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Biomedical subjects

M Mikkelsen

Publications and source records attributed to M Mikkelsen.

At least 37 records · Page 2Linked to original sources
PubMed1996

Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures.

In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM) with placebo as add-on therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b.i.d)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients were randomized to each treatment group. In the intent-to-treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo-treated patients and 43% of the patients treated with TPM experienced > or = 50% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75-100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentration, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefit/risk ratio of TPM in resistant partial epilepsy.

Adolescent↗
PubMed1995

A 10-year survey, 1980-1990, of prenatally diagnosed small supernumerary marker chromosomes, identified by FISH analysis. Outcome and follow-up of 14 cases diagnosed in a series of 12,699 prenatal samples.

A cytogenetic survey and follow-up studies were made of 14 cases with supernumerary marker chromosomes, identified among 12,699 prenatal samples, investigated at our institution over a 10-year period from 1980 to 1990. FISH (fluorescence in situ hybridization) techniques were employed to identify the chromosomal origin of the marker chromosomes. Five cases were familial, all derived from acrocentric chromosomes, and all without apparent phenotypic effects in the children. Nine cases represented de novo aberrations. In two cases (one with a marker from chromosome 14 or 22, the other with a ring-like marker derived from chromosome 17), the pregnancies continued and apparently normal babies were delivered at term, but the child with a marker derived from chromosome 17 showed slight psychomotor retardation at 2 years of age. All other pregnancies with de novo markers were terminated. In three cases, significant abnormalities were found at autopsy. One of these had an isochromosome 12p and the phenotype was consistent with Pallister-Killian syndrome. In conclusion, marker chromosome identification, as well as clinical follow-up, is essential for the purpose of improving genetic counselling.

Chromosome Aberrations↗
PubMed1995

Analysis of a whole arm translocation between chromosomes 18 and 20 using fluorescence in situ hybridization: detection of a break in the centromeric alpha-satellite sequences.

Using classical cytogenetic techniques, we detected a male patient with monosomy 18p/trisomy 20p, originating from a paternal reciprocal translocation of the short arms of chromosomes 18 and 20. To characterize the breakpoints further and to determine the centromeric origin of the chromosomes involved, we analyzed the metaphase chromosomes by fluorescence in situ hybridization using alpha-satellite DNA probes specific to chromosomes 18 and 20. With this approach, we showed that alpha-satellite centromeric fragments were involved in the translocation event and that the chromosome-18-specific centromeric sequences were split into two. Analysis of 14 family members from four generations revealed nine phenotypically normal individuals carrying this reciprocal translocation. These results suggest that breaks in alpha-satellite DNA fragments neither impair the centromeric function nor have clinical effects.

Abnormalities, Multiple↗
PubMed1995

Adjunctive treatment of partial seizures with tiagabine: a placebo-controlled trial.

Tiagabine is a new antiepileptic drug which acts by a novel mechanism, inhibiting the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into neurons and glia. A double-blind, placebo-controlled, crossover trial was undertaken, based upon a response-dependent design. Ninety-four patients with complex partial seizures with or without secondary generalised tonic-clonic seizures were recruited into an open screening phase and tiagabine was added to their existing drug therapy in doses titrated to reduce seizure frequency by > or = 25% or to the limit of tolerance. Forty-six responders were subsequently randomised to a double-blind crossover trial in which tiagabine was compared with placebo. Forty-two patients completed the trial. A significant reduction in the frequency of complex partial and secondary generalised tonic clonic seizures was seen. Twenty-six percent had a reduction of > or = 50% in the frequency of their complex partial seizures, and of the 27 patients who also had secondary generalised tonic clonic seizures, 63% experienced a reduction of > or = 50%. No interactions with baseline antiepileptic drugs were detected and no serious adverse reactions occurred. The commonest adverse events were tiredness, dizziness and headache. We conclude that tiagabine has promising antiepileptic effects. Further trials are underway.

