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H Moser

Publications and source records attributed to H Moser.

At least 73 records · Page 4Linked to original sources
PubMed1991

X-linked centronuclear myopathy: mapping the gene to Xq28.

The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order. St14 (DXS52), fully informative in all families, shows significant linkage to the CNM gene (z = 3.60; theta = 0.05), followed by DX13 (DXS15) (z = 2.03; theta = 0.06) and F8 (z = 1.86; theta = 0.00). Combination of the physical map derived by Kenwrick and Gitschier (1989) and our linkage data lead to the most probable order R/GCP-G6PD-(XLR-CNM-F8)-p767-St14-cpX67-++ +DX13 placing the CNM gene close to F8. The results of this study confirm strong linkage of the CNM gene to the region Xq28 and will permit carrier testing and prenatal diagnosis in CNM families. We conclude that the precise localization of this devastating disorder may be of great importance for genetic counselling in families at risk. The lack of information about gene frequency and mutation rate as well as the severity and burden of the disease point to the inevitable need for accurate clinical diagnosis.

Chromosome Mapping↗
PubMed1991

Behavioral treatment of sleep dysfunction in patients with the Rett syndrome.

Aberrant sleep patterns are commonly experienced by girls with the Rett syndrome. In this investigation, the problematic sleep of three girls with the Rett syndrome was regulated using a bedtime fading procedure with response cost. The treatment involved systematically delaying the bedtime and utilized a response cost component, removing the child from bed for one hour, when the child did not experience short latency to sleep onset. Daytime sleep was interrupted, except during regularly scheduled naps. A fading procedure was then successfully utilized to advance the bedtimes. This treatment resulted in more regular sleep patterns for the girls by increasing appropriate nighttime sleep, reducing inappropriate daytime sleep and reducing problematic nighttime behaviors (e.g., night wakings). These preliminary findings are important because they suggest that the dysfunctional sleep patterns of girls with the Rett syndrome may be amenable to behavioral treatments.

Behavior Therapy↗
PubMed1991

Association between haplotypes and specific mutations in Swiss cystic fibrosis families.

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in Caucasian populations, with an incidence of about 1 in 2000 live births, implying a carrier frequency of about 1 in 22. In 1989, the CF gene was isolated and characterized and the major mutation (delta F508), a 3-bp deletion that results in the loss of a phenylalanine residue at position 508, was detected. To determine the frequency of the delta F508 mutation and the predicted number of additional mutations in our population, we have undertaken a collaborative study of 215 CF patients and 175 CF parents in Switzerland. The delta F508 mutation in exon 10 has been found in 70% of the CF chromosomes, and the exon-11 mutation R553X seems to be the second most common CF mutation in our population, with a frequency of 5.3%, whereas the G551D mutation (also in exon 11) has not been detected at all. Haplotype determination of 430 CF and 175 normal chromosomes using XV-2c, KM19, MP6d-9, and J3.11 has been proven to be very helpful in providing additional carrier risk calculations: Haplotypes 1 (1221), 2 (1222), 6 (2111), and 7 (2221) increase the risk of being a carrier from 1 in 55 (haplotype 6) to 1 in 17 (haplotype 1), whereas haplotypes 3 (1122), 4 (1112), 8 (2222) and 10 (1111) lower the risk from 1 in 144 (haplotype 3) to 1 in 1678 (haplotype 10). Moreover, the mutation R553X shows strong correlation with haplotype 3, leading to the suggestion that haplotypes 1, 2, 5, and 6 may account for four additional mutations in Switzerland.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Aberrations↗
PubMed1991

Altered neurochemical markers in Rett's syndrome.

Rett's syndrome (RS) is a neurologic disorder associated with severe mental deficiency and neurologic manifestations of cortical and extrapyramidal origin. The present report is a preliminary postmortem brain study that compares the levels of endogenous biogenic amines and selected neurotransmitter receptors in five cases with RS and six normal controls of similar age. The level of choline acetyltransferase activity was reduced in several cortical and subcortical regions. Endogenous levels of dopamine in the superior frontal and superior temporal gyri, occipital cortex, and putamen were reduced. The changes in specific neurotransmitter markers, particularly those associated with the basal ganglia and cortex, may underlie the progressive deterioration in motor and cognitive function characteristic of this progressive disorder.

