Incidence of X-linked adrenoleukodystrophy and the relative frequency of its phenotypes.
Explore the source record for details and available documents.
Adrenoleukodystrophy↗
Biomedical subjects
H W Moser
Publications and source records attributed to H W Moser.
Characterization of phytanoyl-Coenzyme A hydroxylase in human liver and activity measurements in patients with peroxisomal disorders.
Phytanoyl-Coenzyme A hydroxylase is a newly recognized peroxisomal enzyme which catalyses the first step in the alpha-oxidation of phytanoyl-Coenzyme A. Since measurement of this enzyme activity in human liver homogenate is of great importance especially in relation to inherited diseases in which this enzyme activity is deficient, we have studied its characteristics in human liver. The results described in this paper show that optimal activity measurements require preformed phytanoyl-Coenzyme A plus 2-oxoglutarate, Fe2+ and ascorbate. The conditions developed can be used to determine phytanoyl-Coenzyme A hydroxylase activity in human liver homogenates which is of utmost importance not only for the diagnosis of patients, but also for the purification of the enzyme from various sources.
Enzyme Inhibitors↗
Neurometabolic disease.
Advances in knowledge of neurometabolic disease continues. Of great interest to the neurologist are the definitions of the molecular defects in Niemann-Pick C disease, Refsum disease, and five of the disorders of peroxisome biogenesis, including rhizomelic chondrodysplasia punctata. Duplication of the proteolipid protein gene is the most common molecular abnormality in Pelizaeus Merzbacher disease. Therapies for guanidinoacetate methyltransferase deficiency and for 3-phosphoglycerated dehydrogenase deficiency appear promising. Animal models have been developed for X-linked adrenoleukodystrophy, metachromatic leukodystrophy and Zellweger syndrome and will aid in the understanding of pathogenesis and the evaluation of therapy.
Animals↗
Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis.
Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. These studies confirm that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are a disease continuum. The gene defect in adreno-leukodystrophy (ALD) / adrenomyeloneuropathy (AMN) involves an integral peroxisomal membrane protein. Neuropathologic lesions are of three major classes: (i) abnormalities in neuronal migration or differentiation, (ii) defects in the formation or maintenance of central white matter, and (iii) postdevelopmental neuronal degenerations. The central white matter lesions are those of: (i) inflammatory demyelination, (ii) non-inflammatory dysmyelination, and (iii) non-specific reductions in myelin volume or staining with or without reactive astrocytosis. The neuronal degenerations are of two major types: (i) the axonopathy of AMN involving ascending and descending tracts of the spinal cord, and (ii) cerebellar atrophy in rhizomelic chondrodysplasia punctata and probably IRD. We postulate that the abnormal fatty acids in peroxisomal disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells. The advent of mouse models for ZS and ALD is anticipated to provide even greater pathogenetic insights into the peroxisomal disorders.
Adrenoleukodystrophy↗
A mouse model for X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired beta-oxidation of very long chain fatty acids (VLCFAs) and reduced function of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) that leads to severe and progressive neurological disability. The X-ALD gene, identified by positional cloning, encodes a peroxisomal membrane protein (adrenoleukodystrophy protein; ALDP) that belongs to the ATP binding cassette transporter protein superfamily. Mutational analyses and functional studies of the X-ALD gene confirm that it and not VLCS is the gene responsible for X-ALD. Its role in the beta-oxidation of VLCFAs and its effect on the function of VLCS are unclear. The complex pathology of X-ALD and the extreme variability of its clinical phenotypes are also unexplained. To facilitate understanding of X-ALD pathophysiology, we developed an X-ALD mouse model by gene targeting. The X-ALD mouse exhibits reduced beta-oxidation of VLCFAs, resulting in significantly elevated levels of saturated VLCFAs in total lipids from all tissues measured and in cholesterol esters from adrenal glands. Lipid cleft inclusions were observed in adrenocortical cells of X-ALD mice under the electron microscope. No neurological involvement has been detected in X-ALD mice up to 6 months. We conclude that X-ALD mice exhibit biochemical defects equivalent to those found in human X-ALD and thus provide an experimental system for testing therapeutic intervention.
Adrenoleukodystrophy↗
A fibroblast cell line defective in alkyl-dihydroxyacetone phosphate synthase: a novel defect in plasmalogen biosynthesis.
