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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serine deficiency disorders comprise a new group of inborn errors of serine metabolism. Patients affected with these disorders present with major neurological symptoms including congenital microcephaly, seizures, psychomotor retardation or polyneuropathy. The diagnosis of serine deficiency is based on the detection of low concentrations of the amino acids serine and glycine in fasted plasma and cerebrospinal fluid (CSF). Amino acid analysis of cerebrospinal fluid is preferable over plasma analysis, because the deficiencies are more pronounced in CSF. Because of the interference of amino acids absorbed from the diet, diagnostic procedures have to be performed in the fasted state. Although the disorders are probably rare and not many cases have been reported, recognition of serine deficiency is important, given the fact that the disorders are potentially treatable. The clinical symptoms respond well to amino acid replacement therapy. So far, three serine deficiency disorders have been reported; 3-phosphoglycerate dehydrogenase deficiency, 3-phosphoserine phosphatase deficiency and a still unexplained serine deficiency disorder. In this paper, we will discuss the various serine deficiency disorders, their biochemical abnormalities and the results of amino acid replacement therapy.
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PMID:Continuing education in neurometabolic disorders--serine deficiency disorders. 1022 52

3-phosphoglycerate dehydrogenase deficiency is a severe but treatable disorder of serine synthesis, first described in 1996 (Jaeken et al. 1996a). The patient presented with West syndrome, severe psychomotor delay, failure to thrive, microcephaly, atypical ocular movements, and pyramidal signs. Treatment with oral L-serine abolished seizures and improved psychomotor development, hyperexcitability, head growth, cortical and subcortical hypotrophy, and hypomyelination of the brain on MRI scans. 3-phosphoglycerate dehydrogenase deficiency is a treatable congenital error that probably leads to West syndrome.
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PMID:3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome. 1103 57

3-phosphoglycerate dehydrogenase (PHGDH) deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures. To investigate the molecular basis for this disorder, the PHGDH mRNA sequence was characterized, and six patients from four families were analyzed for sequence variations. Five patients from three different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine. The sixth patient was homozygous for a valine to methionine substitution at position 425; both mutations are located in the carboxyterminal part of PHGDH. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA-blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurological impairment in our patients, the data presented in this paper suggest an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.
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PMID:Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. 1105 95

White matter abnormalities are a feature of many inborn errors of metabolism and magnetic resonance imaging (MRI) of the brain has become an important tool in the diagnostic work-up of these disorders. Recently, patients were reported with a potentially treatable disorder of serine biosynthesis. They presented with congenital microcephaly, severe psychomotor retardation and intractable seizures. Low concentrations of the amino acids serine, glycine as well as 5-methyltetrahydrofolate were found in plasma and CSF and were due to a deficiency of the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH). We studied four patients aged 10 months to 7 years by MRI before and after treatment with amino acids with a follow-up of 16 months to 6 years. Magnetic resonance spectroscopy (MRS) was performed in two patients at 4 and 16 months of treatment. Pre-treatment MRI demonstrated hypomyelination and profound white matter attenuation in all patients. During treatment, a significant increase in white matter volume was found and a progress of myelination in two patients. The most striking finding on MRS during treatment was an elevated level of white matter choline. Serine biosynthesis defects have to be considered in the differential diagnosis of patients with mental retardation, microcephaly, seizures, and on MRI hypomyelination and white matter attenuation.
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PMID:Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency. 1150 46

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.
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PMID:Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: report on two siblings. 1157 99