Adolescent↗
PubMed1990

Severe neonatal asphyxia due to X-linked centronuclear myopathy.

Severe neonatal centronuclear myopathy is inherited as an X-linked condition characterized by primary asphyxia, extreme muscular hypotonia and absent spontaneous movements. We report seven cases from three families to point out the importance of diagnosis with regard to prognosis, outcome and genetic counselling. In hypotonic diseases, analysis of cerebrospinal fluid, electromyography, nerve conduction velocity creatine kinase and a skin biopsy for fibroblast cultures for metabolic investigations are usually carried out. Needle muscle biopsy is an additional valuable investigation to establish diagnosis. In all our patients we found an increased number of centrally located nuclei with perinuclear halos confirming the diagnosis of centronuclear myopathy. The diagnosis of this disorder will become of greater importance as soon as carrier detection and prenatal diagnosis by DNA-technology are routinely available.

Asphyxia Neonatorum↗
PubMed1990

Cognitive impairment in adult-onset adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a progressive X-linked disorder that produces pathological changes, mainly in the adrenal cortex and the white matter of the central nervous system. The main biochemical abnormality is the accumulation of saturated unbranched fatty acids with a chain length of 24 or more, referred to as very-long-chain fatty acids (VLCFA). Affected children develop large zones of demyelination associated with perivascular lymphoctyic infiltrations resembling those seen in multiple sclerosis. Adults show a more chronic form of the disease, referred to as adrenomyeloneuropathy (AMN). AMN mainly involves the spinal cord ad peripheral nerves, although the cerebral hemispheres may also be affected. Approximately 15% of female carriers have nervous-system involvement that resembles AMN. It is well known that ALD may initially appear as a psychiatric disorder. In the present study, we have assessed the prevalence of cognitive impairment in a group of AMN patients and neurologically symptomatic ALD heterozygotes initially presenting primarily physical complaints. Sixty percent of these patients demonstrated significant neuropsychological impairment, most commonly a pattern of spared and impaired functions typical of a subcortical dementia. We suggest that this progressive cognitive impairment may underlie other behavioral deficits, affirming the significance of the psychological features of this genetically determined disorder.

Adrenoleukodystrophy↗
PubMed1990

Aberrant sleep patterns in children with the Rett syndrome.

Previous studies on the characteristics of disturbed sleep/wake patterns in children with the Rett syndrome have yielded inconsistent findings. In the current study, momentary time sampling procedures were used to measure the sleep/wake patterns of 20 girls with classical Rett syndrome. These patients had significantly more total sleep than age peers (M = 110.1; Zm = 2.58; p = .01), significantly less nighttime sleep (M = 80.8; Zm = -7.53; p less than .0001), and significantly more daytime sleep (M = 24.5; Zm = 8.71; p less than .0001). Night sleep was negatively correlated with age (r = -.59; p less than .01); day sleep was positively correlated with age (r = .54; p = .01). These girls also displayed night wakings on 20.9% of nights, delayed sleep onset on 67.8% of nights and early wakings on 24.5% of nights. These data clearly demonstrate that children with the Rett syndrome have markedly impaired sleep/wake patterns and suggests that the sleep dysfunction may worsen over time.

Adolescent↗
PubMed1990

[Principles of DNA diagnosis].

In an ever-increasing number of the more than 4000 known genetic diseases with Mendelian inheritance, the geneloci have been mapped. In such cases it is possible to predict by DNA techniques whether or not family members are carriers of the mutation and risk having affected children. Using the same methods, disease can also be predicted prenatally from chorionic villi biopsies (CVS) as early as the ninth week of pregnancy. With some diseases it is possible to analyze the DNA of the mutation directly, whereas in others closely linked polymorphic DNA markers have to be analyzed in order to distinguish the mutationbearing chromosome from the one with the normal allele. The techniques of diagnostic DNA investigations are now standard procedures in medical genetic laboratories and are performed almost routinely for many diseases: The total (genomic) DNA, with a length of 3 x 10(9) base pairs (bp), is extracted from cells, mainly leukocytes from EDTA blood samples, then digested by restriction endonucleases into smaller fragments with a length of approx. 10(3) to 10(4) bp. The fragments are separated according to their lengths by agarose gel electrophoresis, then transferred to nitrocellulose ("Southern Blot") and made "single-stranded" by denaturation. The fragment in question can now be recognized by a specific gene probe with a homologous base sequence (hybridization). Since the probe is slightly radioactive, the hybridized genomic DNA fragment is recognized by autoradiography, and its length determined by the relative position it reached during electrophoresis. These analyses can be carried out simultaneously for different DNA fragments within and outside the gene locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Haplotype analysis for CF-linked DNA polymorphisms in Switzerland.

