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PubMed2003

Phenotypic variability (heterogeneity) of peroxisomal disorders.

Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are related to lipid metabolism. Peroxisomal disorders result either from deficiency of a single peroxisomal enzyme or protein, or from a defect in the complex mechanism of peroxisomal biogenesis, resulting in deficiency of several or multiple peroxisomal functions. These can be assessed by a battery of biochemical assays, enabling a biochemical phenotype to be defined that is specific and diagnostic for each of the peroxisomal disorders. Some peroxisomal disorders have unique and specific clinical phenotypes, which may be diagnostic. Others share patterns of clinical abnormalities (particularly neurological dysfunction, craniofacial dysmorphism, skeletal defects, sensory deafness, retinopathy) consistent with defined clinical phenotypes, but with considerable overlap and heterogeneity. To a certain extent, the clinical features of a particular disorder reflect the accumulation or deficiency of specific metabolites. Thus, the same clinical phenotypes may be caused by both single enzyme defects and PBDs. Furthermore, the same defect may present with different clinical phenotypes. In general, the severity of the clinical phenotype correlates with the degree of biochemical dysfunction. The clinical heterogeneity of peroxisomal disorders constitutes a diagnostic challenge demanding a high index of suspicion on the clinician's part.

Chondrodysplasia Punctata, Rhizomelic↗

PubMed1997

Lipoprotein[a] is not present in the plasma of patients with some peroxisomal disorders.

Peroxisomal disorders arise either from defects in the biogenesis of peroxisomes or from the defective synthesis of one or more peroxisomal enzymes. These defects result in metabolic disturbances in peroxisomal beta-oxidation of various fatty acids and derivatives and/or in the biosynthesis of ether lipids. In the current study, lipoprotein levels were determined in plasma samples from patients diagnosed with one of four different peroxisomal disorders. While low density lipoprotein (LDL) levels were found to be within the normal range, lipoprotein[a] (Lp[a]) could not be detected by enzyme-linked immunosorbent assay (ELISA) in plasma from patients with cerebro-hepato-renal (Zellweger) syndrome (ZS) and rhizomelic chondrodysplasia punctata (RCDP). Conversely, Lp[a] was clearly present in control plasma obtained from healthy newborns and from patients affected with one of two other peroxisomal disorders, X-linked adrenoleukodystrophy (X-ALD) and Refsum disease (RD) as determined by ELISA. The lack of Lp[a] in plasma of patients with ZS may result from defective secretion of apolipoprotein[a] (apo[a]) (the distinguishing protein component of Lp[a]), as apo[a] mRNA transcripts were clearly present in ZS livers as assessed by PCR, and intracellular apo[a] protein was detected in total liver homogenates from ZS patients as determined by Western blot analysis. Furthermore, LDL present in the plasma of ZS patients was able to associate with recombinant apo[a] in an in vitro Lp[a] assembly assay.

Adolescent↗

PubMed2004

Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders.

Peroxisomal disorders include a complex spectrum of diseases, characterized by a high heterogeneity from both the clinical and the biochemical points of view. Specific assays are required for the study of peroxisome metabolism. Among these, pipecolic acid evaluation is considered as a supplementary test. We have established the diagnostic role of pipecolic acid in 30 patients affected by a peroxisomal defect (5 Zellweger syndromes, 10 Infantile Refsum diseases, 1 neonatal adrenoleukodystrophy, 6 patients affected by a peroxisomal biogenesis disorder with unclassified phenotype, 1 case of rhizomelic chondrodysplasia punctata (RCDP), 2 acyl-CoA oxidase deficiencies, 2 bifunctional enzyme deficiencies, 2 Refsum diseases, and 1 beta-oxidation deficiency). Pipecolic acid was increased in all generalized peroxisomal disorders, while normal pipecolic acid with abnormal very long chain fatty acid concentrations was strong evidence for a single peroxisomal enzyme deficiency. Unexpectedly, hyperpipecolic acidaemia was found also in a child affected by RCDP and in two patients with Refsum disease. In six patients the suggestion of a peroxisomal disorder was raised by the fortuitous finding of a pipecolic acid peak in amino acid chromatography, routinely performed as a general metabolic screening. For all patients, pipecolic acid proved to be a useful parameter in the biochemical classification of peroxisomal disorders.

Adolescent↗

PubMed2002

Peroxisomal disorders.

