Missense mutations in SGLT1 cause glucose-galactose malabsorption by trafficking defects.
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Glucose-galactose malabsorption (GGM) is an autosomal recessive disorder caused by defects in the Na+/glucose cotransporter (SGLT1). Neonates present with severe diarrhea while on any diet containing glucose and/or galactose [1]. This study focuses on a patient of Swiss and Dominican descent. All 15 exons of SGLT1 were screened using single stranded conformational polymorphism analyses, and aberrant PCR products were sequenced. Two missense mutations, Gly318Arg and Ala468Val, were identified. SGLT1 mutants were expressed in Xenopus laevis oocytes for radiotracer uptake, electrophysiological experiments, and Western blotting. Uptakes of [14C]alpha-methyl-d-glucoside by the mutants were 5% or less than that of wild-type. Two-electrode voltage-clamp experiments confirmed the transport defects, as no noticeable sugar-induced current could be elicited from either mutant [2]. Western blots of cell protein showed levels of each SGLT1 mutant protein comparable to that of wild-type, and that both were core-glycosylated. Presteady-state current measurements indicated an absence of SGLT1 in the plasma membrane. We suggest that the compound heterozygote missense mutations G318R and A468V lead to GGM in this patient by defective trafficking of mutant proteins from the endoplasmic reticulum to the plasma membrane. (+info)
Why is the retention of gonadotrophin secretion common in children with panhypopituitarism due to septo-optic dysplasia?
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Septo-optic dysplasia (De Morsier syndrome) is a developmental anomaly of mid-line brain structures and includes optic nerve hypoplasia, absence of the septum pellucidum and hypothalamo-pituitary abnormalities. We describe seven patients (four female, three male) who had at least two out of the three features necessary for the diagnosis of septo-optic dysplasia. Four patients had hypopituitarism and yet normal gonadotrophin secretion: one of these also had anti-diuretic hormone insufficiency; three had isolated GH deficiency and yet had premature puberty, with the onset of puberty at least a year earlier than would have been expected for their bone age. In any progressive and evolving anterior pituitary lesion it is extremely unusual to lose corticotrophin-releasing hormone/ACTH and TRH/TSH secretion and yet to retain gonadotrophin secretion. GnRH neurons develop in the nasal mucosa and migrate to the hypothalamus in early fetal life. We hypothesise that the arrival of GnRH neurons in the hypothalamus after the development of a midline hypothalamic defect may explain these phenomena. Progress in spontaneous/premature puberty in children with De Morsier syndrome may have important implications for management. The combination of GH deficiency and premature puberty may allow an apparently normal growth rate but with an inappropriately advanced bone age resulting in impaired final stature. GnRH analogues may be a therapeutic option. In conclusion, some patients with De Morsier syndrome appear to retain the ability to secrete gonadotrophins in the face of loss of other hypothalamic releasing factors. The migration of GnRH neurons after the development of the midline defect may be an explanation. (+info)
Variations in genetic assessment and recurrence risks quoted for childhood deafness: a survey of clinical geneticists.
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We report here the results of a questionnaire survey of consultant clinical geneticists in the United Kingdom to which we had an 81% response rate. In this questionnaire we asked about: (1) the nature of services currently offered to families with hearing impaired children, (2) what recurrence risks they quoted in isolated non-syndromic cases, and (3) what they might suggest for improving the range of genetic services available at present. We noted great variation both in these services and in the recurrence risks quoted in isolated cases. Based on the results of the questionnaire, we have proposed a protocol for the investigation of permanent childhood hearing impairment, which we believe to be both comprehensive and practical in an outpatient clinic setting. It is only by improving existing clinical and social understanding and knowledge of childhood hearing impairment that it will become possible to use recent molecular advances to develop comprehensive and consistent services for these families. (+info)
The biological clock of very premature primate infants is responsive to light.
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Each year more than 250,000 infants in the United States are exposed to artificial lighting in hospital nurseries with little consideration given to environmental lighting cycles. Essential in determining whether environmental lighting cycles need to be considered in hospital nurseries is identifying when the infant's endogenous circadian clock becomes responsive to light. Using a non-human primate model of the developing human, we examined when the circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), becomes responsive to light. Preterm infant baboons of different ages were exposed to light (5,000 lux) at night, and then changes in SCN metabolic activity and gene expression were assessed. After exposure to bright light at night, robust increases in SCN metabolic activity and gene expression were seen at ages that were equivalent to human infants at 24 weeks after conception. These data provide direct evidence that the biological clock of very premature primate infants is responsive to light. (+info)
Prediction of life expectancy in patients with primary pulmonary hypertension. A retrospective nationwide survey from 1980-1990.