A total of 295 patients, parents and unaffected sibs from 106 CF-families in central and northeastern Switzerland were investigated with probes 7C22(D7S16), metH, metD, pKM19, pXV-2c and pJ3.11(D7S8) for eight DNA polymorphisms (RFLP's). Linkage disequilibrium to the CF locus and haplotype frequencies were compared to those in other populations. They are comparable to other Caucasian populations and, for pKM 19 and pXV-2c, very close to the findings in Italy. The prevalence of certain haplotypes among the CF and the normal allele-bearing chromosomes indicate that the majority of the CF cases are probably the result of one ancient mutation in a common ancestor, but that there may be allelic heterogeneity accounting for an important proportion of patients, that may differ between countries or regions. Informative family constellations for the different polymorphisms in Switzerland and strategies for carrier detection and prenatal diagnosis are discussed. Haplotype analyses for each country and its ethnic subgroups are recommended.

Chromosome Mapping↗
PubMed1990

X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci.

We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.

Cell Nucleus↗
PubMed1990

RFLPs for Duchenne muscular dystrophy cDNA clones 9 and 10.

The complete 14-kb cDNA for the gene causing the X-linked recessive muscular dystrophy (MD) type Duchenne (DMD) and Becker (BMD) has recently been cloned and made available for deletion/duplication screening in patients. It detects 65 exon-containing nonpolymorphic HindIII fragments spread over a gene locus of about 2,000 kb. When the entire DMD cDNA is used, deletions/duplications can be found in about 65%-70% of affected patients, permitting direct carrier detection by densitometric scanning. But in cases where no deletion/duplication is detectable, RFLP analysis, specially favored within the gene, will be the method for carrier-status determination. Clones 9 and 10-1.2-kb and 0.7-kb fragments, respectively, of the 14-kb DMD cDNA--have been hybridized with human genomic DNA digested by nine different restriction enzymes. Five RFLPs, involving Asp700, PvuII, XbaI, and EcoRV sites, were detected, and Mendelian inheritance could be demonstrated. Since clones 9 and 10 are localized telomeric to the mutation-hot-spot region, their polymorphisms are thought to be very helpful as flanking markers for indirect carrier detection in families with a family history of DMD/BMD. Moreover, these RFLPs can be used for direct carrier detection or exclusion in families with patients showing a deletion/duplication in the region of p9 or p10.

Blotting, Southern↗
PubMed1990

The red-green visual pigment gene region in adrenoleukodystrophy.

Although recent data established that a specific very-long-chain fatty acyl-CoA synthetase is defective in X-linked adrenoleukodystrophy (ALD), the ALD gene is still unidentified. The ALD locus has been mapped to Xq28, like the red and green color pigment genes. Abnormal color vision has been observed in 12 of 27 patients with adrenomyeloneuropathy (AMN), a milder form of ALD. Furthermore, rearrangements of the color vision gene cluster were found in four of eight ALD kindreds. This led us to propose that a single DNA rearrangement could underlie both ALD and abnormal color vision in these patients. Study of 34 French ALD patients failed to reveal a higher than expected frequency of green/red visual pigment rearrangements 3' to the red/green color vision gene complex. The previous report of such rearrangements was based on small numbers and lack of knowledge that the frequency of "abnormal" color vision arrays on molecular analysis was twice as high as expected on the basis of the frequency of phenotypic color vision defects. The red/green color pigment (R/GCP) region was studied by pulsed-field gel electrophoresis in 14 of these patients, and we did not find any fragment size difference between the patients and normal individuals who have the same number of pigment genes. The R/GCP region was also analyzed in 29 French and seven North American ALD patients by using six genomic DNA probes, isolated from a cosmid walk, that flank the color vision genes. No deletions were found with probes that lie 3' of the green pigment genes. One of the eight previously reported ALD individuals has a long deletion 5' of the red pigment gene, a deletion causing blue cone monochromacy. This finding and the previous findings of a 45% frequency of phenotypic color vision defects in patients with AMN may suggest that the ALD/AMN gene lies 5' to the red pigment gene and that the frequent phenotypic color vision anomalies owe their origin to deleted DNA that includes regulatory genes for color vision. It is possible, however, that phenotypic color vision anomalies in AMN may be phenocopies secondary to retinal or neural involvement by the disease. The single case of blue cone monochromacy may therefore be a fortuitous coincidence of two diseases.