Using fluorescence-activated cytotoxicity selection, followed by colony autoradiographic screening of the surviving population, we have isolated a unique plasmalogen-deficient Chinese hamster ovary (CHO) cell line. The mutant, NZel-1, showed a dramatic (90%) reduction in the rate of biosynthesis and levels of plasmalogens, as determined using short- and long-term labeling with 32Pi. Enzymatic assays and lipid supplementation studies showed that NZel-1 was defective in a single step in the biosynthetic pathway for plasmalogens. This step, catalyzed by the peroxisomal enzyme, alkyl-dihydroxyacetone phosphate (DHAP) synthase, is responsible for the introduction of the ether bond found in plasmalogens. The activity of alkyl-DHAP synthase was reduced in whole-cell homogenates from NZel-1 to 18% of wild-type values. Unlike previously described plasmalogen-deficient mutants, NZel-1 contained peroxisomes, as confirmed by immunofluorescence microscopy and catalase release by digitonin. Peroxisomal functions, including the breakdown of very long-chain (>20 carbons) fatty acids, phytanic acid oxidation, and the acylation of DHAP, were normal. Cell fusion studies revealed that the mutation is recessive and belongs to a new complementation group. To our knowledge this is the first report describing the isolation and characterization of a mutant CHO cell line defective in plasmalogen biosynthesis which contains intact, functional peroxisomes. These cells will allow us to examine the role of ether lipids in cellular functions without complications associated with peroxisome deficiency.
Alkyl and Aryl Transferases↗
Localized proton magnetic resonance spectroscopy in patients with adult adrenoleukodystrophy. Increase of choline compounds in normal appearing white matter.
OBJECTIVES: To describe the changes in the results of magnetic resonance imaging and spectroscopy occurring in the normal-appearing white matter of patients with adult adrenoleukodystrophy and to present evidence of a particular change that may serve as a marker for the follow-up of the disease. DESIGN: Neurologic, magnetic resonance imaging, and localized proton spectroscopic examinations were performed in 11 patients with adult adrenoleukodystrophy and compared with 11 sex- and age-matched controls. PATIENTS: Eleven patients with adult adrenoleukodystrophy participated in a trial of dietary therapy with glyceryl trioleate and glyceryl trierucate (Lorenzo's oil) in the Fédération de Neurologie and the Institut National de la Santé et de la Recherche Médicale, Unité 134, at the Hôpital de la Salpêtrière in Paris, France. RESULTS: The results of magnetic resonance imaging of the white matter were normal in 2 patients and showed areas of mild symmetrical hypersignals on T2-weighted images and fluid attenuated inversion recovery sequences, localized in the posterior white matter in 9 patients. The results of spectroscopy indicated that the peak of the area of choline-containing compounds was increased at long echo times in patients with adult adrenoleukodystrophy, which may reflect very long-chain fatty acid accumulation in this disease. The peak of the area of myo-inositol-containing compounds was increased at short echo times in patients with adult adrenoleukodystrophy, which may indicate a rise in this metabolite concentration. The N-acetylaspartate-creatine amplitude ratio was significantly decreased in patients with motor deficit. The significance of this finding remains to be established. CONCLUSIONS: The results of localized proton magnetic resonance spectroscopy show abnormalities in the cerebral white matter of patients with adult adrenoleukodystrophy, which may contribute to the understanding of the pathophysiologic characteristics of the disease. Although changes in the results of spectroscopy found in this disease are not specific, the increase of choline-containing compounds may reflect the accumulation of very long-chain fatty acids in the central nervous system. Localized proton magnetic resonance spectroscopy may prove a valuable technique, in addition to magnetic resonance imaging, for noninvasive investigation of patients with adult adrenoleukodystrophy undergoing future clinical trials.
Adrenoleukodystrophy↗
Phytanoyl-CoA hydroxylase is not only deficient in classical Refsum disease but also in rhizomelic chondrodysplasia punctata.
Explore the source record for details and available documents.
Chondrodysplasia Punctata, Rhizomelic↗
Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders.
