Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transport of the eight amino acids (phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine and methionine) using the large neutral amino acid transporter of the blood-brain barrier (BBB) has been calculated using published kinetic data. The fate of the amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for tyrosine and tryptophan, the hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non-homogeneous system. At physiological levels of these eight amino acids, the largest contribution to the control of the flux of tyrosine is given by the hydroxylase step, followed by the diffusional component of the transport across the BBB. For tryptophan it is the hydroxylase step, followed by the carrier-mediated transport across the BBB. For the other amino acids it is the metabolism, followed by the diffusional component of the BBB transport. These parameters for tyrosine and tryptophan were determined at increased levels of blood phenylalanine, tyrosine or histidine. The flux through tryptophan hydroxylase can be affected by high blood levels of tyrosine and histidine to values also observed in hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with mental retardation, it is concluded that interference with transport across the BBB of tyrosine and tryptophan, as well as the flux through tryptophan hydroxylase leading to the synthesis of 5-hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in hyperphenylalaninaemia. It can be calculated that addition of tyrosine to the diet to raise the blood tyrosine level in phenylketonuria patients may have a beneficial effect for the synthesis of neurotransmitters derived from tyrosine.
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PMID:The control of 5-hydroxytryptamine and dopamine synthesis in the brain: a theoretical approach. 210 47

Autonomic dysfunction is prevalent in girls with Rett syndrome, an X-chromosome-linked disorder of mental retardation resulting from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). This gene plays a role in regulating neuronal activity-dependent gene expression, including brain-derived neurotrophic factor (BDNF), which is a potent serotonergic (5-HT) neuronal growth factor. We analyzed selected parameters of the 5-HT system of the medulla in autopsied patients with Rett syndrome because of the role of BDNF in 5-HT cell development and because 5-HT plays a key role in modulating autonomic control. 5-HT neurons were identified by immunostaining for tryptophan hydroxylase, the biosynthetic enzyme for 5-HT. We quantitated the number of 5-HT cells in the medulla at 2 standardized levels in 11 Rett and 7 control cases. There was no significant difference in 5-HT cell number between the groups. We analyzed binding to the serotonin transporter (SERT) using the radioligand [(125)I]-RTI-55 with tissue autoradiography in 7 Rett and 5 controls in 9 cardiorespiratory-related nuclei. In the dorsal motor nucleus of the vagus (DMX) (preganglionic parasympathetic outflow), SERT binding for the control cases decreased significantly over time (p = 0.049) but did not change in the Rett cases (p = 0.513). Adjusting for age, binding between the Rett and control cases differed significantly in this nucleus (p = 0.022). There was a marginally significant age versus diagnosis interaction (p = 0.06). Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome. These data suggest hypotheses concerning 5-HT modulation of vagal function for testing in MeCP2 knockout mice to understand mechanisms underlying autonomic dysfunction in patients with Rett syndrome.
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PMID:Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction. 1625 96

Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAHenu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.
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PMID:5-Hydroxytryptophan during critical postnatal period improves cognitive performances and promotes dendritic spine maturation in genetic mouse model of phenylketonuria. 2104 Jun 18