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Biomedical subjects

Hugo W Moser

Publications and source records attributed to Hugo W Moser.

28 records · Page 2Linked to original sources
PubMed2004

Genetic causes of mental retardation.

Mental retardation has been categorized into severe mental retardation where genetics plays a very important role and mild mental retardation, in which genetics in some instances plays a role but in which cultural factors also matter a great deal. The pathogenetic, clinical and behavioral characteristics of genetically determined disorders associated with mental retardation differ greatly-as exemplified by two genetic disorders that have been clarified recently, namely Rett syndrome and the Williams syndrome. In the work-up of the developmentally disabled child, previous studies have shown that genetic studies are of have great importance and high yield. Early biochemical diagnosis in newborn screening has tremendous potential and has been strongly supported by NICHD-the PKU story being so much part of what NICHD has done. We must gain a better understanding of structure/function relationships, which becomes more and more possible with neuroimaging. A better understanding of neural plasticity can lead to correction by early intervention.

Humans↗
PubMed2003

Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation.

The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patients--four with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30 degrees C, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.

Amino Acid Sequence↗
PubMed2003

Proton MR spectroscopic imaging in Pelizaeus-Merzbacher disease.

BACKGROUND AND PURPOSE: Pelizeaus-Merzbacher disease (PMD) is a clinically and molecularly heterogeneous disorder linked to deletion, mutations, or duplication of the proteolipid protein (PLP1) gene locus at Xq22. The current study was conducted to characterize the results of proton MR spectroscopic (MRS) imaging in PMD. METHODS: Three boys with PMD (one with the severe connatal form and two with a more mild clinical phenotype [spastic paraplegia type 2]). and three age-matched healthy control subjects (age range, 2-7 years) underwent MR and MRS imaging. All imaging was performed at 1.5 T. For MRS imaging, oblique-axial sections (thickness, 15 mm; intersection gap, 2.5 mm) were recorded parallel to the anterior commissure-posterior commissure line (TR/TE/NEX, 2300/272/1) with lipid and water suppression. Ratios of metabolite peak areas were calculated, and spectra were bilaterally evaluated. RESULTS: Diffuse or focal reductions in N-acetylaspartate were observed in the affected white matter in all three cases. These reductions seemed to be consistent with axonal damage. In addition, mild increases in choline and creatine levels were observed; these may have been due to astrocytic changes. CONCLUSION: Proton MRS imaging may be helpful in evaluating regional pathophysiologic abnormalities in PMD and in distinguishing PMD from other leukodystrophies, which exhibit different metabolic profiles.

Aspartic Acid↗
PubMed2002

Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders.

X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1. ABCD1 resides on Xq28 and encodes an integral peroxisomal membrane protein (ALD protein [ALDP]) that is of unknown function and that belongs to the ATP-binding cassette-transporter superfamily. Individuals with ABCD1 mutations accumulate very-long-chain fatty acids (VLCFA) (carbon length >22). Childhood cerebral X-ALD is the most devastating form of the disease. These children have the earliest onset (age 7.2 +/- 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age. Individuals with either peroxisomal biogenesis disorders (PBD) or single-enzyme deficiencies (SED) in the peroxisomal beta-oxidation pathway--disorders such as acyl CoA oxidase deficiency and bifunctional protein deficiency--also accumulate VLCFA, but they present during the neonatal period. Until now, it has been possible to distinguish unequivocally between individuals with these autosomal recessively inherited syndromes and individuals with ABCD1 mutations, on the basis of the clinical presentation and measurement of other biochemical markers. We have identified three newborn boys who had clinical symptoms and initial biochemical results consistent with PBD or SED. In further study, however, we showed that they lacked ALDP, and we identified deletions that extended into the promoter region of ABCD1 and the neighboring gene, DXS1357E. Mutations in DXS1357E and the ABCD1 promoter region have not been described previously. We propose that the term "contiguous ABCD1 DXS1357E deletion syndrome" (CADDS) be used to identify this new contiguous-gene syndrome. The three patients with CADDS who are described here have important implications for genetic counseling, because individuals with CADDS may previously have been misdiagnosed as having an autosomal recessive PBD or SED

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2002

Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion.

An 8.5-year-old girl with a pathogenic mutation (515insC) of the ATP-binding cassette, subfamily D, member 1 gene (ABCD1) on her maternally derived X chromosome showed clinical, biochemical, and magnetic resonance imaging abnormalities similar to those in affected males. Cytogenetic studies led to the surprise finding of a de novo deletion of Xq27 on the paternally derived X chromosome. A bone marrow transplant had an apparently favorable effect. Cytogenetic studies should be performed in all severely symptomatic X-linked adrenoleukodystrophy heterozygotes.

Adrenoleukodystrophy↗
PubMed2002

Imaging cortical association tracts in the human brain using diffusion-tensor-based axonal tracking.