Peroxisomes are subcellular organelles catalyzing a number of indispensable functions in cellular metabolism. The importance of peroxisomes is stressed by the existence of an expanding number of genetic diseases in which there is an impairment of one or more peroxisomal functions. The prototype of this group of diseases is the cerebro-hepato-renal syndrome of Zellweger (ZS), first described as a familial syndrome of multiple congenital defects in 1964. ZS is characterized by the presence of dysmorphias and polymalformative syndrome, severe neurologic abnormalities including neurosensory defects and hepato-intestinal dysfunction with failure to thrive and usually early death. Other peroxisomal disorders share some of these symptoms, but with varying degrees of organ involvement, severity of dysfunction and duration of survival. This paper provides an overview of the peroxisomal disorders including their clinical, biochemical and molecular characteristics with particular emphasis on the clinical presentation in neonates.

Diagnosis, Differential↗

PubMed2003

Human peroxisomal disorders.

Peroxisomes are single membrane-bound cell organelles performing numerous metabolic functions. The present article aims to give an overview of our current knowledge about inherited peroxisomal disorders in which these organelles are lacking or one or more of their functions are impaired. They are multiorgan disorders and the nervous system is implicated in most. After a summary of the historical names and categories, each having distinct symptoms and prognosis, microscopic pathology is reviewed in detail. Data from the literature are added to experience in the authors' laboratory with 167 liver biopsy and autopsy samples from peroxisomal patients, and with a smaller number of chorion samples for prenatal diagnosis, adrenal-, kidney-, and brain samples. Various light and electron microscopic methods are used including enzyme- and immunocytochemistry, polarizing microscopy, and morphometry. Together with other laboratory investigations and clinical data, this approach continues to contribute to the diagnosis and further characterization of peroxisomal disorders, and the discovery of novel variants. When liver specimens are examined, three main groups including 9 novel variants (33 patients) are distinguished: (1) absence or (2) presence of peroxisomes, and (3) mosaic distribution of cells with and without peroxisomes (10 patients). Renal microcysts, polarizing trilamellar inclusions, and insoluble lipid in macrophages in liver, adrenal cortex, brain, and in interstitial cells of kidney are also valuable for classification. On a genetic basis, complementation of fibroblasts has classified peroxisome biogenesis disorders into 12 complementation groups. Peroxisome biogenesis genes (PEX), knock-out-mice, and induction of redundant genes are briefly reviewed, including some recent results with 4-phenylbutyrate. Finally, regulation of peroxisome expression during development and in cell cultures, and by physiological factors is discussed.

Adrenoleukodystrophy↗

PubMed1989

Prenatal and perinatal diagnosis of peroxisomal disorders.

Peroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified into three groups: (1) disorders of peroxisome biogenesis with a generalized loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidaemia); (2) disorders with a loss of multiple peroxisomal functions (rhizomelic chondrodysplasia punctata and Zellweger-like syndrome; (3) disorders with loss of a single peroxisomal function (X-linked adrenoleukodystrophy, peroxisomal thiolase deficiency, bifunctional protein deficiency, acyl-CoA oxidase deficiency, classic Refsum disease, hyperoxaluria type I and acatalasaemia). Prenatal diagnosis is indicated in all these genetic disorders with the exception of classic Refsum disease, most types of hyperoxaluria type I and acatalasaemia. A variety of techniques is available now for the prenatal diagnosis of peroxisomal disorders in the first or second trimester of gestation. Prenatal diagnosis was performed by us in 70 pregnancies at risk for a disorder of peroxisome biogenesis, three for rhizomelic chondrodysplasia punctata, four for X-linked adrenoleukodystrophy and two for a defect in peroxisomal beta-oxidation. Fourteen affected fetuses were identified; no false negative cases were obtained.

Female↗

PubMed2001

Peroxisomal disorders.

Peroxisomes are membrane-bound subcellular organelles that are involved in a variety of cellular functions. Disorders of peroxisomes, either in their assembly or single enzyme deficiencies, manifest themselves in the nervous system both in development and later in life. Most peroxisomal matrix proteins are targeted using one of the targeting sequences, whereas integral peroxisomal membrane proteins employ a different method. Peroxisomal importation is unique, allowing the importation of oligomerized proteins, and uses a specific extended shuttle system of receptor and cargo. The understanding of peroxisomal assembly is important because peroxisomal biogenesis disorders such as Zellweger syndrome result from these defects, and the resulting failure causes widespread deficiencies in peroxisomal biochemical function. X-linked adrenoleukodystrophy, representing the other group of peroxisomal disorders, is caused by the lack of the adrenoleukodystrophy protein, with an accumulation of very long chain fatty acids. New information on clinical incidence, phenotypic variability, and pathogenesis is becoming available and will have implications for possible therapies.

Adrenoleukodystrophy↗

PubMed1998

[Molecular analysis of peroxisomal disorders].

