Acid Levels In Cerebrospinal Fluid Research Articles

Nervonic acid level in cerebrospinal fluid is a candidate biomarker for depressive and manic symptoms: A pilot study.

ObjectiveOur previous metabolomics study showed that the plasma nervonic acid levels were higher in patients with major depressive disorder (MDD) than those in healthy controls and patients with bipolar disorder (BD). To examine whether the nervonic acid levels differ in the central nervous system, we investigated the levels in the cerebrospinal fluid (CSF) of patients with MDD, BD, and healthy controls.MethodsNervonic acid levels in CSF were measured by gas chromatography time‐of‐flight mass spectrometry. The participants included 30 patients with MDD, 30 patients with BD, and 30 healthy controls.ResultsIn contrast to our previous study, no significant differences were found in the nervonic acid level in the CSF among the patients with MDD, BD, and the healthy controls. Though no significant state‐dependent changes were found among the three groups, we did observe a significant negative correlation between the nervonic acid levels and depressive symptoms in the depressive state of patients with MDD and BD (r = −0.38, p = .046). Further, a significant positive correlation was found between the nervonic acid levels and manic symptoms in the manic state of patients with BD (r = 0.79, p = .031).ConclusionThe nervonic acid levels in the CSF did not differ among the patients with MDD, BD, and the healthy controls; however, a significant negative correlation with depressive symptoms and a positive correlation with manic symptoms was observed. Thus, the nervonic acid levels in the CSF may be a candidate biomarker for mood symptoms.

Dopaminergic Hyperactivity in Neurological Patients with Delirium

Delirium has important etiological, prognostic, and therapeutic implications. The study of neurochemical markers in this condition is relevant to the understanding of its pathophysiology. The assessment of the dopamine system is particularly relevant, as dopamine antagonists are the most used drugs in delirium. To analyze neurotransmission markers in patients with delirium, focusing in the dopamine metabolite, homovanillic acid. A case-control study was performed at the National Institute of Neurology and Neurosurgery, Mexico, including hospitalized patients in which lumbar puncture was obtained for diagnostic purposes. Cases were selected if they fulfilled DSM-5 criteria for delirium. Age-paired controls were patients in which delirium was ruled out, selected at the same clinical scenario, during the same period. Neurological and systemic diagnoses were registered. Delirium was assessed using the DRS-98-R instrument. The dopamine metabolite, homovanillic acid (HVA), was measured by means of high-performance liquid chromatography. Other neurotransmission markers were also measured (5-hydroxyindoleacetic acid, glutamate, aspartate, GABA, glycine, arginine, citrulline, nitrites, and nitrates). A logistic regression model was used to determine pathogenic factors associated with the presence of delirium. 68 neurological patients with delirium and 68 patients without delirium were included. Higher homovanillic acid levels in cerebrospinal fluid were significantly associated with delirium. This result was significant after a subanalysis in patients without exposure to antipsychotics. Male gender and autoimmune limbic encephalitis were also associated with the presence of delirium. In hospitalized neurological patients, dopaminergic hyperactivity and autoimmune limbic encephalitis are pathogenic factors associated with the presence of delirium.

Elevated quinolinic acid levels in cerebrospinal fluid in subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare neurodegenerative disorder caused by a persistent infection with aberrant measles virus. Indoleamine-2, 3-dioxygenase (IDO) initiates the increased production of kynurenine pathway (KP) metabolites quinolinic acid (QUIN), which has an excitotoxic effect for neurons. We measured serum IDO activity and cerebrospinal fluid (CSF) levels of QUIN. The CSF QUIN levels were significantly higher in SSPE patients than in controls, and increased according as neurological disability in a patient studied. Elevation of CSF QUIN and progression of SSPE indicate a pathological role of KP metabolism in the inflammatory neurodestruction.