Adolescent↗
PubMed1995

Selective miscarriage of Down's syndrome fetuses in women aged 35 years and older.

OBJECTIVE: To estimate the fetal loss of Down's syndrome fetuses between the time of chorionic villus sampling (10 weeks gestation) and the time of amniocentesis (16 weeks gestation) and term in women aged 35 years and older. DESIGN: The age specific prevalence rates in the first trimester of Down's syndrome were estimated using the Danish cytogenetic register in combination with results from four published studies. These were compared with the reported prevalence at the time of amniocentesis and at birth. SUBJECTS: 5927 singleton pregnancies undergoing chorionic villus sampling (71 cases of Down's syndrome and 5856 unaffected cases). This was combined with published data on a further 231 cases of Down's syndrome and 16,620 unaffected cases. MAIN OUTCOME MEASURES: Age specific prevalences at the time of chorionic villus sampling. Proportion of pregnancies lost between the time of chorionic villus sampling and the time of amniocentesis and term. RESULTS: Thirty-two percent of Down's syndrome pregnancies are lost between the time of chorionic villus sampling (10 weeks) and the time of amniocentesis (16 weeks) and 54% are lost by term. CONCLUSIONS: The high fetal loss rates of Down's syndrome between the time of chorionic villus sampling and term introduce problems when evaluating first trimester screening tests with respect to their effective detection rates at term. A recommendation for quoting term risks is made.

Abortion, Spontaneous↗
PubMed1994

Significant increase in trisomy 21 in Berlin nine months after the Chernobyl reactor accident: temporal correlation or causal relation?

OBJECTIVE: To assess whether the increased prevalence of trisomy 21 in West Berlin in January 1987 might have been causally related to exposure to ionising radiation as a result of the Chernobyl reactor accident or was merely a chance event. DESIGN: Analysis of monthly prevalence of trisomy 21 in West Berlin from January 1980 to December 1989. SETTING: Confines of West Berlin. RESULTS: Owing to the former "island" situation of West Berlin and its well organised health services, ascertainment of trisomy 21 was thought to be almost complete. A cluster of 12 cases occurred in January 1987 as compared with two or three expected. After exclusion of factors that might have explained the increase, including maternal age distribution, only exposure to radiation as a result of the Chernobyl reactor accident remained. In six of seven cases that could be studied cytogenetically the extra chromosome was of maternal origin, confirming that nondisjunction had occurred at about the time of conception. CONCLUSION: On the basis of two assumptions--(a) that maternal meiosis is an error prone process susceptible to exogenous factors at the time of conception; (b) that owing to the high prevalence of iodine deficiency in Berlin a large amount of iodine-131 would have been accumulated over a short period--it is concluded that the increased prevalence of trisomy 21 in West Berlin in January 1987 was causally related to a short period of exposure to ionising radiation as a result of the Chernobyl reactor accident.

Accidents↗
PubMed1994

Obstetrical and gynecological complications in fragile X carriers: a multicenter study.

We have conducted a multicenter obstetrical and gynecological survey of women in fragile X families. Included in the study were 131 gene carriers (39 with a full mutation and 92 with a premutation) and 109 noncarriers. Analysis indicated that higher numbers of fragile X gene carriers reported having irregular menses and other gynecological complications. As a group they also experienced cessation of menses prior to age 40 years at a significantly higher rate. The data appear to indicate that the FMR1 gene may play a role in the development and proliferation of oogonia.

Abortion, Spontaneous↗
PubMed1994

Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination.

Over 300 cases of trisomy 21 were analyzed to characterize the causes of maternal non-disjunction and to evaluate the basis for maternal age-dependent trisomy 21. We confirmed the observation that recombination along 21q is reduced among non-disjoined chromosomes 21 and further demonstrated that the alterations in recombination are restricted to meiosis I origin. Analysis of the crossover distribution indicates that reduction in recombination is not due simply to failure of pairing and/or absence of recombination in a proportion of cases. Instead, we observed an increase in both zero- and one-exchange events among trisomy 21-generating meioses suggesting that an overall reduction in recombination may be the underlying cause of non-disjunction. Lastly, we observed an age-related reduction in recombination among the meiosis I cases, with older women having less recombination along 21q than younger women. Thus, reduced genetic recombination may be responsible, at least in part, for the association between advancing maternal age and trisomy 21.

