FMR1 CGG-repeat instability in single sperm and lymphocytes of fragile-X premutation males.

To determine the meiotic instability of the CGG-triplet repeat in the fragile-X gene, FMR1, we examined the size of the repeat in single sperm from four premutation males. The males had CGG-repeat sizes of 68, 75, 78, and 100, as determined in peripheral blood samples. All samples showed a broad range of variations, with expansions more common than contractions. Examination of single lymphocytes indicated that somatic cells were relatively more stable than sperm. Surprisingly, the repeats in sperm from the 75- and 78-repeat males had very different size ranges and distribution patterns despite the similarity of the repeat size and AGG interruption in their somatic cells. These results suggest that cis or trans factors may have a role in male germline repeat instability.     

Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia

Premutations of the fragile-X (FRAXA) gene were thought to have no clinical effects until recent reports of an increased incidence of premature ovarian failure in females and a late-onset neurological disorder in males. These patients were identified from families including typical fragile-X males with a full mutation. By analysing a cohort of patients with neurodegenerative disorders referred for genetic analysis of spinocerebellar ataxia genes, we have found that 3 of 59 males carry the premutation. Our patients extend the phenotype associated with the FRAXA premutation and indicate that it may account for a proportion of undiagnosed neurodegenerative disorders.     

Thyroid function and metabolic syndrome in the population-based LifeLines cohort study

Background

The metabolic syndrome (MetS) is a combination of unfavourable health factors which includes abdominal obesity, dyslipidaemia, elevated blood pressure and impaired fasting glucose. Earlier studies have reported a relationship between thyroid function and some MetS components or suggested that serum free thyroxine (FT4) or free triiodothyronine (FT3) levels within the normal range were independently associated with insulin resistance. We assessed how thyroid function relates to MetS prevalence in a large population-based study.

Methods

Data of 26,719 people of western European descent, aged 18–80 years from the Dutch LifeLines Cohort study, all with normal thyroid stimulating hormone (TSH), FT4 and FT3 levels (electrochemiluminescent immunoassay, Roche Modular E170 Analyzer), were available. MetS was defined with the revised National Cholesterol Education Programs Adults Treatment Panel III (NCEP ATP III) criteria. We calculated prevalence of all MetS components according to TSH, FT4 and FT3 quartiles.

Results

At similar TSH levels and age (mean 45 yrs), men had significantly higher levels of FT4, FT3, blood pressure (BP), heart rate, total and LDL-cholesterol, triglycerides (TG), and creatinine, but lower HDL-cholesterol compared to women (all p < 0.001). In total, 11.8% of women and 20.7% of men had MetS. In men, lower FT4 levels were associated with higher prevalence of MetS and all MetS components. In women, lower FT4 quartile was only associated with a higher prevalence of elevated TG, waist circumference, and MetS. However, when corrected for confounding factors like age, BMI, current smoking and alcohol consumption, a significant relationship was found between FT3 and three MetS components in men, and all five components in women. Moreover, the highest quartiles of FT3 and the FT3FT4 ratio predicted a 49% and 67% higher prevalence of MetS in men, and a 62 and 80% higher prevalence in women.

Conclusions

When corrected for possible confounding factors, higher plasma levels of FT3 are associated with several components of the MetS. Only in men, lower FT4 is related to MetS. In the highest FT3 and FT3FT4 quartiles, there is a 50–80% increased risk of having MetS compared to the lowest quartile. Further studies are needed to assess the possible causality of this relationship.

     

Thyroid function in pregnancy

Iodine is required for the production of thyroid hormones. Normal thyroid function during pregnancy is important for both the mother and developing fetus. This review discusses the changes in thyroid physiology that occur during pregnancy, the significance of thyroid function tests and thyroid antibody titers assessed during pregnancy, and the potential obstetric complications associated with maternal hypothyroidism.     

