Glutathione synthetase (GSS) deficiency is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with haemolytic anaemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low GSS activity in erythrocytes or cultured skin fibroblasts. Diagnosis can be confirmed by mutational analysis. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. The most important determinants for outcome and survival in patients with GSS deficiency are early diagnosis and early initiation of treatment. The case of a newborn with GSS deficiency diagnosed by tandem mass spectrometry (MS/MS)-based newborn screening is described. After onset of clinical symptoms on the 2nd day of life, expanded newborn screening revealed normal results for all disorders included in the German screening programme; however, selective MS/MS screening revealed a >10-fold elevation of 5-oxoproline in dried blood, leading to the presumptive diagnosis of GSS deficiency by the 5th day of life. Diagnosis was later confirmed by detection of markedly reduced glutathione concentration in erythrocytes and mutational analysis of the GSS gene. Presently, GSS deficiency is not included in newborn screening programmes in Europe. As outcome depends significantly on early start of treatment, routine inclusion of this disorder in newborn screening panels should be considered.
Passive immunization of chronically ovariectomized gilts against gonadotropin releasing hormone (GnRH) resulted in an abrupt cessation of pulsatile secretion of luteinizing hormone (LH) accompanied by clearance from serum with a mean half-life of 30.9 +/- 2.3 (mean +/- SE) and 918 +/- 200 min for the first and second compartment, respectively. Serum follicle stimulating hormone (FSH) was unaffected immediately by passive immunization against GnRH and declined slowly with a half-life of 4.9 +/- .7 d. After LH and FSH had declined to basal levels in passively immunized gilts, injection of a bolus of LH and FSH resulted in peak values within 5 min and depletion curves with half-lives for the first compartment of 28.0 +/- 1.3 and 36.4 +/- 2.6 min and for the second compartment of 679 +/- 98 and 1,230 +/- 54 min, for LH and FSH respectively. These results show that the half-life of LH is similar following immunoneutralization of GnRH or administration of a bolus of LH in immunized gilts and a difference in clearance rates of LH and FSH after initial passive immunization. These results suggest that secretion of FSH in the ovariectomized gilt is controlled by factors in addition to hypothalamic GnRH.
Chronic renal failure (CRF) is associated with multiple hypothalamic dysfunctions, including reduced secretion of gonadotropin-releasing hormone (GnRH). Because GnRH release is tightly controlled by sympathetic neuronal input, a possible alteration of local noradrenergic neurotransmission in experimental CRF was evaluated. Basal, stimulated, and autoinhibited norepinephrine (NE) release was assessed in hypothalamic and hippocampal tissue slices obtained from 5/6-nephrectomized and control rats. Autoinhibition-free NE release from brain slices, prelabeled with [ 3 H]NE and superfused with physiologic buffer, was stimulated by six electrical pulses, 100 Hz (pseudo-one-pulse stimulation). Autoinhibited NE release was induced by 90 pulses at 3 Hz. The release of tritiated NE was measured upon addition of increasing concentrations of unlabeled NE to exogenously activate the inhibitory ␣ 2 -autoreceptor. Although neither basal nor stimulated NE release differed between the groups, significantly lower pIC 50 and I max estimates of the concentration-response curves of exogenous NE on [ 3 H]NE release were observed in CRF rats, suggesting a diminished autoinhibition of hypothalamic noradrenergic terminals in CRF. Western blotting of tissue homogenates disclosed a significantly reduced abundance of ␣ 2 -autoreceptor protein in hypothalamic tissue from CRF rats. These abnormalities were selectively observed in the hypothalamus, whereas noradrenergic autoinhibition seemed unaltered in the hippocampus. The results suggest a diminished autoinhibition of hypothalamic NE release in CRF. Although impaired hypothalamic NE autoinhibition does not explain reduced GnRH secretion in CRF, it may be involved in the pathogenesis of sympathetic hyperactivity associated with this condition. D isorders of the reproductive system, clinically manifesting by impaired libido and fertility in adults and delayed or arrested puberty in adolescents, are common in chronic renal failure (CRF) (1). We and others previously demonstrated defective neuroendocrine activation of the gonadotropic hormone axis both in patients with CRF and in experimental uremia, with evidence for reduced pulsatile release of gonadotropin releasing hormone (GnRH) from the mediobasal hypothalamus (2-5). Experimental findings suggest that uremia may influence the function of hypothalamic neurons by various mechanisms. We observed abnormal extracellular amino acid neurotransmitter concentrations in the mediobasal hypothalamus of uremic rats, compatible with disturbed regulation of hypothalamic neurons by higher neuronal centers (6). The function of brain synaptosomes is altered in experimental uremia (7-10). However, we also demonstrated direct inhibition of GnRH secretion from cultured hypothalamic neurons by a factor circulating in uremic serum (11).Norepinephrinergic axon terminals are located in proximity of GnRH cells in the anterior hypothalamus (12). Norepinephrine (NE) is able to stimulate GnRH release from the hypothalamus in a concentration-dependent manner in vitro ...
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