Adult↗
PubMed1994

"Compensatory" uniparental disomy of chromosome 21 in two cases.

Two cases of growth failure, microcephaly, facial dysmorphism, muscular hypertonia, and severe psychomotor retardation are described. At birth, both cases had cytogenetic mosaicism in lymphocytes and skin fibroblasts, in case 1 ring chromosome 21 and monosomy 21 and in case 2, deletion of chromosome 21 and monosomy 21. At a later age the lymphocyte karyotype changed almost completely to 46,XX, but the fibroblast karyotype remained as before. DNA polymorphism analysis described elsewhere indicated that the 46,XX lymphocytes contained two identical chromosomes 21 (isodisomy), in case 1 inherited from the father and in case 2 from the mother. The isodisomy was the result of duplication of a chromosome in mitosis after the loss of the homologous abnormal chromosome ("compensatory isodisomy"). We report here that this cytogenetic mechanism can result in false normal cytogenetic findings. The phenotypes were attributed to the cells with monosomy 21 in case 1 and to the deletion and monosomy of chromosome 21 in case 2.

Adolescent↗
PubMed1993

Cytogenetic, FISH and DNA studies in 11 individuals from a family with two siblings with dup(21q) Down syndrome.

A Spanish family has previously been described with two siblings with dup(21q) Down syndrome. The father has a normal karyotype. The mother has a microchromosome. Cytogenetic, fluorescence in situ hybridization and DNA studies have now been carried out on the family. Findings include that the mother has three different chromosome anomalies, viz. (1) a chromosome 22 with an unusual pericentromeric region that contains alphoid DNA from chromosomes 21/13 and chromosome 22, (2) an isochromosome 21p in the frequent cell line and (3) an isochromosome 21q in a rare second cell line. A possible explanation is that the mother developed from a zygote with trisomy 21 and that mitotic error in early development resulted in the formation of two cell lines with karyotypes of 47,XX,+i(21p) and 47,XX,+i(21q), respectively. The unusual chromosome 22 represents a hitherto undescribed chromosome anomaly and one possible explanation is a translocation of the short arms between chromosomes 21/13 and 22 in the ancestry of the family. The relationship between the unusual chromosome 22 and the isochromosome formation in the mother is not known. However, all three chromosome anomalies involve the alphoid DNA of chromosome 21/13, indicating that this is not a chance finding.

Centromere↗
PubMed1993

Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetric and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly.

A high frequency of spontaneous chromosomal breakage, endomitosis, endoreduplication and hypersensitivity toward both the alkylating agent Trenimon and the radiomimetric drug bleomycin was observed in phytohemagglutinin-stimulated peripheral lymphocytes from a girl with craniosynostosis, microcephaly, ptosis, bird-like facies, and moderate mental retardation. We also observed abnormal chromosomal spiralization and some aspects of abnormal cellular division. Several fruitless attempts were made to establish a cell line. The parents were consanguineous, supporting the existence of a new, rare, autosomal, recessive condition in man. The mutation might involve a gene involved in DNA repair and/or regulation of the mitotic cycle.

Adult↗
PubMed1993

Paternal nondisjunction in trisomy 21: excess of male patients.

Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. We have studied 36 cases of free trisomy 21, in which the supernumerary chromosome was of paternal origin, with DNA markers in the pericentromeric region and along the long arm of chromosome 21. Fifteen of the paternal cases were consistent with meiosis II errors, 8 with mitotic errors and only 7 with meiosis I nondisjunction. This contrasts markedly with maternally derived trisomy 21, in which meiosis I errors predominate. An excess of males was observed in the meiotic cases (21 males:6 females), highly significantly different from a 1.06 ratio. A significant difference in mean maternal age was found between cases of paternal origin (28.1 years) and those of maternal origin (31.8 years, n = 429). This indicates that the maternal age effect is confined to maternal nondisjunction.