Adrenoleukodystrophy↗
PubMed1989

Molecular deletion patterns in Duchenne and Becker type muscular dystrophy.

DNA from 80 Duchenne (DMD) and 15 Becker (BMD) index patients was analyzed with 12 genomic probes and the total cDNA. Deletions were detected in 24 DMD (30%) and 10 BMD patients (67%) by genomic probes alone, mostly p20, pXJ, and/or pERT87. All deletions were confirmed by cDNA probes, and an additional 29 DMD deletions were detected, resulting in a total of 63/95 deletions (66%). The majority of the deletions are localized between kb 6.7 and 9.7 of the cDNA; a smaller group, between kb 0.5 and 3.5. Of the deletions, 90% are detected by the three cDNA probes 1-2a, 7, and 8. This can be applied to strategies for carrier detection and prenatal diagnosis. The order of 13 exon-containing HindIII fragments in the region between probes 7 and 9-10, where most of the deletions are found, could be defined. The deletion patterns in DMD and BMD patients are different and well in accordance with the "reading frame theory" of Monaco and coworkers. Thus our findings indicate that a DMD or BMD phenotype may be predicted according to the breakpoint position and the number of deleted exons.

Chromosome Deletion↗
PubMed1989

Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients.

Disorders of peroxisomal biogenesis include the Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum syndrome, and hyperpipecolic acidemia. These names were assigned before the recognition of the peroxisomal defect and the distinction between phenotypes is uncertain. Recent studies have identified at least four complementation groups, and indicate the presence of at least that number of distinct genotypes. The purpose of the present study was to examine the relationship between genotype and phenotype. We studied cultured skin fibroblasts from 19 patients in whom deficiency of peroxisomes had been established. Complementation analysis was performed with the criterion of complementation being the restoration of the capacity to synthesize plasmalogens when fibroblasts from two patients were fused. Six complementation groups were identified, and consisted of one 13 member group, one two member group, and four groups comprising single cases. The phenotype of each group was examined with respect to age of survival, clinical manifestations, and biochemical alterations. The 13 member group included patients with all of the four currently designated phenotypic entities, while the most common phenotype (Zellweger syndrome) was distributed among five of the six groups. We conclude that the currently used clinical categories do not represent distinct genotypes. Apparently different genes code for a similar phenotype and one defective gene may lead to variant phenotypes. Definitive classification and understanding of these disorders await definition of the specific biochemical defect in each of the genotypes.

Adrenoleukodystrophy↗
PubMed1989

The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion.

About 60% of both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is due to deletions of the dystrophin gene. For cases with a deletion mutation, the "reading frame" hypothesis predicts that BMD patients produce a semifunctional, internally deleted dystrophin protein, whereas DMD patients produce a severely truncated protein that would be unstable. To test the validity of this theory, we analyzed 258 independent deletions at the DMD/BMD locus. The correlation between phenotype and type of deletion mutation is in agreement with the "reading frame" theory in 92% of cases and is of diagnostic and prognostic significance. The distribution and frequency of deletions spanning the entire locus suggests that many "in-frame" deletions of the dystrophin gene are not detected because the individuals bearing them are either asymptomatic or exhibit non-DMD/non-BMD clinical features.

Adolescent↗