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Biomedical subjects

R Spiegel

Publications and source records attributed to R Spiegel.

At least 55 records · Page 3Linked to original sources
PubMed1995

Rapid detection of sex chromosomal aneuploidies by PCR.

In this report we present a method to determine sex chromosomal aneuploidies by duplex polymerase chain reaction with sufficient precision to distinguish between one, two and more copies of X and Y sequences. We coamplified an autosomal gene segment (exon 33 of neurofibromatosis type I gene on chromosome 17) as an internal standard for our sequence of interest (AMXY) on X and Y chromosomes. By using this standard as a reference for two gene copies we could visually estimate the relative gene dosage for the X-, and Y-specific AMXY sequences in the DNA sample under consideration. We have evaluated this method in normal males and females and in patients with known sex chromosomal aneuploidies and have found it to be a reliable and quick tool for detection of numerical sex chromosomal abnormalities.

Aneuploidy↗
PubMed1995

Functional expression of human mutant phosphofructokinase in yeast: genetic defects in French Canadian and Swiss patients with phosphofructokinase deficiency.

Human phosphofructokinase (PFK) is a tetrameric enzyme, encoded by muscle, liver, and platelet genes. Deficiency of muscle PFK (PFK-M), glycogenosis type VII (Tarui disease), is an autosomal recessive disorder characterized by an exertional myopathy and hemolytic syndrome. Several disease-causing mutations have been identified in the PFK-M gene in Japanese, Ashkenazi Jewish, and Italian patients. We describe the genetic defects in French Canadian and Swiss patients with the disease, and we use a genetically well-defined yeast system devoid of endogenous PFK for structure-function studies of the mutant PFKs. A G-to-A transition at codon 209-in exon 8 of the PFK-M gene, changing an encoded Gly to Asp, is responsible for the disease in a homozygous French Canadian patient. Gly-209-mutated protein is completely inactive in the yeast system. The Swiss patient is a genetic compound, carrying a G-to-A transition at codon 100 in exon 6 (Arg to Gln) and a G-to-A transition at codon 696 in exon 22 (Arg to His). The mutants expressed in yeast generate functional enzyme with modest changes in thermal stability. The advantages and limitations of the yeast system for expression of human mutant PFKs are discussed.

Adult↗
PubMed1995

[Huntington's chorea: clinical aspects, genetics and current diagnosis].

Huntington's disease is a late manifesting autosomal dominant neurodegenerative disorder. It is characterized by motor disturbance, loss of cognitive functions and psychiatric manifestations. The disease causing mutation, an unstable DNA sequence in the coding region of the Huntington gene on chromosome 2p, has recently been identified. A trinucleotide [CAG] repeat is expanded over the normal range and can be easily detected by standard laboratory methods. Accurate genetic testing can now be offered in clinically questionable cases and to presymptomatic subjects at risk for Huntington's disease. Furthermore, there is a correlation between the size of the expanded CAG repeat and the age of onset in affected individuals. The predictive value of this correlation, however, is limited due to the range of onset ages found at a given repeat length in large series of patients. Expanded triplet repeats exhibit a marked instability especially in male meiosis with a tendency to further increase during transmission over the generations. This is likely to be the molecular mechanism explaining anticipation, as well as the occurrence of juvenile cases and new mutations.

Adolescent↗
PubMed1994

Acute respiratory infections in Nigerian children: prospective cohort study of incidence and case management.

A community-based prospective surveillance and case management study of acute respiratory infection (ARI) in children aged 2-60 months of age was carried out over a 12-month period in Pakata, a semi-urban community in Ilorin, Kwara State, Nigeria. A cohort of 481 children was followed by trained community health assistants with thrice weekly home visits to record all symptoms and signs of ARI, and institute treatment based on WHO recommendations. There were three episodes of mild, moderate, or severe ARI per child per year, including 1.3 pneumonia episodes per child per year. The peak of infection corresponded to the rainy season (July-November), and a smaller peak to the dry season (February-April). Most of the health worker decisions were considered appropriate, although there was a tendency toward over-treatment with antibiotic drugs. An effective referral system was established from the community to a tertiary centre. There were no ARI-related deaths during the study period. These data indicate that a system of case management using trained community health workers can improve case management of ARI and may prevent severe ARI-related disease and deaths.

