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Biomedical subjects

H W Moser

Publications and source records attributed to H W Moser.

At least 91 records · Page 5Linked to original sources
PubMed1996

Peroxisomal disorders.

In 1973 Goldfischer et al reported that patients with the Zellweger cerebro-hepato-renal syndrome lacked demonstrable peroxisomes. This was the first time that a human disease state was attributed to a disorder of peroxisomes, subcellular organelles that had received little attention until that time. Interest in the organelle has increased rapidly during the last 10 years, both in respect to its cellular and molecular biology, and also in respect to its role in clinical medicine. Sixteen peroxisomal disorders have been identified at this time. They are pertinent to the neurologist because 12 of these disorders are associated with severe neurological disability. Furthermore, they are not infrequent: our laboratory has identified more than 3,000 patients. This presentation will provide basic information about peroxisome structure and function and then summarize the classification, diagnosis, genetics, pathogenesis, and therapy of the peroxisomal disorders.

Adolescent↗
PubMed1996

Pathogenetic mechanisms in peroxisomal disorders.

Advances have been made concerning the pathogenesis of the two major classes of peroxisomal disorders. The gene defect in X-linked adrenoleukodystrophy has been firmly established and therapies are emerging. Complementation analysis has permitted categorization of disorders of peroxisome biogenesis, their molecular basis and mutations are being defined, and new therapies are being explored.

Bone Marrow Transplantation↗
PubMed1996

Nerve conduction studies in adrenomyeloneuropathy.

OBJECTIVE: Adrenomyeloneuropathy (AMN) is an X linked metabolic disorder presenting with progressive spastic paraparesis in the third to fifth decade of life. Although peripheral neuropathy is also present in most patients, prominent pyramidal signs may make its clinical recognition difficult. The objective was to characterise the peripheral neuropathy in patients with AMN by nerve conduction studies. METHODS: Nerve conduction studies were performed in 99 men known to have AMN and in 38 heterozygous women, all of whom had neurological disabilities. RESULTS: Of the 13 variables obtained, at least one was abnormal in 82% of patients. The abnormalities were more common in men than in women (87% v 67%); in legs than in arms (77% v 38%); in motor than in sensory conduction (80% v 39%); and in latency (distal and F wave) and velocity compared with amplitude (80% v 29%). Twenty six patients had at least one nerve variable value in the demyelinating range. Four variables (sural velocity, peroneal amplitude, peroneal velocity, and peroneal F wave) were correlated with the expanded disability status scale; five variables (peroneal velocity, tibial H reflex, median distal latency, median conduction velocity, and median F wave latency) were correlated with serum very long chain fatty acids (VLCFAs); and two variables (sural amplitude and peroneal distal latency) were more likely to be abnormal in patients with normal adrenal function than in patients with Addison's disease. CONCLUSIONS: Nerve conduction studies in patients with AMN are often abnormal and suggest a mixture of axonal loss and multifocal demyelination. Their correlation with disability status and serum VLCFAs suggests that measures from nerve conduction studies may be useful in evaluating future treatments.

Adrenoleukodystrophy↗
PubMed1996

Improved tissue characterization in adrenoleukodystrophy using magnetization transfer imaging.

OBJECTIVE: We performed this study to evaluate the usefulness of magnetization transfer (MT) imaging techniques and magnetization transfer ratio (MTR) measurements in assessing patients with adrenoleukodystrophy (ALD). SUBJECTS AND METHODS: Twelve patients who encompassed the range of ALD phenotypes were evaluated prospectively with MR and MT imaging (including digital subtraction images). The MT images and spin-echo MR images were compared by two staff neuroradiologists and a staff neurologist for extent of disease, different zones of involvement, and the presence of enhancement. MTR measurements were obtained from affected and unaffected regions of the brain. RESULTS: Eight of the 12 patients exhibited gadolinium enhancement. In seven of these patients, the MT subtraction images showed two zones of abnormal signal within the affected white matter. Their MTR measurements were classified as zone 1 (mean MTR, 35%; SD, 6%) and zone 2 (mean MTR, 20%; SD, 6%). Three of the other patients showed a single zone of involvement corresponding to the affected white matter on the standard spin-echo MR images. Their MTR measurements were similar to that of zone 1. The remaining two patients had no demonstrable signal abnormalities on any of the images. We noted no difference in any of the 12 subjects in the extent of white matter involvement on any of the imaging techniques. The MTR measurements in the unaffected white matter (mean MTR, 46%; SD, 5%) approximated established MTRs in white matter of normal volunteers. CONCLUSION: MT imaging and MTR measurements are helpful clinical techniques that may improve the evaluation of patients with ALD, particularly in the proposed ability of these techniques to divide the affected white matter into different zones that correspond to specific pathologic areas. These techniques can help the understanding of pathogenetic mechanisms and the evaluation of therapies.