Peroxisome biogenesis disorders (PBD) include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). They are classified into ten complementation groups. Five pathogenic genes have been identified using different model systems of peroxisome deficient mutants. PAF-1 and 2 were identified from CHO mutants and were responsible genes for PBD group F and C. Human PEX 5, 12 and 1, responsible genes for group 2, 3 and 1, respectively, were cloned by homology search between yeast PEX genes and human genes on the cDNA data base. Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, shows phenotypic heterogeneity. Its responsible gene was cloned by positional cloning. It encodes a 75 kDa peroxisomal membrane protein (ALDP) that is a member of the ATP-binding cassette transporter family. There are about 120 different mutations including missense, nonsense and splice mutations, as well as insertions and deletions of a few base pairs. There is no correlation between the clinical phenotype and the ALDP gene mutation. Recently, animal models have been produced by targeted mutation of the PBD and ALD genes. The mouse model should facilitate researches on PBD and ALD, especially those on regulatory factors of their phenotypic heterogeneity and on new therapeutic approaches.

Adrenoleukodystrophy↗

PubMed1999

Peroxisomal disorders.

Peroxisomes, subcellular organelles found in nearly all eukaryotic cells, are involved in numerous biochemical functions within the cell. There has been an increasing understanding of the genetic mechanism of the diseases of the single peroxisomal enzyme abnormalities as well as defects of peroxisome biogenesis. Peroxisome assembly disorders including Zellweger syndrome and rhizomelic chondrodysplasia punctata are caused by genetic defects in PEX genes and the altering of their proteins, peroxins, which are necessary for the importation of targeted proteins into the peroxisomes. Therapies for peroxisomal disorders have been unsatisfactory to date, but there has been interest in docosahexaenoic acid in assembly disorders and phenylbutyrate and lovastatin in adrenoleukodystrophy (ALD). Whether any of these therapies will result in clinical improvement awaits additional study.

Animals↗

PubMed1991

Peroxisomal disorders.

Peroxisomal disorders occur more frequently and have a wider range of clinical manifestations than has been realized in the past. Precise diagnosis can be achieved with non-invasive biochemical assays and all can be diagnosed prenatally, thus providing the option of genetic counseling. Specific therapy is being evaluated for one of these disorders (adrenoleukodystrophy). In addition to these clinical advances, a great deal of information has been gained recently about the biogenesis and normal function of peroxisomes. These latter advances have been stimulated, and in part created, by the study of human disease states. It is for these reasons that a review of these human disease states is relevant for the clinical biochemist.

Amino Acid Sequence↗

PubMedDate not supplied

Peroxisomes, lipid metabolism, and peroxisomal disorders.

Peroxisomes catalyse a large variety of different cellular functions of which most have to do with lipid metabolism. This paper deals with the role of peroxisomes in three key pathways of lipid metabolism, including: (1) etherphospholipid biosynthesis, (2) fatty acid beta-oxidation, and (3) fatty acid alpha-oxidation. Apart from a brief description of the peroxisomal enzymes involved in each of these pathways, the interaction between peroxisomes and other subcellular organelles, notably microsomes and peroxisomes, will be discussed. Finally, the current state of knowledge with respect to the different disorders of peroxisomal lipid metabolism will be described.

Acyl-CoA Oxidase↗

PubMed1997

D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency: a newly identified peroxisomal disorder.

Peroxisomal beta-oxidation proceeds from enoyl-CoA through D-3-hydroxyacyl-CoA to 3-ketoacyl-CoA by the D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxy-acyl-CoA dehydrogenase bifunctional protein (d-bifunctional protein), and the oxidation of bile-acid precursors also has been suggested as being catalyzed by the d-bifunctional protein. Because of the important roles of this protein, we reinvestigated two Japanese patients previously diagnosed as having enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (L-bifunctional protein) deficiency, in complementation studies. We found that both the protein and the enzyme activity of the d-bifunctional protein were hardly detectable in these patients but that the active L-bifunctional protein was present. The mRNA level in patient 1 was very low, and, for patient 2, mRNA was of a smaller size. Sequencing analysis of the cDNA revealed a 52-bp deletion in patient 1 and a 237-bp deletion in patient 2. This seems to be the first report of D-bifunctional protein deficiency. Patients previously diagnosed as cases of L-bifunctional protein deficiency probably should be reexamined for a possible d-bifunctional protein deficiency.

17-Hydroxysteroid Dehydrogenases↗

PubMed1999

Diagnosis and follow-up of a case of peroxisomal disorder with peroxisomal mosaicism.