Acute Disease↗
PubMed1993

[Direct genetic diagnosis in Huntington's chorea].

Huntington's disease is a late manifesting autosomal dominant neurodegenerative disorder. It is characterized by motor disturbance, loss of cognitive functions and psychiatric manifestations. Recently, the disease causing mutation, an unstable DNA sequence in the coding region of the Huntington gene on chromosome 4p, has been identified. A trinucleotide (CAG) repeat is expanded over the normal range and can easily be detected by standard laboratory methods. Accurate genetic testing can now be offered in clinically questionable cases and to subjects at risk for Huntington's disease. Furthermore, there seems to be a correlation between the size of the expanded CAG repeat and the age of onset in affected individuals. We have investigated more than 130 individuals from different affected families and illustrate the advantages and the clinical application of the new method.

Adult↗
PubMed1993

[Turcot syndrome--a rare extra-intestinal manifestation of familial adenomatous polyposis?].

The case of a 15-year-old male with Turcot syndrome is presented. When the patient was aged 10 years a medulloblastoma was diagnosed. Five years later he developed multiple adenomatous polyps of the colon and multiple "congenital hypertrophy of the retina" (CHRPE), the most common extraintestinal manifestation of FAP, were described. Family history revealed familial adenomatous polyposis with 12 family members exhibiting a FAP. The mode of inheritance of Turcot syndrome is controverted. Our case strengthens the hypothesis that the syndrome is a further extraintestinal (rare) manifestation of the FAP gene.

Adenomatous Polyposis Coli↗
PubMed1993

Deletion breakpoints associated with the Prader-Willi and Angelman syndromes (15q11-q13) are not sites of high homologous recombination.

Deletions of 15q11.2-q12 are associated with either the Prader-Willi (PWS) or Angelman (AS) syndromes. It has been suggested that excessive recombination in this region might explain the high frequency of such deletions, and the frequent involvement of chromosome 15 in translocations and nondisjunction. We have studied recombination in the PWS region by linkage analysis of non-PWS families. No recombination was found (with maximum lod scores greater than 3.0) for most pair-wise combinations of probes: 39, IR4-3R, ML34, 189-1, 3-21. A 'hotspot' of recombination is observed between loci detected by p3-21 and pIR10-1. The female recombination fraction in this region was significantly higher than that for males. Close linkage with 0.06 recombination was found for the IR10-1 and CMW-1 pair. No excess recombination was found between sites bounding common breakpoints observed in deletions associated with PWS and AS. It is suggested that these deletions form frequently because of the presence of duplicated DNA sequences and/or inversions in this region, and not because of a high rate of homologous recombination.

Angelman Syndrome↗
PubMed1993

Effects of the novel acetylcholinesterase inhibitor SDZ ENA 713 on sleep in man.

A novel brain-selective acetylcholinesterase inhibitor, SDZ ENA 713, is under development for the treatment of dementia of the Alzheimer type. To determine the threshold dose for central activity, single doses of the compound were administered to 20 young male volunteers in a double-blind cross-over design and the effects on the sleep electroencephalography studied. The first group of eight volunteers received in random order: placebo, 0.5 mg; and 1 mg SDZ ENA 713. The second group of 12 volunteers received: placebo, 1.3 mg; and 2 mg SDZ ENA 713. Sleep quality was not affected by the study medication, which was well tolerated by all subjects. A statistically significant increase in rapid-eye movement sleep density was observed after doses of 1 mg, 1.3 mg, and 2 mg. Rapid-eye movement latency and slow-wave sleep were not altered. The results demonstrate that SDZ ENA 713 is centrally active in man at well-tolerated doses.