Adolescent↗
PubMed1995

Visual system abnormalities in adrenomyeloneuropathy.

We studied the visual system in 59 men with adrenomyeloneuropathy. Pattern-reversal visual evoked potentials, magnetic resonance imaging, and clinical examination revealed that visual pathways are affected in 63% of patients, involving the optic discs, optic nerves, lateral geniculate bodies, optic radiations, and parietooccipital cortex. This indicates both primary demyelination of the optic nerves and discs, and more diffuse involvement of postchiasmal structures.

Adrenoleukodystrophy↗
PubMed1995

Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies.

The clinical distinction between patients with a disorder of peroxisome assembly (e.g., Zellweger syndrome) and those with a defect in a peroxisomal fatty acid beta-oxidation enzyme can be difficult. We studied 29 patients suspected of belonging to the latter group. Using complementation analysis, 24 were found to be deficient in enoylcoenzyme A hydratase/3-hydroxyacylcoenzyme A dehydrogenase bifunctional enzyme and 5 were deficient in acyl-CoA oxidase. Elevated plasma very long-chain fatty acids (VLCFA), impaired fibroblast VLCFA beta-oxidation, decreased fibroblast phytanic acid oxidation, normal plasmalogen synthesis, normal plasma L-pipecolic acid level, and normal subcellular catalase distribution were characteristic findings in both disorders. The elevation in plasma VLCFA levels and impairment in fibroblast VLCFA beta-oxidation were more severe in bifunctional-deficient than in oxidase-deficient patients. The clinical course in bifunctional deficiency (profound hypotonia, neonatal seizures, dysmorphic features, age at death approximately 9 months) was more severe than in oxidase deficiency (moderate hypotonia without dysmorphic features, development of a leukodystrophy, age at death approximately 4 yr). Based on these findings, accurate early diagnosis of these deficiencies of peroxisomal beta-oxidation enzymes is possible.

Acyl-CoA Oxidase↗
PubMed1995

Sulfatide and sphingomyelin loading of living cells as tools for the study of ceramide turnover by lysosomal ceramidase--implications for the diagnosis of Farber disease.

The ceramide turnover by lysosomal ceramidase in intact, living cells was investigated by loading radiolabeled sulfatide or sphingomyelin in situ on skin fibroblasts and lymphoid cells. The cells originated from normal individuals and from patients with acid ceramidase deficiency (Farber disease). While fibroblasts from individuals with Farber disease exhibited some impairment in the degradation of the ceramide produced by sulfatide hydrolysis, lymphoid cells from individuals with Farber disease metabolized the ceramide as readily as did normal cells, suggesting the existence in lymphoid cells of a non-lysosomal degradation pathway for the sulfatide-derived ceramide. In contrast, sphingomyelin loading in the presence of serum showed a considerably decreased turnover of ceramide in both fibroblasts and lymphoid cells from individuals with Farber disease. Further methodologic variation led to the use of LDL-associated radioactive sphingomyelin; LDL-association promoted the targeting of exogenous sphingomyelin to lysosomes. As a result, an almost complete deficiency of ceramide degradation was found in cells from severely affected patients with Farber disease. Our data with this novel method show that sphingomyelin loading of intact living cells is a simple, alternative means for determining ceramide degradation by lysosomal ceramidase and for diagnosing Farber disease.

Acid Ceramidase↗
PubMed1995

Komrower Lecture. Adrenoleukodystrophy: natural history, treatment and outcome.

Our laboratory has identified nearly 2000 patients with X-linked adrenoleukodystrophy (ALD) and conducted therapeutic trials in groups of patients who represent the major phenotypes. We report recent results of dietary therapy with a mixture of glyceryl trioleate and glyceryl trierucate oil, also referred to as Lorenzo's Oil, in the asymptomatic and childhood cerebral phenotypes. Fifty-three patients started this therapy at a mean age of 7.5 years at a time when they were free of neurological symptoms. Although analysis of data is hampered by the lack of a concurrent control group, follow-up studies after 39 months of therapy suggest that subsequent neurological involvement was less frequent and less severe than anticipated from historical controls. Retrospective analysis of the effect of the oil in patients with the severe childhood cerebral phenotype indicates that there was a slight but statistically significant slowing of clinical progression and delay of death.