Lysophosphatidic acid levels in cerebrospinal fluid and plasma samples in patients with major depressive disorder

Major depressive disorder (MDD) is the most common psychiatric disorders. However, a biochemical marker has yet to be established for clinical purposes. It is proposed that lysophosphatidic acid (LPA, 1-acyl-2-sn-glycerol-3-phosphoate) plays some important roles in emotional regulation of experimental animals. Therefore, in this study, we measured LPA levels using enzyme-linked immunosorbent assays of cerebrospinal fluid (CSF) and plasma samples from patients with MDD. The participants were 52 patients and 49 normal healthy controls for CSF study, and 47 patients and 44 controls for plasma study. We used the Japanese version of the GRID Hamilton Depression Rating Scale (17-item version) for the assessment of depressive symptoms. We found no associations between LPA levels (CSF or plasma) and either diagnosis or severity of MDD, or with psychotropic medication. In conclusion, our data suggest that LPA levels likely would not serve as a practical biomarker of MDD.

Gamma-aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders.

Gamma-aminobutyric acid (GABA) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co-transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid (CSF) free-GABA concentrations in a large cohort of patients (n=85) with different neurological disorders. GABA was measured in the CSF of neuropaediatric patients using capillary electrophoresis with laser-induced fluorescence detection. Other neurotransmitters (amino acids and monoamines) were also analysed. GABA concentrations in CSF were abnormal, with a greater frequency (44%) than monoamines (20%) in neuropaediatric patients compared with our reference values. Although we included a few patients with inborn errors of metabolism, GABA levels in CSF were more frequently abnormal in metabolic disorders than in other nosological groups. Our work suggests further research into brain GABAergic status in neuropaediatric disorders, which could also lead to new therapeutic strategies. Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain. The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency. GABA alterations are not specific for any clinical or neuroimaging presentation.

Normal Pressure Hydrocephalus, Dementia and Kynurenic Acid

A female 49 years old patient with vestibular schwannoma developed normal pressure hydrocephalus. Patient complained about gait disturbance, urinary incontinence and memory impairment. Investigation of clinical parameter and measurement of kynurenic acid in the cerebrospinal fluid (CSF) and serum in patients with normal pressure hydrocephalus and in corresponding controls (CO; N=15) were performed. Within investigated parameters significant increase of protein and IgG levels in CSF were found in patient with normal pressure hydrocephalus. Furthermore, kynurenic acid was increased in the CSF by 60% and in the serum by 40%, comparing to CO subjects. Kynurenic acid level in CO was in the CSF and serum 2.77 ± 0.23 and 53.4 ± 4.0 nM, respectively. Three lumbar punctures were applied to patient with normal pressure hydrocephalus and clinical parameters partially normalized and lowering of kynurenic acid levels in CSF and serum were observed. Patient was improving after each lumbar puncture but the effect was transient, therefore permanent CSF shunting was recommended. After that a complete remission of symptoms occurred. Revealed data indicate a significant advantage of single punctures in management of treatment for normal pressure hydrocephalus. Increase of kynurenic acid in CSF represents interesting parameter. It is questionable if occurrence of cognition impairment and/or dementia in patients with normal pressure hydrocephalus might be related to an enhancement of kynurenic acid in the CNS.

Kynurenic Acid levels in cerebrospinal fluid from patients with Alzheimer's disease or dementia with lewy bodies.

Kynurenic acid (KYNA) is implicated in cognitive functions. Altered concentrations of the compound are found in serum and cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD). Further studies to determine whether KYNA serves as a biomarker for cognitive decline and dementia progression are required. In this study, we measured CSF KYNA levels in AD patients (n = 19), patients with dementia with Lewy bodies (DLB) (n = 18), and healthy age-matched controls (Ctrls)) (n = 20) to further explore possible correlations between KYNA levels, cognitive decline, and well-established AD and inflammatory markers. Neither DLB patients nor AD patients showed significantly altered CSF KYNA levels compared to Ctrls. However, female AD patients displayed significantly higher KYNA levels compared to male AD patients, a gender difference not seen in the Ctrl or DLB group. Levels of KYNA significantly correlated with the AD-biomarker P-tau and the inflammation marker soluble intercellular adhesion molecule-1 (sICAM-1) in the AD patient group. No associations between KYNA and cognitive functions were found. Our study shows that, although KYNA was not associated with cognitive decline in AD or DLB patients, it may be implicated in AD-related hyperphosphorylation of tau and inflammation. Further studies on larger patient cohorts are required to understand the potential role of KYNA in AD and DLB.