A deficiency of 3-phosphoglycerate dehydrogenase (PHGDH) is a disorder of serine biosynthesis identified in children with congenital microcephaly, seizures, and severe psychomotor retardation. We report here the identification of the 1468G-->A (V490M) mutation of this gene in two siblings of an Ashkenazi Jewish family, providing further evidence that the V490M mutation is a common, panethnic cause of this deficiency. Using a novel, DNA-based diagnostic test, the mutation was not detected in 400 non-Jewish controls; one heterozygote was found among 400 persons of Ashkenazi Jewish ethnicity. Extensive biochemical studies were undertaken to characterize the effect of this mutation on enzyme activity, turnover, and stability. The V490M PHGDH yielded less than 35% of the activity observed for the wild-type enzyme when overexpressed by transient transfection or when comparing the endogenous activity in fibroblast cells from the patients with controls. Immunoblotting studies showed a comparable reduction in the level of immunoreactive PHGDH in cells expressing the mutant enzyme. Pulse-chase experiments with metabolically labeled PHGDH indicated that this resulted from an increased rate of degradation of the mutant enzyme following its synthesis. Thermolability analyses of mutant and wild-type enzyme activity revealed no significant differences. While others have proposed that the V490M mutation decreases the V(max) of the enzyme, we conclude that this mutation impairs the folding and/or assembly of PHGDH but has minimal effects on the activity or stability of that portion of the V490M mutant that reaches a mature conformation.
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PMID:V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme. 1175 22

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.
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PMID:Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. 1211 26

Serine deficiency disorders are rare defects in the biosynthesis of the amino acid L-serine. At present two disorders have been reported: 3-phosphoglycerate dehydrogenase deficiency and 3-phosphoserine phosphatase deficiency. These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition in patients with 3-phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to a variable degree to treatment with L-serine, sometimes combined with glycine. In this paper the current practice of amino acid treatment with L-serine and glycine in serine deficiency is reviewed.
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PMID:Treatment with amino acids in serine deficiency disorders. 1676

Numerous numbers of pre-, peri- and postnatal damages cause West syndrome in early infancy, however, etiology in many cases are not still elucidated despite intensive biochemical and neuroradiologic investigations. We described four patients having early onset epileptic encephalopathy with severe hypomyelination and reduction in cerebral white matter. The clinical symptoms of these patients are impaired visual attention, acquired microcephaly, spastic tetraplegia, profound psychomotor delay and infantile spasms since early infancy. All patients had striking hypomyelination of cerebrum, reduced volume of white matter and cortical atrophy on MRI. Serial MRI investigations in three patients showed absence of myelination of the white matter. On EEG, one patient revealed suppression-burst and other three had hypsarrhythmia. Despite having intractable seizures, no patient showed deterioration of neurological development. The group of these findings is mimicking to clinical manifestations of 3-phosphoglycerate dehydrogenase deficiency, and has some overlap with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) like syndrome, however it is not compatible with these two conditions. The findings observed in our patients can be regarded as a new clinical condition associated with early onset West syndrome.
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PMID:Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter. 1806 76

Three-phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare recessive inborn error in the biosynthesis of the amino acid L-serine characterized clinically by congenital microcephaly, psychomotor retardation, and intractable seizures. The biochemical abnormalities associated with this disorder are low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF). Only two missense mutations (p.V425M and p.V490M) have been identified in PHGDH, the gene encoding 3-PGDH, but it is currently unclear how these mutations in the carboxy-terminal regulatory domain of the protein affect enzyme function. We now describe five novel mutations in five patients with 3-PGDH deficiency; one frameshift mutation (p.G238fsX), and four missense mutations (p.R135W, p.V261M, p.A373T, and p.G377S). The missense mutations were located in the nucleotide binding and regulatory domains of 3-PGDH and did not affect steady-state expression, protein stability, and protein degradation rates. Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations. In transient overexpression studies in HEK293T cells, the p.A373T, p.V425M, and p.V490M mutations resulted in almost undetectable enzyme activities. Molecular modeling of the p.R135W and p.V261M mutations onto the partial crystal structure of 3-PGDH predicted that these mutations affect substrate and cofactor binding. This prediction was confirmed by the results of kinetic measurements in fibroblasts and transiently transfected HEK293T cells, which revealed a markedly decreased V(max) and an increase in K(m) values, respectively. Taken together, these data suggest that missense mutations associated with 3-PGDH deficiency either primarily affect substrate binding or result in very low residual enzymatic activity.
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PMID:Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. 1923 32


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