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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An elderly man with mental retardation who had never received dietary treatment for his phenylketonuria was placed on a phenylalanine-restricted diet. Social skills and walking gait improved and a new interest in the objects in his environment developed spontaneously. A 2-year analysis of diet, blood plasma phenylalanine levels and behavioural state indicated that small differences in phenylalanine intake impacted his well-being. Of significant note, leg tremor and spasm that precipitated severe self-injury were only reversible when plasma blood phenylalanine concentrations were titrated to near normal ranges and daily phenylalanine intake was strictly controlled. This case may offer a potential explanation for some of the late treatment failures that have been reported and suggest new avenues to explore in the late treatment of PKU.
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PMID:Benefits of normalizing plasma phenylalanine: impact on behaviour and health. A case report. 987 Feb 3

Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development. Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease. However, compliance with dietary treatment is difficult and when it is for life, as now recommended by an internationally used set of guidelines, is probably unrealistic. Herein we describe experiments on a mouse model using another modality for treatment of PKU compatible with better compliance using ancillary phenylalanine ammonia lyase (PAL, EC 4.3.1.5) to degrade phenylalanine, the harmful nutrient in PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase (EC 1.14.16.1), which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. We describe (i) an efficient recombinant approach to produce PAL enzyme, (ii) testing of PAL in orthologous N-ethyl-N'-nitrosourea (ENU) mutant mouse strains with HPA, and (iii) proofs of principle (PAL reduces HPA)-both pharmacologic (with a clear dose-response effect vs. HPA after PAL injection) and physiologic (protected enteral PAL is significantly effective vs. HPA). These findings open another way to facilitate treatment of this classic genetic disease.
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PMID:A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. 1005 48

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) in the liver. Patients with PKU show increased L-phenylalanine in blood, which leads to mental retardation and hypopigmentation of skin and hair. As a step toward gene therapy for PKU, we constructed a replication-defective, E1/E3-deleted recombinant adenovirus harboring human PAH cDNA under the control of a potent CAG promoter. When a solution containing 1.2 x 10(9) plaque-forming units of the recombinant adenovirus was infused into tail veins of PKU model mice (Pah(enu2)), predominant expression of PAH activity was observed in the liver. The gene transfer normalized the serum phenylalanine level within 24 h. However, it also provoked a profound host immune response against the recombinant virus; as a consequence, the biochemical changes lasted for only 10 d and rechallenge with the virus failed to reduce the serum phenylalanine concentration. Administration of an immunosuppressant, FK506, to mice successfully blocked the host immune response, prolonged the duration of gene expression to more than 35 d, and allowed repeated gene delivery. We noted a change in coat pigmentation from grayish to black after gene delivery. The current study is the first to demonstrate the reversal of hypopigmentation, one of the major clinical phenotypes of PKU in mice as well as in humans, by adenovirus-mediated gene transfer, suggesting the feasibility of gene therapy for PKU.
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PMID:Reversal of hypopigmentation in phenylketonuria mice by adenovirus-mediated gene transfer. 1020 36

Maternal phenylketonuria (M-PKU) is a syndrome of embryo- and fetopathy observed in the offsprings of mothers with increased blood level of phenylalanine. These women fall into two groups: phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP). The Phe--level safe for the fetus is 4-6 mg%. Typical for M-PKU syndrome is: microcephalia, mental retardation, intrauterine growth retardation, congenital heart diseases and other anomalies like esophageal atresia, meningocoele, Pierre-Robin syndrome, cataract. The only way to prevent this syndrome is Phe--restricted diet that should be initiated before conception. We reviewed updated literature on the pathogenesis of this syndrome, clinic, possibility of prophylaxis and treatment. We present also 5 pregnancies of 3 patients with PKU, treated in National Research Institute of Mother and Child in Warsaw. On that ground we propose the scheme of prevention of maternal PKU syndrome.
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PMID:[Maternal PKU syndrome as an obstetric problem: literature review and own clinical experience]. 1022 66

The blood sample for phenylketonuria (PKU) screening should be obtained at least 12 hours after the infant's birth. Newborn screening for PKU has largely eliminated mental retardation caused by this disease. If the first phenylalanine test demonstrates positive results, a repeat test should be performed. Treatment to prevent sequelae from this disorder is best carried out in cooperation with an experienced PKU center. Dietary care is expensive, and financial assistance may be necessary for many families. A phenylalanine-restricted diet should be started as soon as possible. Occasionally, cases of PKU are missed by newborn screening. Thus, a repeat PKU test should be performed in an infant who exhibits slow development.
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PMID:Issues in newborn screening for phenylketonuria. 1052 90

We studied the pathogenetic role of iminodipeptides, and the effects of corticosteroids on the skin lesions of two adult female siblings with prolidase deficiency. The elder sister had had severe skin ulcers and mental retardation since childhood, while the younger sister had shown milder clinical manifestations since late adolescence. The ulcers showed vascular wall thickening and neutrophil infiltration. Oral prednisolone at moderate doses was not effective, but corticosteroid pulse therapy followed by a moderate dose of prednisolone improved the preulcerative indurated lesions and ulcers. A 2-year follow-up of the younger patient indicated that N-formyl methionyl leucyl phenylalanine-induced neutrophil superoxide generation was elevated, in parallel with an increase in the serum iminodipeptide level, when the skin ulcers and preulcerative indurated lesions were most active. Corticosteroid pulse therapy downregulated the superoxide generation by neutrophils. The serum iminodipeptide level, however, did not decrease during 25 days after pulse therapy. These findings suggest that iminodipeptides may play an important part in aggravating the skin lesions by priming neutrophil superoxide generation, and that high-dose corticosteroids improve the skin lesions, probably by inhibiting the infiltration, and superoxide generation by, neutrophils. Neutrophil superoxide generation was more prominent in the elder sister, suggesting that clinical severity may depend on the response of neutrophils to the iminodipeptides. Chronic stimulation by superoxide may cause thickening of cerebral blood vessels and eventual mental retardation.
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PMID:Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting iminodipeptide-primed neutrophil superoxide generation. 1058 65