Diffusion-tensor fiber tracking was used to identify the cores of several long-association fibers, including the anterior (ATR) and posterior (PTR) thalamic radiations, and the uncinate (UNC), superior longitudinal (SLF), inferior longitudinal (ILF), and inferior fronto-occipital (IFO) fasciculi. Tracking results were compared to existing anatomical knowledge, and showed good qualitative agreement. Guidelines were developed to reproducibly track these fibers in vivo. The interindividual variability of these reconstructions was assessed in a common spatial reference frame (Talairach space) using probabilistic mapping. As a first illustration of this technical capability, a reduction in brain connectivity in a patient with a childhood neurodegenerative disease (X-linked adrenoleukodystrophy) was demonstrated.

Adrenoleukodystrophy↗
PubMed2002

Brain glucose metabolism in Rett Syndrome.

Rett syndrome is a progressive neurologic disorder affecting girls in early childhood with loss of achieved psychomotor abilities and mental retardation. Six sedated female patients (4 to 15 years of age) with a diagnosis of Rett syndrome were studied with [(18)F]fluorodeoxyglucose (FDG) and underwent positron emission tomography scanning of the brain. Relative tracer concentrations between different areas of the brain were assessed, and results were compared with 18 age-matched control subjects. Patients were divided into two age groups: 3 to 8 years of age and 9 to 15 years of age. A relative decrease in [(18)F]FDG uptake in the lateral occipital areas in relation with the whole brain and a relative increase in the cerebellum was evident in both age groups (P < 0.001, unpaired Student t test). A relative increase in frontal tracer uptake was observed in the younger group. Sensorimotor areas and relations between cortical and subcortical structures were preserved in all patients. Changes in glucose cerebral metabolism resemble the regional distribution of normal children less than 1 year of age, likely reflecting a maturational arrest. Changes in frontal areas parallel those in postmortem N-methyl-D-aspartate receptor densities and could correlate with different clinical stages of the disease. This pattern differs from those described in Down syndrome, autism, and Alzheimer's disease.

Adolescent↗
PubMed2002

Anti-ganglioside antibodies bind with enhanced affinity to gangliosides containing very long chain fatty acids.

Gangliosides function in both physiological and pathological molecular recognition. Although much research has focused on the role of ganglioside glycans in recognition, fewer studies have addressed the role of the ceramide moiety. Ceramides of major brain gangliosides are composed predominantly of monounsaturated 18-carbon and 20-carbon long chain bases with a saturated 18-carbon fatty acid amide. In contrast, gangliosides of X-linked adrenoleukodystrophy patients are characterized by abnormal very long chain fatty acids that are proposed to be associated with autoimmune inflammation. In the current study we synthesized and characterized derivatives of the major brain ganglioside GD1a bearing defined very long chain fatty acid amides (C24:0, C24:1, and C26:0). When tested in a solid phase binding assay in the presence of auxiliary membrane lipids, GD1a species with long chain fatty acids were up to 8-fold more potent than normal brain GD1a in binding four different anti-GD1a monoclonal antibodies. These data support the hypothesis that gangliosides bearing very long chain fatty acids are differentially displayed on membranes, which may lead to altered antigenicity.

Animals↗
PubMed2002

Proton MR spectroscopic and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience.

PURPOSE: To compare conventional magnetic resonance (MR) imaging, proton MR spectroscopic imaging, and diffusion tensor (DT) MR imaging findings in patients with X chromosome-linked adrenoleukodystrophy (X-ALD). MATERIALS AND METHODS: Multisection proton MR spectroscopy and DT imaging were performed in 11 patients with X-ALD and in 11 healthy control subjects. Quantitative measures of N-acetylaspartate (NAA), choline, and creatine values and of isotropic apparent diffusion coefficient (IADC) and fractional anisotropy (FA) were obtained from coregistered regions of interest. DT imaging and metabolic parameters were compared by using regression analysis. In addition, differences in DT imaging and metabolite measurements between normal- and abnormal-appearing white matter on conventional MR images were evaluated by using a nonparametric (Mann-Whitney) test. RESULTS: A strong logarithmic relationship between NAA value and FA (r = 0.64, P <.001) and an inverse logarithmic relationship were found between NAA value and IADC (r = -0.69, P <.001). Creatine and choline values correlated poorly with IADC and FA. In the normal-appearing white matter of asymptomatic patients, the NAA value was 17% lower than that in the healthy control subjects (P =.016), whereas no significant difference in DT imaging measures was seen in these regions. CONCLUSION: In patients with X-ALD, MR spectroscopic imaging can depict abnormalities in white matter that have a normal appearance on both conventional MR and DT images; this finding suggests that it may be the most sensitive technique for detecting early abnormalities of demyelination or axonal loss in patients with X-ALD.

Adolescent↗