Effects of low-level lead on glycolytic enzymes and pyruvate dehydrogenase of rat brain in vitro: relevance to sporadic Alzheimer's disease?

Summary. Lead is known to be a potent inhibitor of many enzymes working in the brain, thus possibly inducing functional problems in the brain under pathophysiological conditions. Among such enzymes are those involved in glucose metabolism and energy production. We investigated the inhibitory effects of low-level lead on brain hexokinase (HK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK) and pyruvate dehydrogenase complex (PDHc) with rat brain homogenate. PDHc was distinctively inhibited when low-dose lead acetate was added last of all (IC₅₀ = 5 μM) to the reaction mixture. The other enzymes were completely resistant to 5 μM of lead acetate. When the homogenate was preincubated with lead acetate HK was dramatically inhibited by low-level lead acetate (1–5 μM), in a manner dependent on both preincubation time and lead concentration. However, the inhibitory effect was abolished by coincubation with its substrates, glucose or ATP. The results suggest that exposure to low levels of lead may increase the risk of cerebral hypometabolism caused by direct inhibition of specific glucose-utilizing enzymes. In this context, lead might be regarded as a risk factor in the abnormal glucose metabolism seen in some kinds of neurodegenerative disorders such as sporadic Alzheimer's disease. Received March 9, 1999; accepted August 18, 1999     

Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis

Aim To describe the phenotype and genotype of pyruvate dehydrogenase complex (PDHc) deficiency. Method Twenty‐two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15‐year period. Results Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non‐progressive infantile encephalopathy (three males, three females; age at diagnosis 2–9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1–13mo); and (4) those with relapsing ataxia (three males; 18–30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non‐progressive encephalopathy and long‐term survival in four cases. Interpretation Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non‐progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.     

(r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia,but not in Alzheimer dementia

Summary. In dementia of Alzheimer type (DAT), cerebral glucose metabolism is reduced in vivo, and enzymes involved in glucose breakdown are impaired in post-mortem brain tissue. Pyruvate dehydrogenase complex activity (PDHc) is one of the enzymes known to be reduced, while succinate dehydrogenase activity (SDH), another enzyme of oxidative glucose metabolism is unchanged. In dementia of vascular type (DVT), variable changes in glucose metabolism have been demonstrated in vivo, while changes of enzyme activities in post-mortem brain tissue are unknown. Here, PDHc and SDH activity were stimulated with each of the two stereoisomers of alpha lipoic acid in post-mortem parietal brain cortex of patients with DAT, DVT, and one case of Picks disease and compared to stimulation effects in a control group, matched for age, sex, post-mortem delay, and storage time of brain tissue. PDHc in DAT and DVT, but not in Picks disease was reduced. PDHc activity could be slightly stimulated by 10µM of the physiological stereoisomer (r)-alpha-lipoic acid, in controls and DVT (possibly also in Picks disease), but not in DAT. In all groups investigated SDH was activated by 100µM and 1mM of both isomers of alpha-lipoic acid, whereas 10mM of both stereoisomers of alpha-lipoic acid caused an inhibition of both, PDHc and SDH activity. The loss of basal and of (r)-alpha-lipoic acid stimulated PDHc activity indicate that a functional or structural impairment of PDHc may exist in DAT and DVT which is not merely attributable to loss of mitochondria since basal and stimulated SDH activities are similar in controls, DVT and DAT, thus indicating selective vulnerability of PDHc.     

MRI features of 4 female patients with pyruvate dehydrogenase E1 alpha deficiency

Pyruvate dehydrogenase complex is a key intramitochondrial multienzyme complex required for the conversion of pyruvate to acetyl-CoA. Most patients with pyruvate dehydrogenase deficiency have a defect in the E1 alpha subunit, associated with mutations in the PDHA1 gene. In this report, we submit detailed magnetic resonance images in 4 affected female patients with PDHA1 mutations who had with severe cortical atrophy, dilated ventricles, and an incomplete corpus callosum. In one of these patients, the magnetic resonance imaging pattern prompted molecular diagnostic testing when enzymatic testing was normal. We underscore that this constellation of features, which may be misdiagnosed as periventricular leukomalacia, illustrates a pattern highly suggestive of a deficiency of pyruvate dehydrogenase E1 alpha in female patients and should trigger appropriate diagnostic investigations.     

