase activity. An increase in erythrocyte plasmalogen levels following therapy was clearly demonstrated in the milder patient, and neither patient showed evidence of toxicity. Evaluation of therapy by comparison to the usual clinical course of Zellweger syndrome was not helpful because of the variability and incomplete documentation of 90 previously reported cases. The literature survey did provide criteria for classic Zellweger syndrome, which include hypotonia with or without deformation of limbs, large fontanels and split sutures, prominent forehead, flattened facial profile with hypoplastic supraorbital ridges, anteverted nares, highly arched palate, cryptorchidism or labial hypoplasia, hepatomegaly or elevated liver enzymes, peripheral pigmentation of the retina, renal cortical cysts, and characteristic neuropathology involving decreased myelinization, abnormal neuronal migration, and sudanophilic macrophages. Less severe patients, as exemplified by our case 2 and others from the literature, will not have all the classic features and can be recognized only by a growing panel of biochemical indicators. Our patient studies illustrate the complexity of designing comprehensive therapy for Zellweger-like conditions, suggest other diseases that may involve peroxisomal alterations, and emphasize the need for multicenter, collaborative studies to evaluate biochemical heterogeneity and therapy of peroxisomal disorders.

Adrenoleukodystrophy↗
PubMedDate not supplied

Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome).

The Zellweger syndrome is a lethal hereditary disease characterized by the absence of peroxisomes (microbodies) in liver and kidney, and variable abnormalities in mitochondria. We show here that tissues from five infants that had died of this syndrome contain less than 10% of the normal levels of phosphatidylethanolamine plasmalogen (pPE), a major phospholipid component of cellular membranes. Heart and muscle, but not other tissues, also contain a substantial fraction of phosphatidylcholine plasmalogen (pPC), and this fraction is also strongly reduced in the Zellweger patients. No other abnormalities in cellular phospholipids were detected. Key enzymes of the biosynthesis of plasmalogens have previously been shown to be exclusively located in the peroxisomes of rodent liver and the microperoxisomes of rodent brain. We infer that the corresponding enzymes are also located in peroxisomes in man and that the absence of peroxisomes in Zellweger patients leads to their inability to synthesize plasmalogens. Our results support the notion that the biosynthetic role of peroxisomes in mammals has thus far been underestimated. We suggest that the defect in plasmalogen synthesis and possibly as yet unknown peroxisomal reactions are responsible for the diverse abnormalities observed in Zellweger patients.

Abnormalities, Multiple↗
PubMed2005

Caudothalamic groove cysts in Zellweger syndrome.

The cerebro-hepato-renal syndrome of Zellweger is the most severe peroxisome biogenesis disorder. Zellweger syndrome is caused by a disturbance in the peroxisomal protein import machinery and leads to multiple organ defects and death usually within the first year of life. Here we report a 3-month-old girl with Zellweger syndrome who was found to have cysts in the caudothalamic groove on cranial magnetic resonance imaging.

Caudate Nucleus↗