Phenylketonuria is the most common inborn error of amino acid metabolism. It is due to a deficiency of phenylalanine hydroxylase, which normally converts phenylalanine to tyrosine. A diet low in phenylalanine starting in the first month of life can significantly reduce mental retardation, the most important feature of the disease. The aim of the review is to discuss the difficulties found in the diagnosis of PKU and its variants, ranging from classic phenylketonuria to mild hyperphenylalaninaemia, and the effects of dietary restriction of phenylalanine on the growth and development of children. Also, we present the current controversies about the age of discontinuing the dietary treatment. This review summarizes the benefits and problems emerging from a prolonged therapy taking into account dietary compliance in different age groups, and discusses dietary alternatives to the synthetic amino acid mixtures free of phenylalanine, based on low phenylalanine protein hydrolysates. In addition, we show some information about the effects of maternal phenylketonuria on pregnancy outcome and infant development, if exposed to high phenylalanine levels intra uterineo.
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PMID:[Importance of the diagnoses and treatment of phenylketonuria]. 1076 67

Diet has long been recognized as the primary treatment modality for individuals with phenylketonuria (PKU) during infancy and childhood. Recent findings from the Maternal PKU Collaborative Study clearly indicate that dietary restriction of phenylalanine is also necessary to prevent the adverse effects of an elevated plasma phenylalanine concentration during pregnancy, which include microcephaly, physical anomalies, and mental retardation.
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PMID:Importance of diet in maternal phenylketonuria. 1094 61

Phenylketonuria is a genetic defect that, without strict dietary control, results in the accumulation of phenylalanine (Phe) in body fluids. If a low-Phe diet is not maintained during pregnancy, the offspring of phenylketonuric women are born with mental retardation and microcephaly. Primary cultures of rat cerebellar granule cells, rat cortical astrocytes, human fetal astrocytes, and human neuroblastoma (SY5Y) cells and human astrocytoma (1321N1) cells were used to test the hypothesis that the microencephaly may be a result of neuronal cell death and reduced astrocyte proliferation. Exposure to Phe or to six Phe metabolites [phenylacetic acid (PAA), phenyllactic acid, hydroxyphenylacetic acid, phenylpyruvic acid, phenylethylamine (PEA), and mandelic acid] did not result in astroglial or neuronal cell cytotoxicity. Treatment of 1321N1 cells, human fetal astrocytes, or rat astrocytes with 5 mM Phe for 24 h decreased DNA synthesis 19 +/- 4, 30 +/- 4, and 60 +/- 6%, respectively. This effect was concentration dependent, and flow cytometry revealed that Phe treatment resulted in the accumulation of cells in the G(0)/G(1) phase of the cell cycle. In addition, in 1321N1 cells, exposure to 5 mM PAA, and in rat astrocytes, exposure to 0.5 mM PEA inhibited cell proliferation 42 +/- 4 and 55 +/- 4%, respectively. These metabolites also resulted in the accumulation of cells in the G(0)/G(1) phase of the cell cycle. In human fetal astrocytes, 0.5 mM PEA and 0.5 mM PAA resulted in a 41 +/- 12 and 52 +/- 11% reduction proliferation, respectively.
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PMID:Effect of phenylalanine and its metabolites on the proliferation and viability of neuronal and astroglial cells: possible relevance in maternal phenylketonuria. 1099 93

The recent literature on polyunsaturated fatty acid metabolism in phenylketonuria (PKU) is critically analyzed. The data suggest that developmental impairment of the accretion of brain arachidonic (20:4n-6) and docosahexaenoic (22:6n-3, DHA) acids is a major etiological factor in the microcephaly and mental retardation of uncontrolled PKU and maternal PKU. These fatty acids appear to be synthesized by the recently elucidated carnitine-dependent, channeled, mitochondrial fatty acid desaturases for which alpha-tocopherolquinone (alpha-TQ) is an essential enzyme cofactor. alpha-TQ can be synthesized either de novo or from alpha-tocopherol. The fetus and newborn would primarily rely on de novo alpha-TQ synthesis for these mitochondrial desaturases because of low maternal transfer of alpha-tocopherol. Homogentisate, a pivotal intermediate in the de novo pathway of alpha-TQ synthesis, is synthesized by 4-hydroxyphenylpyruvate dioxygenase. The major catabolic products of excess phenylalanine, viz. phenylpyruvate and phenyllactate, are proposed to inhibit alpha-TQ synthesis at the level of the dioxygenase reaction by competing with its 4-hydroxyphenylpyruvate substrate, thus leading to a developmental impairment of 20:4n-6 and 22:6n-3 synthesis in uncontrolled PKU and fetuses of PKU mothers. The data suggest that dietary supplementation with carnitine, 20:4n-6, and 22:6n-3 may have therapeutic value for PKU mothers and for PKU patients who have been shown to have a low plasma status of these essential metabolites.
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PMID:Impaired arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acid synthesis by phenylalanine metabolites as etiological factors in the neuropathology of phenylketonuria. 1124 24


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