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)

Ornithine transcarbamylase deficiency is an X linked disorder and the most common inherited cause of hyperammonaemia. Fluctuating concentrations of ammonia, glutamine, and other excitotoxic amino acids result in a chronic or episodically recurring encephalopathy. A heterozygous female patient first presented with protein intolerance, attacks of vomiting, and signs of mental retardation in early childhood. At the age of 16 complex partial seizures occurred which were treated with sodium valproate. Seven days after initiation of valproate therapy, she developed severe hyperammonaemic encephalopathy with deep somnolence. The maximum concentration of ammonia was 480 micromol/l. After withdrawal of valproate, three cycles of plasma dialysis, and initiation of a specific therapy for the inborn metabolic disease, ammonia concentrations fell to normal values. The patient remitted, returning to her premorbid state. Valproate can cause high concentrations of ammonia in serum in patients with normal urea cycle enzymes and may worsen a pre-existing hyperammonaemia caused by an enzymatic defect of the urea cycle. Sufficient diagnostic tests for the detection of metabolic disorders must be performed before prescribing valproate for patients with a history of encephalopathy.
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PMID:Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. 959 92

West syndrome is an age-specific epileptic syndrome with onset in infancy. It comprises infantile spasms (usually flexion convulsions), EEG pattern of hypsarrhythmia and mental retardation. Current therapy involves ACTH, corticosteroids, valproic acid, pyridoxine and vigabatrine. The treatment is difficult and more effective antiepileptic drugs are required. Unfortunately, there is no animal model of West syndrome that would accurately depict the situation found in humans. N-methyl-D-asparate (NMDA)-induced seizures in infant rats have certain features of the West syndrome model. These seizures are age-specific (they occur before 25 days of age), include hyperflection (emprosthotonus), their EEG is not specific and they somewhat respond to treatment with the benzodiazepine clonazepam. In 12 and 18 day old rats, we tested the effects of hydrocortisone, pyridoxine and sodium valproate against the seizures induced by 15 and 45 mg/kg of NMDA i.p., respectively. There were weak effects of sodium valproate against the NMDA-induced emprosthotonus. In contrast, high doses of pyridoxine were proconvulsant and hydrocortisone worsened the damage of nerve cells induced by NMDA. The data show that NMDA-induced seizures although similar to West syndrome are extremely resistant to therapy and may not be a good model of the West syndrome. However, the search for an adequate model that would allow for determination of possible mechanisms and testing of putative antiepileptic drugs will continue.
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PMID:West syndrome model: seek and you will find. 960 4

Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [3H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M1 sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer's disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and alpha-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation.
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PMID:Evidence for a central cholinergic deficit in congenital ornithine transcarbamylase deficiency. 977 87

440 kD ankyrin-B and 480/270 kD ankyrin-G are membrane skeletal proteins with closely related biochemical properties yet distinctive physiological roles in axons. These proteins associate with spectrin-actin networks and also bind to integral membrane proteins including the L1 CAM family of cell adhesion molecules and voltage-gated sodium channels. 440 kD ankyrin-B is expressed with L1 in premyelinated axon tracts, and is essential for survival of these axons, at least in the case of the optic nerve. 440 ankyrin-B may collaborate with L1 in transcellular structures that mediate axon fasciculation and mechanically stabilize axon bundles, although these proteins may also be involved in axon pathfinding. Ankyrin-B (-/-) mice exhibit loss of L1 from premyelinated axon tracts and a similar, although much more severe, phenotype to L1 (-/-) mice and humans with L1 mutations. Ankyrin-B and L1 thus are candidates to collaborate in the same structural pathway and defects in this pathway can lead to nervous system malformations and mental retardation. 480/270 kD ankyrin-G are highly concentrated along with the L1CAM family members neurofascin and NrCAM at nodes of Ranvier and axon initial segments. Voltage-gated sodium channels bind directly to ankyrins, and are likely to associate in a ternary complex containing neurofascin/NrCAM, and ankyrin-G. Mice with ankyrin-G expression abolished in the cerebellum exhibit loss of ability of Purkinje neurons to fire action potentials, as well as loss of restriction of neurofascin/NrCAM to axon initial segments. Ankyrin-G thus is a key component in assembly of functional components of the axon initial segment and possibly the node of Ranvier.
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PMID:Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels. 1073 73

Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts. The genetic defect in DM is a CTG repeat expansion located in the 3' untranslated region of DMPK and 5' of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5). There are three mechanisms by which CTG expansion can result in DM. First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3' of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10,11). Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted. Our results demonstrate that the rate and severity of cataract formation is inversely related to Six5 dosage and is temporally progressive. Six5+/- and Six5-/- mice show increased steady-state levels of the Na+/K+-ATPase alpha-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM. Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5.
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PMID:Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. 1080 68