The effect of albumin on astrocyte energy metabolism is not brought about through the control of cytosolic Ca2+ concentrations but by free-fatty acid sequestration

Albumin is an important serum protein that under normal circumstances is not present in the brain. However, during development, under hypoxia, or after breakdown of the blood-brain barrier, albumin is found in the brain, where it is able to regulate energy metabolism. In this work the mechanism through which albumin regulates astrocyte metabolism was investigated. Our results show that albumin strongly increases (more than 100%) the flux of glucose and lactate through the pyruvate dehydrogenase-catalyzed reaction in astrocytes from primary culture. However, albumin only slightly stimulated other metabolic pathways, such as the tricarboxylic acid cycle or the pentose phosphate shunt, indicating that it exerts its effect specifically on the reaction catalyzed by pyruvate dehydrogenase. Although albumin increased cytosolic Ca²⁺ concentrations in astrocytes, our results show that the increase in pyruvate dehydrogenase activity promoted by albumin is not due to the enhancement of Ca²⁺ concentrations. Indeed, highly purified albumins failed to increase the Ca²⁺ concentration but did enhance lactate oxidation. In agreement with this, the effect of albumin on lactate oxidation was not abolished after Ca²⁺ depletion. Instead, the presence of fatty acids inhibited lactate oxidation and counteracted the effect of albumin, suggesting that albumin activates pyruvate dehydrogenase by binding free fatty acids and/or their CoA-derivatives. GLIA 25:1–9, 1999. © 1999 Wiley-Liss, Inc.     

Changes in pyruvate dehydrogenase complex (PDHc) activity and [3H]QNB-receptor binding in rat brain subsequent to intracerebroventricular injection of bromopyruvate

Summary Pyruvate dehydrogenase complex (PDHc), a link between carbohydrate and acetylcholine metabolism, is a regulatory enzyme for glucose and neurotransmitter metabolism in the brain and is reduced in Alzheimer-diseased brain. To study functional consequences of an inhibition of PDHc on muscarinic receptor binding, bromopyruvate, a suicide inhibitor of PDHc, was injected intracerebroventricularly (icv) in rats. Bromopyruvate caused a reduction of PDHc activity in the 3 brain regions examined, however, reaching significance only in the cerebral cortex and the hippocampus and not in the striatum, 24h after injection. 3, 6, and 12 weeks later, there was a normalization or transiently increased activity, respectively, of PDHc in these brain regions. No changes in concentrations of energy-rich phosphates could be demonstrated in the cerebral cortex 12 weeks after brompyruvate injection. The number of muscarinic receptors was significantly reduced in the cerebral cortex 12 weeks after injection. the data indicate that a transient reduction of brain PDHc activity in vivo is associated with a long-lasting reduction in muscarinic cholinergic receptors. Because comparable changes of PDHc and muscarinic receptors are found in dementia of Alzheimer type, the model of bromopyruvate inhibition of PDHc in rats is suggested to be useful for experimental dementia research.     

Late-onset presentation of pyruvate dehydrogenase deficiency.

Two brothers presented in their mid-forties with movement disorders including atypical parkinsonism, choreiform movements, stereotypies, ataxia and dysarthria. Both brothers showed putaminal lucencies on imaging and, in the proband, a deficiency of the pyruvate dehydrogenase complex (PDHC) was found on skin fibroblast assay.     

Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado-Joseph disease

To identify the metabolic alterations related to mitochondrial functions in Machado-Joseph disease (MJD), we analyzed the cerebrospinal fluid (CSF) levels of lactate, pyruvate, and citric acid cycle intermediates by high performance liquid chromatography (HPLC) in 7 Japanese patients with that disease and then measured some mitochondrial enzymes. Their mean age was 46 years. Diseased controls were matched by age to the patients studied. The CSF level of lactate was significantly elevated, pyruvate was significantly decreased, and the lactate/pyruvate (L/P) ratio was significantly elevated in the patients with MJD. There were no significant differences of citric acid cycle intermediates of the CSF between the patients and the controls. We measured the native and dichloroacetate (DCA)-activated pyruvate dehydrogenase complex (PDHC) activities, and mitochondrial electron transport activities in 3 patients with MJD, and found these activities to be normal. Therefore, the increased CSF lactate, increased lactate/pyruvate ratio, and decreased pyruvate may reflect the decreased regional cerebral blood flow rather than metabolic derangement of the mitochondria.     

Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism

Glutaric acidemia type I is an inherited metabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric and 3-hydroxyglutaric acids in the brain tissue of the affected patients. Considering that a toxic role was recently postulated for quinolinic acid in the neuropathology of glutaric acidemia type I, in the present work we investigated whether the combination of quinolinic acid with glutaric or 3-hydroxyglutaric acids or the mixture of glutaric plus 3-hydroxyglutaric acids could alter brain energy metabolism. The parameters evaluated in cerebral cortex from young rats were glucose utilization, lactate formation and (14)CO(2) production from labeled glucose and acetate, as well as the activities of pyruvate dehydrogenase and creatine kinase. We first observed that glutaric (5 mM), 3-hydroxyglutaric (1 mM) and quinolinic acids (0.1 microM) per se did not alter these parameters. Similarly, no change of these parameters occurred when combining glutaric with quinolinic acids or 3-hydroxyglutaric with quinolinic acids. In contrast, co-incubation of glutaric plus 3-hydroxyglutaric acids increased glucose utilization, decreased (14)CO(2) generation from glucose, inhibited pyruvate dehydrogenase activity as well as total and mitochondrial creatine kinase activities. The glutaric plus 3-hydroxyglutaric acids-induced inhibitory effects on creatine kinase were prevented by the antioxidants glutathione and catalase plus superoxide dismutase, indicating the participation of reactive oxygen species. Our data indicate a synergic action of glutaric and 3-hydroxyglutaric acids disturbing energy metabolism in cerebral cortex of young rats.     

Defects of pyruvate metabolism and the Krebs cycle

Seizures and metabolic disease are frequently associated, either indirectly as a consequence of the metabolically caused brain dysgenesis or directly by the metabolic derangement. This article describes defects in pyruvate metabolism (pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency) and Krebs cycle defects such as fumarase deficiency. Clinical characterizations and diagnostic strategies have been developed for each of these diseases. In contrast, very little is known about the specific epileptic features in these disorders. In females with a pyruvate dehydrogenase deficiency E1alpha owing to the mutation in the subunit E1alpha of the pyruvate dehydrogenase complex West's syndrome associated with large ventricles and corpus callosum agenesis on magnetic resonance imaging can be the main feature of the disease. In fumarase deficiency, prenatal brain dysgenesis is the most prominent feature of the disease. Diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid, analysis of amino acids in plasma and organic acids in urine, and neuroradiologic investigations. Further biochemical and molecular analysis leads to a definitive diagnosis and opens the way to adequate treatment, genetic counseling, and prenatal diagnosis.     

Metabolic approach of absence seizures in a genetic model of absence epilepsy, the GAERS: study of the leucine-glutamate cycle.