Adrenoleukodystrophy↗
PubMed1995

Neurodegenerative course in ceramidase deficiency (Farber disease) correlates with the residual lysosomal ceramide turnover in cultured living patient cells.

Farber's lipogranulomatosis is an inborn lipid storage disease characterized by tissue accumulation of ceramide due to deficient activity of lysosomal ceramidase. Symptoms include painful swelling of joints, subcutaneous nodules, a hoarse cry, hepatosplenomegaly and nervous system dysfunction of markedly variable degree. In most cases the neural dysfunction rather than the general dystrophy, seems to limit the duration of Farber disease. We examined whether the severity can be shown as a function of ceramide turnover by lysosomal ceramidase. The lysosomal degradation of sphingomyelin-derived ceramide was studied in situ in patient skin fibroblasts and lymphoid cells loaded with LDL-associated radioactive sphingomyelin. We could show for the first time a significant correlation between the ceramide accumulated in situ and the severity of Farber disease. Our method provides an alternative means for determining ceramide degradation by lysosomal ceramidase, but in intact cells. The relatively simple method is at least of the same diagnostic use for Farber disease as the in vitro assay of acid ceramidase using cell homogenates and may also have some prognostic use.

Acid Ceramidase↗
PubMed1995

Tumor necrosis factor-alpha and X-linked adrenoleukodystrophy.

The two most common forms of X-linked adrenoleukodystrophy (X-ALD), the childhood cerebral form (CCER) and the adult form, adrenomyeloneuropathy (AMN), arise from the same mutations in the X-ALD gene at Xq28. These two forms are distinguished by the degree of cerebral inflammation. Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X-ALD. Thus, a modifying gene could be involved in initiating or promoting the inflammatory response. In this study we detected a difference in tumor necrosis factor-alpha (TNF-alpha) bioactivity, but not TNF-alpha protein levels, in serum from some advanced CCER patients. Early-stage CCER patients and AMN patients were in the normal range. Allelic differences in TNF-alpha or levels of soluble TNF receptor did not account for bioactivity differences or phenotypic heterogeneity in X-ALD.

Adolescent↗
PubMed1995

Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders.

The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases caused by defects in peroxisome assembly. We have isolated PXR1, a human homologue of the yeast P. pastoris PAS8 (peroxisome assembly) gene. PXR1, like PAS8, encodes a receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Mutations in PXR1 define complementation group 2 of PBDs and expression of PXR1 rescues the PTS1 import defect of fibroblasts from these patients. Based on the observation that PXR1 exists both in the cytosol and in association with peroxisomes, we propose that PXR1 protein recognizes PTS1-containing proteins in the cytosol and directs them to the peroxisome.

Amino Acid Sequence↗
PubMed1995

Clinical and therapeutic aspects of adrenoleukodystrophy and adrenomyeloneuropathy.

Adrenoleukodystrophy (ALD) and its adult variant adrenomyeloneuropathy (AMN) are X-linked diseases in which a deficiency of lignoceroyl-CoA ligase, a peroxisomal enzyme needed for the degradation of very long chain fatty acids (VLCFA), has been reported. The responsible gene recently has been cloned; it codes for a peroxisomal membrane protein, ALDP, which is a member of the ABC (ATP binding cassette) transporter superfamily. Elevations in VLCFA, particularly C24 and C26, have proven useful in the diagnosis of the childhood, adolescent and adult cerebral forms and AMN. ALD and AMN commonly coexist in the same families; the same VLCFA elevations and gene mutations have been recognized in both ALD and AMN. This phenotypic heterogeneity suggests the influence of an autosomal modifier gene. Dietary manipulation using glyceryl trioleate-trieurucate oil (Lorenzo's oil) has been highly successful in lowering VLCFA, but not in affecting the rate of neurologic deterioration in symptomatic ALD boys or AMN adults. Dietary pretreatment of neurologically asymptomatic ALD patients may have some benefit and is advisable at the present time. Currently, we recommend bone marrow transplantation for those patients who show evidence of early cerebral involvement and for whom a well-matched donor is available. A drug therapy trial utilizing beta interferon and thalidomide is underway.

Adolescent↗
PubMed1995

Adrenoleukodystrophy.