The peroxisome biogenesis disorders (PBDs) are a group of lethal autosomal-recessive diseases caused by defects in peroxisomal matrix protein import, with the concomitant loss of multiple peroxisomal enzyme activities. Ten complementation groups (CGs) have been identified for the PBDs, with CG1 accounting for 51% of all PBD patients. We identified the human orthologue of yeast PEX1, a gene required for peroxisomal matrix protein import. Expression of human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1 patients, and PEX1 mutations were detected in multiple CG1 probands. A common PEX1 allele, G843D, is present in approximately half of CG1 patients and has a deleterious effect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells revealed severe defects in peroxisomal matrix protein import and destabilization of PEX5, the receptor for the type-1 peroxisomal targetting signal, even though peroxisomes were present in these cells and capable of importing peroxisomal membrane proteins. These data demonstrate an important role for PEX1 in peroxisome biogenesis and suggest that mutations in this gene are the most common cause of the PBDs.
Alleles↗
Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy.
To date, in utero bone marrow transplantation (BMT) has had limited success, largely because of poor donor engraftment. The poor engraftment is probably the result of performing the procedure late in gestation after significant fetal immunocompetence has developed and/or transplanting insufficient numbers of donor hematopoietic stem cells for competing successfully with ongoing fetal hematopoiesis. To overcome these problems, we performed in utero BMT on a fetus with globoid cell leukodystrophy during the first trimester of gestation using selected paternal bone marrow stem (CD34+) cells. CD34 selection allowed a substantially greater number of stem cells to be transplanted. Although the fetus died 7 weeks after the procedure (during the 20th week of gestation), full donor engraftment was established. Moreover, the cause of death appeared to be overwhelming donor engraftment and leukostasis with paternal myeloid cells infiltrating most tissues. The ability of in utero BMT to produce this degree of engraftment provides great promise for the use of this approach in the treatment of a variety of inherited disorders that can be diagnosed prenatally.
Bone Marrow Transplantation↗
Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy.
The occasion of the presentation of the eighth Gordon Holmes Lecture left me feeling both honoured and awed, as a result of my review of the Selected Papers of Gordon Holmes (Phillips CG: Selected Papers of Gordon Holmes, compiled and edited for the Guarantors of Brain. Oxford University Press, 1979), kindly presented to me by the sponsors of the meeting. This volume lists 174 publications produced over a 55-year period, and contains reprints of contributions to neuroanatomy, neuropathology, and to disorders that affected the adrenal cortex, the spinal cord, the cerebellum and the cerebral cortex. Yet I also feel a sense of sadness; the invitation to present the lecture came from the late Anita Harding who, such a short time before her illness, gave me personal guidance and encouragement. In this lecture I endeavour to follow the example of Gordon Holmes, namely the stepwise analysis of a clinical problem, first by observation of the patient, followed by the application of techniques that can clarify it, leading to new knowledge not only about the specific disorder, but also about the nervous system and human biology in general and, it is to be hoped, to more effective therapy.
Adolescent↗
Somatosensory evoked potentials in adrenomyeloneuropathy.
Adrenomyeloneuropathy (AMN) is an X-linked metabolic disorder causing accumulation of very-long-chain fatty acids with multifocal nervous system demyelination of the peripheral nerves, spinal cord, and cerebrum. The extent to which the disorder affects upper versus lower limbs or peripheral versus CNS has not been electrophysiologically defined in a large population nor differentiated in men and women. To determine patterns of nervous system demyelination and define gender differences, we studied 83 AMN patients with short latency median and posterior tibial nerve somatosensory evoked potentials (SSEPs). Most women (10/16) had abnormal median SSEPs all involving central pathways, whereas most men (59/67) had abnormal median SSEPs involving both peripheral and central pathways. Tibial SSEPs were abnormal in both sexes (14/15 women, 67/67 men), with either peripheral or central pathway involvement. This study demonstrates the frequent widespread involvement of both peripheral nerve and central somatosensory pathways in men with AMN and the predominantly central involvement in women.
Adolescent↗
Peroxisomal disorders: overview.
Explore the source record for details and available documents.
3-Hydroxyacyl CoA Dehydrogenases↗
Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome: direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans.