We suggest that a dysregulation of energy metabolism in the brain of genetic absence epilepsy rats from Strasbourg (GAERS) could create a specific cerebral environment that would favor the expression of spike-and-wave discharges (SWD) in the thalamocortical loop, largely dependent on glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurotransmissions. We tested several aspects of metabolic activity in the brain of GAERS compared to a genetic strain of nonepileptic (NE) rats. Glucose metabolism was higher in all brain regions of GAERS compared to those of NE rats along the whole glycolytic and aerobic pathways, as assessed by regional histochemical measurement of lactate dehydrogenase and cytochrome oxidase activities. Branched-chain amino acids (BCAA) and alpha-ketoisocaproate (alpha-KIC), the ketoacid of leucine, when injected intraperitoneally, increased the number of SWD in GAERS but had only a slight effect on their duration. These data speak in favor of a BCAA- or alpha-KIC-induced change in neuronal excitability. Leucine and alpha-KIC decreased the concentration of glutamate in thalamus and cortex without affecting GABA concentrations. Thus, BCAA and alpha-KIC, by decreasing glutamatergic neurotransmission, could favor GABAergic neurotransmission, which is known to increase the occurrence of seizures in GAERS. Finally, the transport of [1-(14)C]alpha-KIC in freshly isolated cortical neurons was lower in GAERS than in NE rats, and this difference was shown to be of metabolic origin. The addition of gabapentin, a specific inhibitor of BCAA transaminase (BCAT), reduced the transport of [1-(14)C]alpha-KIC in GAERS and NE rats to a level that became identical in both strains. This strain-dependent change was not related to a difference in the activity of BCAT, which was identical in GAERS and NE rats. The exact origin of this apparent metabolic dysregulation of energy metabolism in GAERS that could underlie the origin of seizures in that strain remains to be explored further.     

Acetyl‐CoA production from pyruvate is not necessary for preservation of myelin

Oligodendrocytes and Schwann cells not only form myelin in the central and peripheral nervous system, but also provide metabolic and trophic support to the axons they ensheathe. Acetyl‐CoA is potentially a key molecule in Schwann cells and oligodendrocytes because it is at the crossroads of cellular lipid biosynthesis and energy generation. The main route for acetyl‐CoA production is the oxidation of pyruvate by the pyruvate dehydrogenase complex (PDC). PDC deficiency in humans results in neurodegeneration and developmental impairments in both white and gray matter structures. To address the importance of PDC in myelinating glia, we deleted Pdha1 gene specifically in oligodendrocytes and Schwann cells. Surprisingly, sciatic and optic nerve morphology and the motor performance of Pdha1^f/Y; Cnp^Cre/+ mice are undistinguishable from those of controls at 1 month of age. In addition, myelin is stably maintained for at least 10 months. However, Pdha1^f/Y; Cnp^Cre/+ mice showed reduced fiber density and signs of axonal degeneration in both sciatic and optic nerves from 6 months of age. In contrast, 10 month‐old mice bearing a floxed Pdha1 gene with either P0‐Cre (expressed only by Schwann cells) or NG2‐Cre^ER (expressed in oligodendrocyte precursor cells) do not show any sign of axonal pathology or alterations in myelin structure or thickness. This indicates that the axonopathy is specific to the Pdha1^f/Y; Cnp^Cre/+ mice. Taken together, these results suggest that acetyl‐CoA derived from pyruvate is not necessary for myelin maintenance and, thus, myelin‐forming cells are not likely to contribute to the pathophysiology of PDC deficiency.     

Histological changes of muscle in a patient with pyruvate dehydrogenase deficiency

Histological changes of muscle from a 17-month-old boy with pyruvate dehydrogenase deficiency are presented. The patient had muscle hypotonia, mental retardation, seizures, lactic acidosis and hyperalaninemia. Deficient activity of the pyruvate dehydrogenase complex was found in his platelets (about 25% of normal) and of pyruvate dehydrogenase in his biopsied muscle (about 5% of normal). A muscle biopsy specimen showed an increased proportion of type IIC fibers (24%), fiber-type grouping and lipid droplet accumulation.     

Glut1 deficiency (G1D): Epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype

Brain glucose supplies most of the carbon required for acetyl-coenzyme A (acetyl-CoA) generation (an important step for myelin synthesis) and for neurotransmitter production via further metabolism of acetyl-CoA in the tricarboxylic acid (TCA) cycle. However, it is not known whether reduced brain glucose transporter type I (GLUT-1) activity, the hallmark of the GLUT-1 deficiency (G1D) syndrome, leads to acetyl-CoA, TCA or neurotransmitter depletion. This question is relevant because, in its most common form in man, G1D is associated with cerebral hypomyelination (manifested as microcephaly) and epilepsy, suggestive of acetyl-CoA depletion and neurotransmitter dysfunction, respectively. Yet, brain metabolism in G1D remains underexplored both theoretically and experimentally, partly because computational models of limited brain glucose transport are subordinate to metabolic assumptions and partly because current hemizygous G1D mouse models manifest a mild phenotype not easily amenable to investigation. In contrast, adult antisense G1D mice replicate the human phenotype of spontaneous epilepsy associated with robust thalamocortical electrical oscillations. Additionally, and in consonance with human metabolic imaging observations, thalamus and cerebral cortex display the lowest GLUT-1 expression and glucose uptake in the mutant mouse. This depletion of brain glucose is associated with diminished plasma fatty acids and elevated ketone body levels, and with decreased brain acetyl-CoA and fatty acid contents, consistent with brain ketone body consumption and with stimulation of brain beta-oxidation and/or diminished cerebral lipid synthesis. In contrast with other epilepsies, astrocyte glutamine synthetase expression, cerebral TCA cycle intermediates, amino acid and amine neurotransmitter contents are also intact in G1D. The data suggest that the TCA cycle is preserved in G1D because reduced glycolysis and acetyl-CoA formation can be balanced by enhanced ketone body utilization. These results are incompatible with global cerebral energy failure or with neurotransmitter depletion as responsible for epilepsy in G1D and point to an unknown mechanism by which glycolysis critically regulates cortical excitability.     

Leigh's disease due to a new mutation in the PDHX gene

OBJECTIVE: To describe the clinical course, neuroradiological presentation, biochemical and molecular studies of a new patient with pyruvate dehydrogenase complex (PDHc) deficiency. To compare this case with the data on other published cases. METHODS: Brain magnetic resonance imaging (MRI), basal metabolic investigations with lactate measurements in body fluids, PDHc activity assay on cultured skin fibroblasts, immunoblot analysis and molecular studies (polymerase chain reaction [PCR] and sequencing procedures). RESULTS: Our patient accused an unspecific encephalopathy for years and presented at 13 years of age an acute deterioration with basal ganglia necrosis and subcortical white matter involvement. PDHc deficiency was secondary to a large deletion (3913 bp) in the PDHX gene, which encodes E3 binding protein (E3BP) subunit. INTERPRETATION: These data provide an additional case of E3BP deficiency with a unique and previously unreported deletion in the PDHX gene.     

Metabolic reprogramming by the pyruvate dehydrogenase kinase–lactic acid axis: Linking metabolism and diverse neuropathophysiologies

Emerging evidence indicates that there is a complex interplay between metabolism and chronic disorders in the nervous system. In particular, the pyruvate dehydrogenase (PDH) kinase (PDK)–lactic acid axis is a critical link that connects metabolic reprogramming and the pathophysiology of neurological disorders. PDKs, via regulation of PDH complex activity, orchestrate the conversion of pyruvate either aerobically to acetyl-CoA, or anaerobically to lactate. The kinases are also involved in neurometabolic dysregulation under pathological conditions. Lactate, an energy substrate for neurons, is also a recently acknowledged signaling molecule involved in neuronal plasticity, neuron–glia interactions, neuroimmune communication, and nociception. More recently, the PDK–lactic acid axis has been recognized to modulate neuronal and glial phenotypes and activities, contributing to the pathophysiologies of diverse neurological disorders. This review covers the recent advances that implicate the PDK–lactic acid axis as a novel linker of metabolism and diverse neuropathophysiologies. We finally explore the possibilities of employing the PDK–lactic acid axis and its downstream mediators as putative future therapeutic strategies aimed at prevention or treatment of neurological disorders.     

A 1.1 million base pair X-chromosomal deletion covering the PDHA1 and CDKL5 genes in a female patient with west syndrome and pyruvate oxidation deficiency