No founder effect detected in Jewish Ashkenazi patients with fragile-X syndrome

Several studies on small homogenous populations suggested that fragile-X syndrome originated from a limited number of founder chromosomes. The Israeli Jewish population could serve as an adequate model for tracing a founder effect due to the unique ethnic makeup and traditional lifestyle. Furthermore, a common haplotype for Jewish Tunisian fragile X patients was recently reported. To test for a similar occurrence in the Jewish Ashkenazi population, we performed haplotype analysis of 23 fragile-X patients and 28 normal chromosomes, all Jewish Ashkenazi, using microsatellite markers within and flanking the FMR-1 gene: FRAXAC1, FRAXAC2, and DXS548. The combined triple-marker analysis identified a wide range of diverse haplotypes in patients and controls, with no distinct haplotype prevalent in the patient group. Our data suggest that no common ancestral X chromosome is associated with the fragile-X syndrome in the Israeli Jewish Ashkenazi patient population studied. These findings are in contrast to other reports on founder effect associated with fragile-X syndrome in distinct European as well as Jewish Tunisian populations. On this basis, a more complex mechanism for the development of fragile-X syndrome in the Jewish Ashkenazi population should be considered. Received: 12 May 1997 / Accepted: 24 July 1997     

Thyroid function in lung cancer

Thyroid function was assessed at the time of initial diagnosis in 204 patients with lung cancer and compared with that of age and sex-matched patients with non-malignant lung disease. Abnormalities in thyroid function were found in 67 patients (33%). The most prevalent abnormality was a low T3 concentration; this was not associated with other clinical or biochemical evidence of hypothyroidism, but the short-term prognosis of these patients was worse than that of matched patients with lung cancer having normal T3 concentrations. Primary hypothyroidism occurred in three patients, low T4 concentrations and free thyroxine index (FTI) with normal thyrotrophin (TSH) concentrations in four patients, and moderately raised TSH with normal thyroid hormone concentrations in six patients; nine patients had a raised FTI with or without raised T4 concentration as the sole abnormality.Overall, the pattern of thyroid hormone metabolism in lung cancer was a tendency towards reduced T3 concentrations with significantly increased T4/T3 ratios and modestly increased 3,3′,5′-triiodothyronine (rT3) concentrations. The altered T4/T3 ratio was particularly noticeable in patients with anaplastic tumours of small (“oat cell”) and large cell types, but was not apparently related to detectable extrathoracic metastases.These data suggest that thyroid hormone metabolism is altered in patients with lung cancer by decreased 5′-monodeiodination of T4. The resulting low T3 concentrations and altered T4/T3 ratio may be partly responsible for the reduced ratio of androsterone to aetiocholanolone observed in lung cancer, which is known to be a poor prognostic sign.     

Thyroid gland function in heatstroke]

Development of thermal stroke in rats with the action of high external temperature (45 degrees C) was accompanied by a reduction of accumulation of I131 in the thyroid gland, a fall in the protein-bound-iodine--I131 and in the amount of thyroxin in the peripheral blood plasma, and also by a fall in the rate of disappearance from the blood of Nal131 injected intravenously. A relative decrease of the content of mono- and particularly of diiodthyrosines, and also, slightly, of iodthyronines occurred in the trypsine hydrolyzates of the thyroid gland at the moment of the thermal stroke development.     

A new DNA probe of potential use for diagnosis of the fragile-X syndrome

A new cloned DNA probe (U6.2), which recognizes a TaqI polymorphism near the locus for the fragile-X syndrome, was tested in a great Xq-fra pedigree. In the corresponding four families studied, the probe is informative and no recombinations were observed between the probe and the disease locus, although recombinational events were observed with several other probes tested in the past. The locus defined by the probe, DXS304, cosegregated with the fragile-X phenotype in 20 informative meioses (z = 3.09, theta = 0.00). The degree of polymorphism at this locus and its proximity to the fragile-X locus makes it useful for diagnostic applications.     

Isolation of a DNA probe of potential use for diagnosis of the fragile-X syndrome

Summary A new cloned DNA probe (U6.2), which recognizes polymorphisms near the locus for the fragile-X syndrome, was isolated. No recombinations were observed between the probe and the disease locus, although recombinations were observed with several other probes known to be located close to the fragile site. The locus defined by the probe, DXS304, cosegregated with the fragile-X phenotype in 29 informative meioses (=4.97, Ô=0.00). The degree of polymorphism at this locus and its proximity to the fragile-X locus makes it useful for carrier diagnosis and as a new starting point for attempts to clone the gene responsible for the disease.     

