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 case of a three-year-old boy with mental retardation, moderate muscular hypotony and speech delay is presented. The mild form of maple syrup urine disease was suspected at the first blood screening test by means of ion-exchange thin-layer chromatography. The diagnosis was confirmed by quantitative serum amino acid analysis and protein loading. On a low protein (2 g/kg body weight) diet completed with leucine-isoleucine-valine free formula prompt and lasting normalization of the serum amino acid level ensued with steady improvement of the clinical and neurological status.
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PMID:Mild variant of maple syrup urine disease. 70 84

An 11-year old girl with spastic paraplegia and mental retardation has suffered from attacks of metabolic acidosis since the age of 18 months. "Ketotic hyperglycinemia" was diagnosed when she was 3 years old. Reinvestigation at 9 1/2 years included a two-day load with L-isoleucine, and propionyl-CoA carboxylase assay in cultured fibroblasts. The following compounds increased following the load: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric acid, 2-ethylhydracrylic acid, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, 2-oxo-3-methylvaleric acid, 2-methyl-3-oxovaleric acid, N-tiglylglycine, methylcitric acid and butanone. Small amounts of alloisoleucine appeared in plasma. Propionyl-CoA carboxylase deficiency was suggested by this metabolite pattern and demonstrated in cultured fibroblasts.
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PMID:Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels. 75 79

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

Recent work has shown that in phenylketonuria, PKU, in which phenylalanine accumulates in the blood, the damage to the brain, which so often leads to mental retardation, is not solely due to the large quantities of phenylalanine that enter the brain. The raised levels of phenylalanine in the blood lead to a partial exclusion of various other amino acids from the brain and this exclusion in itself damages the brain. Based on this evidence, that in PKU some amino acids are partially excluded from entering the brain, proposals are made for a modified dietary treatment of this disease. In this diet the phenylalainine is not so greatly reduced as in the standard diet for PKU, whilst supplements of other amino acids are added. The rationale for this new diet is that the partial exclusion from the brain of various amino acids (methionine, tryptophan, histidine, tryosine, isoleucine, leucine and valine) by the raised level of phenylalanine in the blood, acting as a competitive inhibitor, can be largely prevented by increasing the blood levels of these excluded amino acids. Raising slightly their blood levels overcomes the excluding effect of moderately raised levels of phenylalanine in the blood. The advantages of the new diet are that not only is it more palatable than a diet very low in phenylalanine, so that it is more likely to continue to prove acceptable to older children and adolescents, as well as to PKU women who expect to become pregnant, but also that its margin of safety is greater if the patient does take unsuitable food.
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PMID:A new approach to the treatment of phenylketonuria. 719 42

We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C4-C5(n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-)acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of (14C)isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause.
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PMID:A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. 796 45

All of vitamin B12 in nature is of microbial origin. Cobalamin, as vitamin B12 should correctly be termed, is a large polar molecule that must be bound to specialized transport proteins to gain entry into cells. Entry from the lumen of the intestine under physiological conditions occurs only in the ileum and only when bound to intrinsic factor. It is transported into all other cells only when bound to another transport protein, transcobalamin II. Congenital absence or defective synthesis of intrinsic factor or transcobalamin II result in megaloblastic anemia. The Immerslund-Graesbeck syndrome, a congenital defect in the transcellular transport of cobalamin through the ileal cell during absorption, also presents with megaloblastic anemia, but with accompanying albuminuria. In most bacteria and in all mammals, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, the conversion of N5-methyltetrahydrofolate to tetrahydrofolate, which in turn is linked to the conversion of homocysteine to methionine. This reaction occurs in the cytoplasm, and it is catalyzed by methionine synthase, which requires methyl cobalamin (MeCbl), one of the two coenzyme forms of the vitamin, as a cofactor. Defects in the generation of MeCbl (cobalamin E and G diseases) result in homocystinuria; affected infants present with megaloblastic anemia, retardation, and neurological and ocular defects. 5'-Deoxyadenosyl cobalamin (AdoCbl), the other coenzyme form of cobalamin, is present within mitochondria, and it is an essential cofactor for the enzyme Methylmalonyl-CoA mutase, which converts L-methylmalonyl CoA to succinyl CoA. This reaction is in the pathway for the metabolism of odd chain fatty acids via propionic acid, as well as that of the amino acids isoleucine, methionine, threonine, and valine. Impaired synthesis of AdoCbl (cobalamin A or B disease) results in infants with methylmalonic aciduria who are mentally retarded, hypotonic, and who present with metabolic acidosis, hypoglycemia, ketonemia, hyperglycinemia, and hyperammonemia. Megaloblastic anemia does not develop in these children because adequate amounts of MeCbl are present, but the effect of methylmalonic acid on marrow stem cells may give rise to pancytopenia. Congenital absence of reductases in the cytoplasm, which normally reduce the cobalt atom in cobalamin from its oxidized to its reduced state (cobalamin C and D diseases), results in impaired synthesis of both MeCbl and AdoCbl. Both methylmalonic aciduria and homocystinuria therefore develop in these children, and they present with megaloblastosis, mental retardation, a host of neurological and ocular disorders, and failure to thrive; however, they do not have hyperglycinemia or hyperammonemia. A similar biochemical profile and clinical presentation is also seen in cobalamin F disease, which results from a defect in the release of cobalamin from lysosomes, following receptor-mediated endocytosis of the transcobalamin II-cobalamin complex into cells. It is important to recognize these inborn errors of cobalamin absorption, transport, or function as soon after birth as possible, because most respond (in some patients more fully than others) to parenteral administration of cobalamin. Delays in diagnosis can lead to grave clinical consequences.
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PMID:Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport. 877 94