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Primary pulmonary hypertension (PPH) is a progressive disease of unknown etiology usually followed by death within 5 years after diagnosis. Although heart-lung or lung transplantation is now offered to patients with advanced PPH, adequate criteria assessing an accurate prediction of life expectancy in PPH has been difficult to establish. The aims of this study were to identify the characteristic features associated with a poor prognosis in patients with PPH, and to attempt to establish an individual prognostic index that predicts with great accuracy survival or death of PPH after one year, thereby helping to define criteria for patient selection for transplantation. In 1991, a retrospective nation-wide survey on PPH was conducted in Japan, and the clinical and cardiorespiratory variables of 223 PPH cases (female; 144, male; 79) in the period from 1980-1990 were obtained. The mean pulmonary arterial pressure (PPA) was 57.5+/-17.2 mm Hg (mean+/-SD), and the overall median survival time was 32.5 months since the first diagnostic catheterization. The characteristic features of 61 patients who died within one year of catheterization (Nonsurvivors group) were compared to 141 patients who survived one year or more from the time of catheterization (Survivors group). Among several clinical and cardiorespiratory variables, heart rate, PPA, right atrial pressure (PRA), stroke volume index (SI), pulmonary vascular resistance, and partial pressure of carbon dioxide (PaCO2) were significantly different between the two groups. As the independent factors, PPA, PRA, SI, and PaCO2 were selected for the multiple logistic analysis. Using a 0.7 probability cut-point to separate Nonsurvivors from Survivors, 84.6% of Nonsurvivors and Survivors could be correctly predicted from this logistic regression equation. Predictive equations like the present preliminary one can be used in the future to better assess life expectancy in patients with PPH in whom transplantation will be considered. (+info)
Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11.
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Derivative 22 (der[22]) syndrome is a rare disorder associated with multiple congenital anomalies, including profound mental retardation, preauricular skin tags or pits, and conotruncal heart defects. It can occur in offspring of carriers of the constitutional t(11;22)(q23;q11) translocation, owing to a 3:1 meiotic malsegregation event resulting in partial trisomy of chromosomes 11 and 22. The trisomic region on chromosome 22 overlaps the region hemizygously deleted in another congenital anomaly disorder, velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Most patients with VCFS/DGS have a similar 3-Mb deletion, whereas some have a nested distal deletion endpoint resulting in a 1.5-Mb deletion, and a few rare patients have unique deletions. To define the interval on 22q11 containing the t(11;22) breakpoint, haplotype analysis and FISH mapping were performed for five patients with der(22) syndrome. Analysis of all the patients was consistent with 3:1 meiotic malsegregation in the t(11;22) carrier parent. FISH-mapping studies showed that the t(11;22) breakpoint occurred in the same interval as the 1.5-Mb distal deletion breakpoint for VCFS. The deletion breakpoint of one VCFS patient with an unbalanced t(18;22) translocation also occurred in the same region. Hamster-human somatic hybrid cell lines from a patient with der(22) syndrome and a patient with VCFS showed that the breakpoints occurred in an interval containing low-copy repeats, distal to RANBP1 and proximal to ZNF74. The presence of low-copy repetitive sequences may confer susceptibility to chromosome rearrangements. A 1.5-Mb region of overlap on 22q11 in both syndromes suggests the presence of dosage-dependent genes in this interval. (+info)
Nitrogen dioxide formation during inhaled nitric oxide therapy.
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BACKGROUND: Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial. METHODS: The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy. RESULTS: Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature. CONCLUSIONS: Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time. (+info)
Variation in subglottic size in children.
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The incidence of variation in the subglottic size was investigated in 3304 infants and children. A mild degree of congenital subglottic stenosis was found in 0.91% and a moderate degree of stenosis in 0.06% of the patients. A mild degree of congenital subglottic enlargement was noted in 0.7% and moderate enlargement in 0.06% of the patients. (+info)