Thyroid function after bronchography with propyliodone

Thyroid function was studied in 27 subjects who underwent bronchography with propyliodone (18-70 ml, containing 30% of organic iodine). Sustained elevations of serum non-hormonal iodine were observed, indicating that significant amounts of propyliodone were absorbed from the bronchial tree and also that elimination may take several weeks. During the period of anaesthesia, there was an increase in thyroxine-binding globulin and all thyroid hormones which was transient and probably reflected vascular response to the anaesthetic. T4-T3 conversion was inhibited with a nadir of T3 and a peak of rT3 occurring on the 2nd day after propyliodone exposure. FT4 increased gradually during the 2 weeks after bronchography, but remained within the normal range. 6 out of the 27 patients developed pathologic T4 levels, 3 elevated T3 levels, and 2 an abnormal response to thyrotropin-releasing hormone; these changes might have been confused with hyperthyroidism. None of the patients developed clinical thyrotoxicosis; however, in patients with autonomous thyroid tissue, the same precautions should be taken with propyliodone as with other iodine-containing agents which are known to induce hyperthyroidism in this situation.     

Thyroid status in the obese syndrome of rats

The thyroid function was explored by comparing serum total and free iodothyronine levels in young male genetically obese Zucker rats and in their lean littermates, aged from 6 to 8 weeks old. Total and free thyroxine (T4) and 3,5,3'triiodothyronine (T3) levels were significantly decreased in obese rat serum while total 3,3',5'-triiodothyronine (rT3) remained constant. Radioactive T4 half life is slower in the plasma of obese rats. Peripheral synthesis of T3 from deiodination of T4 is also decreased in obese rat liver homogenate. These modifications produce changes in liver mitochondria oxidative phosphorylation and in marker enzyme activity, which are usually associated with hypothyroidism and hypothalamic disturbances. Genetic obesity probably involves activation of peripheral deiodination of T4 to rT3 which induces biochemical and metabolic changes.     

Molecular genetics of the fragile-X syndrome: a novel type of unstable mutation.

Fragile-X syndrome, the most common inherited form of mental retardation, has a very unusual mode of inheritance. The disease is caused by a multistep expansion, in successive generations, of a polymorphic CGG repeat localized in a 5' exon of FMR-1, a gene of unknown function. Two main mutation types have been categorized. Premutations are moderate expansions of the repeat and do not cause mental retardation. Full mutations are found in affected individuals and involve larger expansions of the repeat, with abnormal methylation of the neighboring CpG island. The full mutations demonstrate striking somatic instability and extinguish expression of FMR-1. Premutations are changed to full mutation only when transmitted by a female with a frequency that increases up to 100% as a function of the initial size of the premutation. Direct detection of the mutations provides an accurate test for pre- and postnatal diagnosis of the disease, and for carrier detection. A similar unstable expansion of a trinucleotide repeat occurs in myotonic dystrophy.     

Thyroid function and obesity in children and adolescents

The aim of this retrospective study was to investigate the frequency of thyroid dysfunction as assessed by TSH, T3 and T4 in a large cohort of 290 obese and 280 healthy children. In addition, thyroid autoantibodies were measured in random subgroups of 123 obese and 80 control children, iodine excretion in 50 and thyroid volume in 23 of the obese children. Elevated TSH levels (>4 U/l) were found in 22 obese children (7.5%), but only in one control (0.3%). The medians of TSH and T3 concentrations were normal, but significantly higher in the obese group than in the controls, while T4 levels did not differ. The prevalence of positive thyroid autoantibodies was increased in the obese children, for the most part in those with elevated TSH. There was no evidence for iodine deficiency as a cause of the average increase of TSH. We conclude that in childhood obesity TSH and T3 levels are significantly increased; in most cases, however, these increases are not accounted for by thyroid autoimmunity or iodine deficiency. As a consequence, TSH elevations with normal thyroid hormone levels in obese children don't need any thyroxine treatment, if thyroid disorders were definitely excluded beforehand.