Maple syrup urine disease (MSUD) or branched-chain alpha-ketoaciduria is an autosomally inherited disorder in the catabolism of branched-chain amino acids leucine, isoleucine, and valine. The disease is characterized by severe ketoacidosis, mental retardation, and neurological impairments. MSUD can be classified into genetic subtypes according to the genes of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex which are affected in patients. We describe here four intronic deletions and an intronic nucleotide substitution in the E2 transacylase gene of type II MSUD, in which the E2 subunit of the BCKD complex is deficient. These new E2 mutations comprise an internal 3.2-kb deletion in intron 4 (causing a 17-bp insertion in mRNA), an internal 12-bp (ttaccttgttac) deletion in intron 4 (creating a 10-bp insertion), a 10-bp (catttctaG) deletion in intron 10/ exon 11 junction (leading to a 21-bp deletion), a 2-bp deletion in the exon 5/intron 5 junction (ATgt--> A-t) (resulting in the skipping of exon 5), and a G to A transition at nucleotide -7 of intron 9 (causing a 6-bp insertion). These intronic mutations were initially detected by secondary alterations in the mutant E2 mRNA, as a result of aberrant splicing. The 3.2-kb deletion in intron 4 was determined by the amplification of the entire intron from both a normal subject (11.2 kb) and a homozygous patient (8 kb) by long PCR, followed by subcloning and sequencing of regions flanking the deletion. Similar methods were used to identify and characterize the other intronic alterations. Our results depict heretofore undescribed splicing errors caused by the deletion of internal intronic segments, and provide an approach for detecting this class of novel and rare human mutation. The association of the thiamine-responsive phenotype with a subset of the type II MSUD patients studied is also discussed.
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PMID:E2 transacylase-deficient (type II) maple syrup urine disease. Aberrant splicing of E2 mRNA caused by internal intronic deletions and association with thiamine-responsive phenotype. 923 22

The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.
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PMID:Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene. 1280 99

Maple syrup urine disease (MSUD) is an inherited disorder caused by deficiency of branched-chain L-2-keto acid dehydrogenase complex activity. Affected patients present severe brain dysfunction manifested as convulsions, coma, psychomotor delay and mental retardation. However, the underlying mechanisms of these neurological findings are virtually unknown. In this study, we tested the in vitro effect of L-leucine, L-isoleucine and L-valine, the amino acids accumulating in MSUD, on the lipid peroxidation parameters chemiluminescence and thiobarbituric acid-reactive substances (TBA-RS), as well as on total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in cerebral cortex from 30-day-old rats. L-Leucine significantly increased chemiluminescence and TBA-RS measurements and markedly decreased TRAP and TAR values. L-Isoleucine increased chemiluminescence and decreased TRAP measurements, but TAR and TBA-RS levels were not altered by the amino acid. Finally, TRAP measurement was diminished by L-valine. The results indicate a stimulation of lipid peroxidation and a reduction of brain capacity to efficiently modulate the damage associated with an increased production of free radicals by the branched-chain amino acids (BCAAs) accumulated in MSUD. It is therefore tempting to speculate that oxidative stress may be implicated in the brain damage found in MSUD patients.
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PMID:Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. 1292 81

Mutations in the coding region of the angiotensin II type 2 receptor gene (AGTR2) were recently identified to cause X-linked recessive mental retardation. We report a mutation screening of the AGTR2 gene in 57 Finnish male patients with non-syndromic mental retardation. We identified two mutations, a 62G-->T transversion, which leads to a substitution of glycine for valine (G21V) and a 157A-->T transversion, which causes a substitution of isoleucine for phenylalanine (I53F). The patients with AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech.
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PMID:Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation. 1472 54


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