The main advances concerning adrenoleukodystrophy have been in the fields of genetics and therapy. Abnormalities in the 'putative gene' reported in 1993 have been confirmed. Mutations in this gene have been demonstrated in all of the 80 adrenoleukodystrophy families studied so far in various parts of the world. The same unusual dinucleotide deletion was present in approximately 20% of families. The remaining deletions involved nearly all parts of the gene and in most instances were unique in each family. There was no correlation between the phenotype and the nature or location of the mutation. Follow-up of patients treated with Lorenzo's Oil suggests that this therapy does not alter the course of the illness in symptomatic patients. However, dietary therapy started before the development of symptoms may reduce the frequency and severity of subsequent neurological disability.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed1995

Adrenoleukodystrophy: molecular genetics, pathology, and Lorenzo's oil.

Knowledge about adrenoleukodystrophy (ALD), a disorder which was described first in 1923, has increased greatly during recent years. The principal biochemical abnormality, the presumed enzyme defect, and the gene defect, have been defined. A dietary therapy has been proposed and attracted world-wide attention through a motion picture. Nevertheless, many questions remain and cannot be answered without a more fundamental understanding of pathology and pathogenesis. This article will provide a review of the history, clinical features, pathology, biochemistry, and the gene defect, and then appraise current efforts to clarify pathogenesis and develop therapeutic approaches.

Child, Preschool↗
PubMed1995

Dietary management of X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder that involves mainly the nervous system white matter and adrenal cortex. It is associated with the accumulation of saturated very-long-chain fatty acids (VLCFAs), such as hexacosanoic acid (C26:0), that occurs as a result of the impaired capacity to degrade these substances, a reaction that normally takes place in the peroxisome. The VLCFAs originate from the diet and are also synthesized endogenously. Interest in dietary therapy arose from the observation that the administration of oils containing erucic and oleic acid (Lorenzo's oil), when combined with restriction of dietary intake of VLCFAs, can normalize plasma VLCFA levels in ALD patients. Clinical results in patients who are already symptomatic have been disappointing. However, preliminary data, still in need of confirmation, suggest that dietary therapy begun in asymptomatic patients can reduce the frequency and severity of later neurological disability.

Adrenoleukodystrophy↗
PubMed1995

Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders.

Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and classical rhizomelic chondrodysplasia punctata are lethal genetic disorders caused by defects in peroxisome biogenesis. We report here a characterization of the peroxisomal matrix protein import capabilities of fibroblasts from 62 of these peroxisome biogenesis disorder patients representing all ten known complementation groups. Using an immunofluorescence microscopy assay, we identified three distinct peroxisomal protein import defects among these patients. Type-1 cells have a specific inability to import proteins containing the PTS1 peroxisomal targeting signal, type-2 cells have a specific defect in import of proteins containing the PTS2 signal, and type-3 cells exhibit a loss of, or reduction in, the import of both PTS1 and PTS2 proteins. Considering that the common cellular phenotype of Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum's disease has been proposed to be a complete defect in peroxisomal matrix protein import, the observation that 85% (40/47) of the type-3 cell lines imported a low but detectable amount of both PTS1 and PTS2 proteins was surprising. Furthermore, different cell lines with the type-3 defect exhibited a broad spectrum of different phenotypes; some showed a complete absence of matrix protein import while others contained 50-100 matrix protein-containing peroxisomes per cell. We also noted certain relationships between the import phenotypes and clinical diagnoses: both type-1 cell lines were from neonatal adrenoleukodystrophy patients, all 13 type-2 cell lines were from classical rhizomelic chondrodysplasia punctata patients, and the type-3 import defect was found in the vast majority of Zellweger syndrome (22/22), neonatal adrenoleukodytrophy (17/19), and infantile Refsum's disease (7/7) patients. Our finding that all type-1 cell lines were from the second complementation group (CG2), all 13 type-2 cell lines were from CG11, and that cells from the eight remaining complementation groups only exhibit the type-3 defect indicates that mutations in particular genes give rise to the different types of peroxisomal protein import defects. This hypothesis is further supported by correlations between certain complementation groups and particular type-3 subphenotypes: all patient cell lines belonging to CG3 and CG10 showed a complete absence of peroxisomal matrix protein import while those from CG6, CG7, and CG8 imported some peroxisomal matrix proteins. However, the fact that cell lines from within particular complementation groups (CG1, CG4) could have different matrix protein import characteristics suggests that allelic heterogeneity also plays an important role in generating different import phenotypes in certain patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenoleukodystrophy↗