Adolescent↗
PubMed1993

Influence of the cholinergic agonist SDZ 210-086 on sleep in healthy subjects.

The administration of 1.0 mg SDZ 210-086, an orally acting muscarinic agonist, shortened rapid-eye movement (REM) latency, increased REM percent of sleep period time and the total duration of REM sleep, and decreased slow-wave sleep in 12 healthy male subjects. The administration of 0.5 mg SDZ 210-086 had no statistically significant effect on sleep variables. Although the tonic components of REM sleep (REM duration, the REM percent of sleep period time) were increased, REM density percent (total) was significantly decreased due to the prolongation of total REM duration (in minutes) and a parallel reduction of the total number of eye movements. This finding is in contrast to studies using other cholinomimetics (i.e., physostigmine, arecoline, and RS 86) and may implicate different generating systems of phasic and tonic REM sleep components.

Adult↗
PubMed1993

Parental origin of the supernumerary chromosome in trisomy 18.

The parental origin of an extra chromosome in Edwards syndrome has been investigated in 23 families by the combination of the VNTR probe pERT25, two microsatellite polymorphisms for D18S34 and D18S40, and several two-allele polymorphisms. Of the 23 cases, 22 were informative, with 17 (77%) being maternal and 5 (23%) paternal in origin. These results support the previous investigations, suggesting that trisomy 18 is predominantly of maternal origin, although a higher rate of paternally derived cases was observed than previously reported. A significant increase in maternal age was found to be associated with meiotic nondisjunction. Parental age was increased in both the maternally and paternally derived cases, but the size of the latter class was small and did not reach statistical significance.

Adult↗
PubMed1992

[Molecular genetics diagnosis of Steinert's myotonic dystrophy].

Myotonic dystrophy (DM) is the most common neuromuscular disease with adult onset (incidence 1 in 8000). The biochemical basis of this autosomal dominantly inherited disease is still unknown. The most striking features are myotonia and progressive muscular wasting. There is high variability of disease severity in patients from different families, but also within the same family. For practical reasons three subtypes can be defined: The classical adult onset form of the disease, a mild form with late onset and/or very moderate symptoms, eg. cataracts only, and the most severe congenital form which is transmitted by affected females. Furthermore, the progression of DM in affected families may exhibit an increase in the severity of the disease in successive generations. This observation is called anticipation. Very recently the DM gene has been cloned and an unstable DNA sequence specific for the disease has been characterized. Detection of an enlarged DNA fragment due to the expansion of a trinucleotide (CTG) repeat within the DM gene can be used for direct DNA diagnosis in affected individuals and persons at risk. Furthermore, there is a strong correlation between the length of fragment expansion and the degree of disease severity in gene carriers. We report here our preliminary results of the investigation of over 70 patients and demonstrate the clinical usefulness of this new method by the findings in three families.

Adult↗
PubMed1992

Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy.

Expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene is associated with a rare motor neuron disorder, X-linked spinal and bulbar muscular atrophy. We have found that expanded (CAG)n alleles undergo alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of instability in male meiosis than in female meiosis. We also found evidence for a correlation between disease severity and CAG repeat length, but other factors seem to contribute to the phenotypic variability in this disorder.

Base Sequence↗
PubMed1992

Prenatal prediction of Werdnig-Hoffmann disease using linked polymorphic DNA probes.

Werdnig-Hoffmann disease is a common autosomal recessive neuromuscular disorder that results in paralysis and death. No treatment to prevent this disease or to alter its unremitting course has been found. Recently, linkage analysis with cloned DNA probes has shown that the mutation causing Werdnig-Hoffmann disease is located on chromosome 5q12-q14. We performed genetic analysis for the prenatal diagnosis of Werdnig-Hoffmann disease in seven at risk families. Two fetuses were diagnosed as being affected and the remainder as unaffected, and this was confirmed after birth. This study shows that prenatal diagnosis of Werdnig-Hoffmann disease has become feasible.

Chromosomes, Human, Pair 5↗