Mutations in the X-linked E1α subunit of the pyruvate dehydrogenase complex (PHDC) are the most frequent causes of PDHC deficiency. The clinical picture is heterogeneous depending on residual enzyme activity and X-inactivation. We report on a girl who presented at an age of 3 weeks with muscular hypotonia, vomiting, hyperlactatemia, microcephaly, enlarged ventricles, partial agenesis of the corpus callosum, and seizures. PDHA1 sequencing was normal in DNA from blood. In muscle, normal PDHC activity was measured while substrate oxidation rates revealed moderately diminished pyruvate oxidation. Quantitative PCR analysis revealed hemizygosity of the whole PDHA1 gene. Homozygosity mapping and determination of the breakpoint showed a 1.1 million base pair deletion on the X-chromosome including the CDKL5 and PDHA1 genes. The difficulty in the diagnosis of PDHC deficiency is evident: (1) enzyme activity can be normal depending on the X-inactivation; (2) large deletions can be missed by routine genetic analysis; and (3) only quantification of the PDHA1 gene content revealed the mutation in our patient. We recommend to revisit patients who are clinically suspicious for a mitochondrial disorder especially for hidden PDHA1 mutations, such as large deletions.     

Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy

PURPOSE: Pathophysiologic mechanisms underlying temporal lobe epilepsy (TLE) are still poorly understood. One major hypothesis links alterations in energy metabolism to glutamate excitotoxicity associated with seizures in TLE. The purpose of this study was to determine whether changes in the activities of enzymes critical in energy and neurotransmitter metabolism contributed to the alterations in metabolic status leading to the excitotoxic effects of glutamate. METHODS: Activities of four key enzymes involved in energy metabolism and glutamate cycling in the brain [aspartate aminotransferase (AAT), citrate synthase (CS), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH)] were measured in anterolateral temporal neocortical and hippocampal tissues obtained from three different groups of medically intractable epilepsy patients having either mesial, paradoxical, or mass lesion-associated temporal lobe epilepsy (MTLE, PTLE, MaTLE), respectively. RESULTS: We found that GDH activity was significantly decreased in the temporal cortex mainly in the MTLE group. A similar trend was recognized in the hippocampus of the MTLE. In all three patient groups, GDH activity was considerably lower, and AAT and LDH activities were higher in cortex of MTLE as compared with the corresponding activities in hippocampus (p<0.05). In the MTLE cortex and hippocampus, GDH activities were negatively correlated with the duration since the first intractable seizure. CONCLUSIONS: Our results support the hypothesis suggesting major alteration in GDH activity mainly in the MTLE group. It is proposed that significant alterations in the enzyme activities may be contributing to decreased metabolism of glutamate, leading to its accumulation.     

Intravenous ketogenic diet therapy for neonatal-onset pyruvate dehydrogenase complex deficiency

BackgroundPyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that causes lactic acidosis and neurodevelopmental changes. Five causative genes have been identified: PDHA1, PDHB, DLAT, DLD, and PDHX. Four neurological phenotypes have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome, and relapsing ataxia. Of these, neonatal encephalopathy has the worst mortality and morbidity and there is no effective treatment.Subjects and methodsWe studied two girls who were clinically diagnosed with PDHC deficiency as neonates; they were subsequently found to have PDHA1 mutations. The clinical diagnosis was based on white matter loss and a lateral ventricular septum on fetal MRI, spasticity of the lower extremities, and lactic acidosis worsening after birth. Intravenous ketogenic diets were started within 24 h after birth. The ketogenic ratio was increased until the blood lactate level was controlled, while monitoring for side effects.ResultsIn both cases, the lactic acidosis improved immediately with no apparent side effects. Both children had better developmental outcomes than previously reported cases; neither exhibited epilepsy.ConclusionsIntravenous ketogenic diet therapy is a treatment option for neonatal-onset PDHC deficiency. Further studies are needed to optimize this therapy.     

Pyruvate Metabolism in Lafora Disease

Lafora disease is an autosomal recessive and progressive degenerative disorder of the central nervous system (CNS). The pathogenic mechanism has been presumed to be an inborn error of carbohydrate metabolism, although this has never been proved. In a case of proven Lafora disease, pyruvate metabolism, which has a central position in carbohydrate metabolism, was studied in body fluids under various conditions and in brain biopsy material. No abnormalities in this metabolic pathway were found. This finding plus earlier reports in the literature exclude a defect in glycolysis; thus, a disturbance of carbohydrate metabolism as the pathogenic mechanism of Lafora disease is unlikely.