Peroxisomal disorder phenotypes are the result of mutations that cause defective peroxisomal assembly or alterations in the import mechanism of peroxisomal proteins that lead to multiple peroxisomal dysfunctions, or the result of a peroxisomal enzymatic deficiency with a single peroxisomal dysfunction. With complementation analysis, 16 groups have been found. Assignment of the genetic defect has been described for some of the complementation groups. We describe the clinical evolution and follow-up over 10 years of a patient who belongs to complementation group 4, although he showed a milder clinical course. It has been found in fibroblasts different peroxisome populations, normal processing and expression of beta-oxidation PTS1 and PTS2 proteins, abnormal ALD protein distribution and normal plasmalogen biosynthesis; abnormal beta-oxidation metabolites have also been detected in serum. Ultrastructural studies in liver showed peroxisomal mosaicism as in fibroblasts. It has been taken into account that peroxisomal mosaicism may lead to variability in peroxisomal diagnostic parameters, making difficult the final diagnosis in these patients.

Adolescent↗

PubMed1988

Clinical biochemistry of peroxisomal disorders.

Peroxisomes have been shown to participate in a variety of pathological processes. Peroxisomal anomalities are central features of Zellweger's cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease and several other genetic metabolic disorders (pseudo-Zellweger syndrome, Leber congenital amaurosis, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata). In disorders with general loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) an accumulation of very long-chain fatty acids and pathological bile acids are found. Patients have a defective synthesis of plasmalogens and show increased excretion of dicarboxylic acids of medium chain length and of pipecolic acid in the urine. These anomalities which are due to the lack of peroxisomal enzymes, supply the basis for clinical laboratory tests. The study of these peroxisomal disorders has presented valuable information on the normal function of peroxisomes.

Humans↗

PubMed1994

[Liver pathologies due to peroxisome disorders].

Peroxisomes or microbodies are peculiar subcellular organelles with an important role in the metabolism of a variety of different organic compounds. Particularly they are an important site of bile acids synthesis. Some hepatic diseases, mainly cholestatic, can to be reconnected at disorders of bile acids synthesis by these organelles. From the biochemical point some diseases present alterations of the cholesterol side chain (Zellweger syndrome, pseudo-Zellweger syndrome, infantile Refsum's disease, neonatal adrenoleukodystrophy), other diseases present errors involving the steroid nucleus (familial giant cell hepatitis). Zellweger disease or cerebro-hepato-renal syndrome is characterized clinically by skeletal changes, muscle hypotonia, renal cysts, psychosomatic retardation and persistent cholestasis and from the ultrastructural standpoint by the virtual absence of liver cell peroxisomes. Pseudo-Zellweger disease shows many of the clinical features of Zellweger disease but differs from this condition on account of the presence of abundant peroxisomes in the liver cells. Infantile Refsum's disease and neonatal adrenoleukodystrophy show typical clinical disorders and liver damage leading to cirrhosis. "Familial giant cell hepatitis" is characterized by jaundice from the first days of life, hepatosplenomegaly, cholestasis, lack of physical malformations. The disorder is due to defective biosynthesis of the bile acids with formation of allo-bile acids.

Adrenoleukodystrophy↗

PubMed2000

Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders.

Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22:6n-3) and low DHA concentrations in all tissues and the blood. Given the fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.

Brain↗

PubMed2006

Peroxisomal disorders: the single peroxisomal enzyme deficiencies.

Peroxisomal disorders are a group of inherited diseases in man in which either peroxisome biogenesis or one or more peroxisomal functions are impaired. The peroxisomal disorders identified to date are usually classified in two groups including: (1) the disorders of peroxisome biogenesis, and (2) the single peroxisomal enzyme deficiencies. This review is focused on the second group of disorders, which currently includes ten different diseases in which the mutant gene affects a protein involved in one of the following peroxisomal functions: (1) ether phospholipid (plasmalogen) biosynthesis; (2) fatty acid beta-oxidation; (3) peroxisomal alpha-oxidation; (4) glyoxylate detoxification, and (5) H2O2 metabolism.

Fatty Acids↗

PubMed1999

[Introduction to the study of peroxisomal disorders].

The peroxisome is an organelle found in all nucleated cells of mammalian. Its name is due to H2O2 formation as result of cell respiration catalyzed by oxidases and catalases and play and important role on myelination and neuronal migration. Peroxisomes are formed by assembling of membrane proteins (structural, receptors and transporters) into peroxisomal membrane. Peroxisomal proteins are encoded by nuclear genes, synthesized on cytosol ribosomes and imported into peroxisomal matrix, mediated by receptors and transporters membrane proteins. There are two main categories of peroxisomal disorders: disorder of peroxisome biogenesis exemplified by Zellweger syndrome, where multiple peroxisomal protein, functions are deficient and disorders which involves a single peroxisomal protein, exemplified by X-adrenoleukodystrophy, where the organelle is apparently intact.

Biological Transport↗