Effect of Buyang Huanwu decoction on amino acid content in cerebrospinal fluid of rats during ischemic/reperfusion injury

The inhibitory effect of Buyang Huanwu decoction (BYHWD) on ischemic injury has been proven, but it is not clear how amino acid levels in cerebrospinal fluid (CSF) are associated with BYHWD treatment, nor the mechanism by which BYHWD protects the brain from ischemia/reperfusion injury. We investigated the effect of BYHWD on the amino acid content of CSF in rats during ischemia-reperfusion injury. Ischemia was imposed by right middle cerebral artery occlusion (MCAO). CSF was continuously collected from the striatum via brain microdialysis before and after ischemia/reperfusion. We used on-line derivatization combined with high-performance liquid chromatography with fluorescence detection (HPLC-FD) to determine levels of glutamate (Glu), aspartate (Asp), glycine (Gly), taurine (Tau), and γ-aminobutyric acid (GABA) in CSF. The MCAO model displayed an infarct lesion in the ipsilateral hemisphere and nerve injuries, as the left upper limb was unable to extend and turn leftward. Significant increases in excitatory and inhibitory amino acids were observed in the CSF of the ischemic rats relative to the sham-operated group (P<0.01). Treatment with BYHWD reduced the areas of cerebral infarction and improved the neurological behavior scores of rats after MCAO. BYHWD treatment was also associated with a significant decrease in excitatory amino acids and increase in inhibitory amino acids in the CSF. Only the higher dose of BYHWD (20mg/kg) affected all these levels significantly. Attenuated excitatory toxicity and reduced areas of cerebral infarction associated with BYHWD treatment might be due to a protective mechanism induced by BYHWD against ischemia/reperfusion injury.

Schizophrenia: brain morphology and treatment aspects

Since the first findings of enlarged ventricles in computer tomography studies and with the development of MRIbased segmentation, brain morphology findings in schizophrenia point to abnormal structural findings in several brain regions involved in neuronal circuits [1]. One of the often cited environmental risk factors in schizophrenia is cannabis abuse. In an invited review, Malchow et al. [2], however, found inconclusive results with respect to alterations in brain morphology. They assume that chronic cannabis abuse may induce structural changes, whereas in first-episode and high-risk patients, studies need replication. In subjects at high risk and patients with schizophrenia, the gyrification index as a measure of cortico-cortical connection differed from healthy controls in the frontal and parietal cortex [3]. This may be based on the neurodevelopmental abnormalities, since the gyrification pattern is determined during the perinatal period. Accordingly, in a recent postmortem study, a reduced gyrification index has been observed in the parietal cortex in schizophrenia [4] showing no differences between monozygotic twins compared to dizygotic twin pairs which points to the influence of different intrauterine and postnatal factors [5]. Postmortem studies with a resolution on the cellular and even molecular level with, for example, focus on synaptic structural elements [6] may contribute to elucidate the pathophysiology of schizophrenia. Williams et al. [7] investigated neuronal cell density and found decreased pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia patients. They additionally report decreased astrocyte density in the subgenual cingulated cortex and callosal genu for their sample [8], which extends neurobiological hypotheses on the dysfunction of astrocytes in maintaining synaptic stability. Investigations in healthy subjects are indispensable to elucidate risk factors influencing brain volumes and for exclusion of confounding factors such as other diseaserelated and treatment effects. Beside environmental factors, schizophrenia risk genes may contribute to altered brain structures. Trost et al. [9] found a dysbindin-1 gene variant to be associated with hippocampal and prefrontal gray matter volumes. On the molecular level, another risk gene such as brain-derived neurotrophic factor (BDNF) val66met polymorphism has been shown to affect the glutamate system [10]. Moreover, D-amino acid oxidase activator gene (DAOA) variation has been found to affect homovanillic acid levels in cerebrospinal fluid [11]. Unraveling neurobiological effects of such risk factors may contribute to develop a more personalized medicine in psychiatry [12]. Even effects of traditional neuroleptic treatment strategies may be influenced by genetic factors. Giegling et al. [13] found that three haplotype blocks, one among ankyrin repeat and kinase domain containing 1 (ANKK1) and two among dopamine receptor D2 (DRD2) genes, were associated with better clinical improvement in schizophrenia patients. These often are heavy smokers attempting to treat negative and cognitive symptoms themselves. In a clinical trial investigating effects of transdermal nicotine patch, Chen et al. [14], however, found no correlation with replacement doses and only a low smoking cessation rate. They recommend more effective smoking cessation programs for this group of hospitalized patients. Due to restricted therapeutic effects of current treatment strategies in severe psychiatric disorders, the editorial A. Schmitt (&) P. Falkai Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nusbaumstr. 7, 80336 Munich, Germany e-mail: Andrea.Schmitt@med.uni-muenchen.de

