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Tests the hypothesis that hepatocyte nuclear factor (HNF)-1alpha mutations contribute to early-onset diabetes in the Ashkenazi Jewish population. Potential biological consequences of the nonsense and missense variants; Assessment of the possible biological consequences of the R514H variant.

Background: Reduced sensitivity to thyroid hormone (RSTH) syndrome describes a group of rare heterogeneous genetic disorders. Precise diagnosis is essential to avoid unnecessary treatment., Objectives: To identify and characterize previously undiagnosed patients with RSTH in Israel., Methods: Patients with suspected RSTH throughout Israel were referred for study. After clinical evaluation, genomic DNA was obtained and all coding exons of the thyroid hormone receptor beta (THRB) gene were sequenced. If mutations were found, all available blood relatives were evaluated. The common polymorphism rs2596623, a putative intronic regulatory variant, was also genotyped. Genotype/phenotype correlations were sought, and the effect of mutation status on pregnancy outcome was determined., Results: Eight mutations (one novel; two de-novo, six dominant) were identified in eight probands and 13 family members. Clinical and genetic features were similar to those reported in other populations. Previous suggestions that rs2596623 predicts clinical features were not confirmed. There was no evidence of increased risk of miscarriage or fetal viability. Mothers carrying a THRB mutation tended to have increased gestational hypertension and low weight gain during pregnancy. Their affected offspring had increased risk of small-for-gestational age and poor postnatal weight gain., Conclusions: Clinical heterogeneity due to THRB mutations cannot be explained by the variant rs2596623. Mothers and newborns with THRB mutations seem to be at increased risk of certain complications, such as gestational hypertension and poor intrauterine and postnatal growth. However, these issues are usually mild, suggesting that routine intervention to regulate thyroid hormone levels may not be warranted in these patients.

Objective: Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample., Method: Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests., Results: The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects., Conclusions: Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.

Twenty-two male volunteers in Jerusalem were subjected to a battery of psychological tests at the height of the Iraqi Scud missile attacks on Israeli cities during the 1991 Persian Gulf War and again after the cessation of hostilities. Venous blood samples were taken at each time point. The separated mononuclear cells and plasma were cryopreserved, and a spectrum of immunological and neuroendocrine assays were performed on the preserved samples. Psychological testing indicated levels of anxiety were higher during the war than they were after the war ended, and both anxiety and anger during the hostilities were significantly elevated in comparison with prewar data. During the war, specific war-related pressures were greater than everyday pressures, and problem-focused coping was more evident than emotion-focused coping. Natural-killer cell activity and cell-mediated lympholysis were significantly elevated during the war, as were plasma levels of adrenocorticotrophic hormone, neurotensin, and substance P. The only biological test parameter found to be reduced during the war period was mononuclear cell thymidine incorporated in nonstimulated cultures.

Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) is a rare disease characterized clinically by persistent hypoglycemia with inappropriately elevated circulating insulin concentrations. Here we report on 7 pedigrees including 21 cases. The pedigrees are derived from 3 distinct ethnic groups, and include a very large Bedouin family, and Arab family, and 5 smaller pedigrees of Jewish families all of Eastern European origin. Data obtained from these families and from other families reported in the literature strongly suggest that PHHI is inherited as an autosomal recessive disorder.