To study the phenotypic spectrum and management of holoprosencephaly (HPE), we reviewed the findings of eight children with HPE from 3 to 10 years of age, who underwent intervention programs and rehabilitation at our center. One patient had alobar HPE, three semilobar HPE, and four lobar HPE. All patients had postnatal growth retardation, and seven showed a decreased BMI (< 25% tile). All patients had severe developmental delay and mental retardation (DQ < 40), showing no obvious correlation between their severity and the type of HPE. Neurologically seven patients had spasticity (3 spastic quadriplegia, 2 spastic diplegia, 2 mixed-type), except one patient with a 7q deletion [46,XY,del(7) (q35)] who had generalized hypotonia. Seven had variable types of seizures. All patients had feeding difficulties and were assessed by speech-language therapists. Four patients required tube feeding, four had gastroesophageal reflux disease. Recurrent respiratory tract infection was common. Three patients had abnormal serum sodium concentration (1 diabetes insipidus, 1 idiopathic hypernatremia, 1 hyponatremia). No family history of HPE was elicited. In conclusion, patients with HPE should be followed up closely for complications such as feeding difficulty, malnutrition, seizures, spasticity, infection, and osmoreceptor-hypothalamus-hypophyseal axis abnormalities.
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PMID:[Clinical spectrum and management of holoprosencephaly]. 1091 68

Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na+/HCO3- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na+/HCO3- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
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PMID:Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. 1127 32

The long-term effectiveness of acetazolamide (AZA) and its side effects, especially the formation of renal calculi, were investigated in a prospective study when AZA was used as an adjunct to other antiepileptic drugs in the treatment of refractory epilepsies. The subjects comprised 37 patients aged from 1 to 17 years (mean age, 8 years and 1 month) whose seizures were hard to control with the use of two or more drugs among sodium valproate, carbamazepine and clonazepam. Thirty-two of the 37 patients were complicated with mental retardation. A daily dose of 10mg/kg of AZA was first administered and then the dosage was increased up to 20mg/kg based on the clinical response and side effects. The maintenance daily dosage of AZA (12.2+/-4.2mg/kg) produced a steady-state plasma concentration of 6.2+/-4.5 microg/ml. Among the 37 patients, complete seizure control for more than 3 years was obtained in four patients. Although there were no significant differences, all of the four patients were classified as having symptomatic localization-related epilepsies. Seizures recurred in five after complete remission for at least 6 months, and six showed >50% decrease in seizure frequency for more than 6 months after the introduction of AZA. Twenty-eight patients, who were taking AZA for 10 months to 14 years (mean, 6 years and 5 months), were examined for the formation of renal calculi. None of them showed evidence of renal calculi. This study reinforces the idea that AZA may be a useful adjunct drug in selected patients with refractory symptomatic localization-related epilepsies.
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PMID:Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies. 1193 10

Human chromosome Xp11.3-Xp11.23 encompasses the map location for a growing number of diseases with a genetic basis or genetic component. These include several eye disorders, syndromic and nonsyndromic forms of X-linked mental retardation (XLMR), X-linked neuromuscular diseases and susceptibility loci for schizophrenia, type 1 diabetes, and Graves' disease. We have constructed an approximately 2.7-Mb high-resolution physical map extending from DXS8026 to ELK1, corresponding to a genetic distance of approximately 5.5 cM. A combination of chromosome walking and sequence-tagged site (STS)-content mapping resulted in an integrated framework and transcript map, precisely positioning 10 polymorphic microsatellites (one of which is novel), 16 ESTs, and 12 known genes (RP2, PCTK1, UHX1, UBE1, RBM10, ZNF157, SYN1, ARAF1, TIMP1, PFC, ELK1, UXT). The composite map is currently anchored with 89 STSs to give an average resolution of approximately 1 STS every 30 kb. By a combination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped several novel genes within this interval: a Na+/H+ exchanger (SLC9A7), at least two zincfinger transcription factors (KIAA0215 and Hs.68318), carbohydrate sulfotransferase-7 (CHST7), regucalcin (RGN), inactivation-escape-1 (INE1), the human ortholog of mouse neuronal protein 15.6, and four putative novel genes. Further genomic analysis enabled annotation of the sequence interval with 20 predicted pseudogenes and 21 UniGene clusters of unknown function. The combined PAC/BAC transcript map and YAC scaffold presented here clarifies previously conflicting data for markers and genes within the Xp11.3-Xp11.23 interval and provides a powerful integrated resource for functional characterization of this clonally unstable, yet gene-rich and clinically significant region of proximal Xp.
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PMID:An integrated, functionally annotated gene map of the DXS8026-ELK1 interval on human Xp11.3-Xp11.23: potential hotspot for neurogenetic disorders. 1194 89

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO3-) reabsorption in the renal proximal tubules, characterized by a decreased HCO3- threshold. pRTA commonly occurs as a manifestation of a generalized functional defect in proximal tubules. In contrast, pRTA can occur without other functional defects in proximal tubules (isolated pRTA). Most of the isolated pRTA in children are hereditary. Recent progress in molecular biological analyses is unraveling the molecular basis of hereditary pRTA. Mutations in the kidney type Na+/HCO3- cotransporter gene (SLC4A4) cause permanent isolated proximal RTA with ocular abnormalities. Mutations in carbonic anhydrase II gene lead to osteopetrosis, RTA (pRTA, distal RTA or combined proximal and distal RTA), cerebral calcification, and mental retardation. SLC9A3, encoding the Na+/H+ exchanger, is a candidate gene for pRTA without other manifestations. These results help further understand the molecular basis of hereditary pRTA and characterize the clinical and genetic manifestations of the disorder.
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PMID:Molecular basis of proximal renal tubular acidosis. 1202 12


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