Excitatory amino acids and monoaminergic neurotransmitters in cerebrospinal fluid of acute ischemic stroke patients

Background and purposeImproved insight in the role of neurotransmitters in acute cerebral ischemic injury may be fundamental for the successful development of novel therapeutic approaches. We investigated excitatory amino acids and monoaminergic neurotransmitters in cerebrospinal fluid (CSF) of acute ischemic stroke patients and their relation to stroke characteristics. MethodsCSF concentrations of glutamate, aspartate, glutamine, glycine, proline, taurine, norepinephrine, 5-hydroxyindoleacetic acid, homovanillic acid and 3,4-dihydroxyphenylacetic acid were assessed in 89 stroke patients at admission (median 6.3h after stroke onset) and in 31 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIHSS score at admission, lesion volume), (b) stroke evolution in the subacute phase, (c) long-term stroke outcome, (d) lesion location, and (e) stroke etiology. ResultsNeurotransmitter systems display relevant interrelations, however, no significant associations between neurotransmitter concentrations in CSF and stroke characteristics were found, with the exception of higher 5-hydroxyindoleacetic acid levels in CSF of patients with progressing stroke and poor long-term outcome. ConclusionsThe study results question the added value of neurotransmitter assessment in CSF for research on ischemic cerebral injury.

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy.

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type.

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients. It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.

Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression

Major depression and the metabolic syndrome (MetS) are interacting clinical conditions influenced by genetic susceptibility. For both disorders, impaired serotonergic neurotransmission in specific brain areas has been suggested. This led us to investigate whether variants in the gene coding for tryptophan hydroxylase 2 (TPH2), the brain-specific and rate-limiting enzyme for serotonin biosynthesis, might be predictive for an increased liability for the development of MetS in depressed patients. In a case-control study consisting of 988 patients with recurrent unipolar depression (RUD) and 1023 psychiatric healthy controls, MetS components were ascertained according to the International Diabetes Foundation criteria. A total of 41 single nucleotide polymorphisms fully covering the TPH2 gene region were genotyped in stage 1 (300 patients/300 controls), resulting in significant genetic associations of polymorphisms located in exon 7 and intron 8 of TPH2 and the occurrence of MetS in depressed patients after correction for age, gender and multiple testing (51 RUD-MetS/179 RUD-non-MetS). We were able to confirm the significant association of rs17110690 in stage 2 (688 patients/723 controls; 110 RUD-MetS/549 RUD-non-MetS) and to link risk-genotypes and risk-haplotypes for MetS to lower TPH2 mRNA expression and to lower 5-hydroxyindoleacetic acid levels in cerebrospinal fluid previously reported in functional studies. Our findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders induced by a genotype-dependent impairment of serotonergic neurotransmission. Identifying depressed patients at high risk for MetS using genetic variants could have direct clinical impact on individualized disease management and prevention strategies.