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which accumulates in a number of inherited diseases in human. Because beta-oxidation is blocked by the methyl group at C-3, phytanic acid first undergoes decarboxylation via an alpha-oxidation mechanism. The structure and subcellular localization of the phytanic acid alpha-oxidation pathway have remained enigmatic through the years, although they have generally been assumed to involve phytanic acid and not its CoA-ester. This view has recently been challenged by the findings that in rat liver phytanic acid first has to be activated to its CoA-ester before alpha-oxidation and by the discovery of a new enzyme, phytanoyl-CoA hydroxylase, which converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. We now show that this newly discovered enzyme is also present in human liver. Furthermore, we show that this enzyme is located in peroxisomes and deficient in liver from Zellweger patients who lack morphologically distinguishable peroxisomes, which provides an explanation for the long-known deficient oxidation of phytanic acid in these patients. These results suggest that phytanic acid alpha-oxidation is peroxisomal and that it utilizes the coenzyme A derivative as substrate, thus giving further support in favour of the new, revised pathway of phytanic acid alpha-oxidation.
Cell Compartmentation↗
The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.
In humans, defects in peroxisome assembly result in the peroxisome biogenesis disorders (PBDs), a group of genetically heterogeneous, lethal recessive diseases. We have identified the human gene PXAAA1 based upon its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 (CG4) of the PBD. Consistent with this observation, CG4 patients carry mutations in PXAAA1. The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. Substitution of an arginine for the conserved lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity, suggesting that Pxaaa1p is an ATPase. Furthermore, Pxaaa1p is required for stability of the predominantly cytoplasmic PTS1 receptor, Pxr1p. We conclude that Pxaaa1p plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity.
Adenosine Triphosphatases↗
Urinary bile acids and peroxisomal bifunctional enzyme deficiency.
The biosynthesis of normal bile acids involves beta-oxidation of the 8-carbon side-chain of cholesterol, in addition to numerous modifications of the sterol nucleus. Because beta-oxidation of the sterol side-chain has been localized to the peroxisome, bile acid analysis has been suggested to be useful in the diagnostic evaluation of individuals suspected of having peroxisomal disorders. Although data from subjects with generalized peroxisomal disorders support this, few data exist regarding the bile acids in individuals having single peroxisomal beta-oxidation enzyme disorders. In this study, we analyzed the urinary bile acids from 12 patients with peroxisomal bifunctional protein deficiency using continuous flow fast atom bombardment mass spectrometry. All 12 patients had abnormal spectra, although their ion profiles and rank order of intensity of ions varied considerably. Ten of 12 individuals had abnormal spectra with presence of taurine-conjugated tetrahydroxycholestenoates, allowing a definite diagnosis of a peroxisomal beta-oxidation defect and a presumptive diagnosis of bifunctional protein deficiency; the other two cases were nondiagnostically abnormal. The strengths and limitations of urinary bile acid analysis for the diagnosis of peroxisomal beta-oxidation disorders are discussed.
3-Hydroxyacyl CoA Dehydrogenases↗
Neuronal migration abnormality in peroxisomal bifunctional enzyme defect.
Patterns of brain dysgenesis that resemble those in the Zellweger syndrome were demonstrated in a boy with an isolated defect of the peroxisomal bifunctional enzyme. There was bilateral centrosylvian pachygyria and polymicrogyria, diffuse hemispheric hypomyelination with heterotopic neurons, Purkinje cell heterotopias, and simplified convolutions of the dentate nucleus and inferior olive. This association of Zellweger syndrome-like brain dysgenesis with a defect of a single peroxisomal enzyme provides new opportunities for the study of pathogenetic mechanisms in peroxisomal disorders.
3-Hydroxyacyl CoA Dehydrogenases↗
Cognitive and brain magnetic resonance imaging findings in adrenomyeloneuropathy.
Neuropsychological functioning and brain magnetic resonance imaging (MRI) were evaluated in 84 men with adrenomyeloneuropathy (AMN). MRI was normal in 61%, the "pure AMN" group, while 39%, the "cerebral AMN" group, showed brain white matter abnormalities. Except for mild deficits in psychomotor speed and visual memory, neuropsychological function was normal in pure AMN. Most patients with cerebral AMN had normal IQ and language but evidenced impaired psychomotor speed, spatial cognition, memory, and executive functions. Patients with MRI evidence of very severe cerebral disease had global and language impairment as well, and deficits in all patients were highly correlated with degree of brain MRI involvement.
Adrenoleukodystrophy↗