Adolescent↗
PubMed1993

Chromosome painting using FISH (fluorescence in situ hybridization) with chromosome-6-specific library demonstrates the origin of a de novo 6q+ marker chromosome.

We report the application of chromosome painting using FISH (fluorescence) in situ hybridization) to demonstrate the origin of a de novo 6q+ marker chromosome. A girl with a mental retardation/multiple malformation syndrome was shown to have the karyotype 46,XX, 6q+. Banding analysis could not determine the origin of the extra chromosomal material. Using FISH with a chromosome-6-specific library we showed that the marker chromosome was completely painted, indicating an origin from chromosome 6. The child's phenotype was compared with previously reported cases with partial chromosome 6 trisomy. A clinically recognized syndrome emerged, although she apparently also demonstrated novel features.

Abnormalities, Multiple↗
PubMed1993

Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment.

Efficacy and tolerability of the new antiepileptic drug oxcarbazepine, was evaluated in a retrospective multicentre study. The records of all 947 epilepsy patients treated with oxcarbazepine in the eight participating centres from 1981 through 1990 were examined. The median daily dose of oxcarbazepine was 30 mg/kg in children, 18 mg/kg in adults, and 15 mg/kg in elderly patients, given b.i.d. or t.i.d. The mean plasma levels of the main active metabolite of oxcarbazepine was 88, 79, and 68 mumol/l in children, adults, and elderly, respectively. In patients shifted to oxcarbazepine treatment, seizure frequency was unchanged in 51-66%, 32-48% had a decrease, and 1-10% an increase in seizure frequency, considering the individual seizure types separately. Adverse events were reported in one third of patients, most frequently affecting the CNS (dizziness: 6%; sedation: 6%; fatigue: 6%). Rash was reported in 6% of patients, half of these patients had previously had an allergic reaction to carbamazepine. Hyponatremia was found in about a quarter of the patients from whom data were available. No congenital malformations were seen in nine live-born, first trimester oxcarbazepine-exposed children.

Adolescent↗
PubMed1992

Uniparental isodisomy due to duplication of chromosome 21 occurring in somatic cells monosomic for chromosome 21.

Uniparental disomy has been recently recognized as an important phenomenon in non-Mendelian inheritance of human genetic disorders. Several mechanisms for uniparental disomy, i.e., the presence of two homologous chromosomes derived from one parent, have been proposed. We studied two independent cases of abnormalities of chromosome 21 in which there were abnormal karyotypes at birth but blood cells with normal karyotype predominated later in life, and the cells with abnormalities disappeared. Uniparental isodisomy was observed in the normal cells in these individuals. The uniparental disomy in these families was the result of duplication of a chromosome in mitosis after the loss of the homologous abnormal chromosome. The duplication can be seen as mechanism for cell survival and is called here "compensatory" isodisomy, which provided a selective advantage for the cell population with the normal number of chromosomes 21.

Abnormalities, Multiple↗
PubMed1992

Ring chromosome 13: lack of distinct syndromes based on different breakpoints on 13q.

A stillborn male child with anencephaly and multiple malformations was found to have the karyotype 46,XY,r(13) (p11q21.1). The breakpoint at 13q21.1, determined by high resolution banding, is the most proximal breakpoint ever reported in patients with ring chromosome 13. In situ hybridisation with the probe L1.26 confirmed the derivation from chromosome 13 and DNA polymorphism analysis showed maternal origin of the ring chromosome. Our results, together with a review of previous reports of cases with ring chromosome 13 with identified breakpoints, could neither support the theory of distinct clinical syndromes based on different breakpoints on 13q nor correlate the severity of symptoms with instability of the ring.

Abnormalities, Multiple↗