A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia

Clinical trials demonstrated that d-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous d-serine may contribute to the N-methyl d-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) d-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and d-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in d-serine levels and d/ l-serine ratio in CSF of schizophrenia patients, while parietal-cortex d-serine was unaltered. Levels of l-serine, l-glutamine and l-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/ d-amino acid oxidase ratio (34%) were reduced. Hippocampal d-amino-acid-oxidase protein levels significantly correlated with duration of illness ( r = 0.6, p = 0.019) but not age. d-amino acid oxidase levels in patients with DOI > 20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated d-amino acid oxidase protein levels may contribute to the lower CSF d-serine levels in schizophrenia.

Extraordinary changes in excitatory amino acid levels in cerebrospinal fluid of influenza-associated encephalopathy of children.

The correlation between the glutamate-glutamine cycle and nitric oxide (NO) production in the central nervous system (CNS) of a new type of influenza-associated encephalopathy in children is discussed. When measurements of several amino acids and NOx (nitrite/nitrate) levels in the cerebrospinal fluid (CSF) using HPLC-fluorescence and -UV methods, respectively, were made. the CSF glutamate levels of patients with the new type of encephalitis were significantly lower, and both glutamine and NOx levels were significantly higher than those of the control group and the patients of the meningitis group. Results indicate that the turnover rate of glutamate in CNS, particularly in the brain, increases in the influenza-associated encephalopathy. The high mortality in the disease may correlate with the hyperactivity of supra-spinal glutamate neurons and the subsequent high activity levels of NOx in CNS.

Acetic acid and 3-hydroxybutyric acid levels in cerebrospinal fluid of cattle

Acetic acid and 3-hydroxybutyric acid levels in cerebrospinal fluid of cattle

Acetic acid and 3-hydroxybutyric acid levels in cerebrospinal fluid of cattle

To evaluate the importance of acetic acid and 3-hydroxybutyric acid (3-HB) in cerebrospinal fluid (CSF) of cattle, CSF samples were taken from a population of 60 cattle including healthy and sick animals with central nervous disorders. Mean acetic acid and 3-HB levels in blood plasma were 0.30 (SD 0.24) and 0.30 (SD 0.28) mM, and those in CSF were 0.14 (SD 0.06) and 0.08 (SD 0.07) mM, respectively. Significant differences were observed between plasma and CSF samples for both acetic acid and 3-HB levels. Acetic acid levels in CSF showed less relationship with those in blood plasma, whereas plasma 3-HB levels accompanied proportional changes with its CSF levels, which were about 30% of plasma 3-HB. It was revealed that both acetic acid and 3-HB levels in plasma and CSF have less relationship to glucose levels in plasma and CSF; therefore, the decrease of glucose levels in plasma or CSF is not necessarily accompanied by hyperketonemia.

Schizophrenia, psychosis, and cerebral spinal fluid homovanillic acid concentrations.

Neuroleptic drugs block brain dopamine receptors and are effective in treating psychoses of diverse origins. This finding has become a cornerstone of the dopamine theory of schizophrenia, but clinical studies relating schizophrenia, per se, to brain dopamine metabolism have ranged from controversial to negative. This article presents new evidence that cerebrospinal fluid levels of the dopamine metabolite homovanillic acid are related to the severity of psychosis in schizophrenia. These results support the concept that homovanillic acid levels in cerebrospinal fluid vary as a function of psychosis rather than being related to the diagnosis of schizophrenia per se.

Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: Relation to clinical and biochemical variable

In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutaric Aciduria Type 1: First Reported Cases in Three Saudi Patients

The clinical and biochemical findings in three patients with glutaric aciduria Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreoathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed white matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicates the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.