Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1 alpha subunit of the complex. Two of these patients illustrate typical presentations of PDH E1 alpha deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1 alpha gene. This mutation, a C-to-T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patient, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1 alpha deficiency. The genetic basis of the variable expression of X-linked PDH E1 alpha deficiency in heterozygous females is discussed.
 ...
PMID:X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. 129 79

We investigated both blood and cerebrospinal fluid (CSF) lactate and pyruvate levels in seven girls with the Rett syndrome (RS) and evaluated the relationship between CSF lactate and pyruvate levels and the clinical manifestations, particularly seizures, anticonvulsant medication, and breathing dysfunction including breath holding, apnea and hyperventilation. Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients. Elevated CSF lactate correlated significantly with the clinical occurrence of hyperventilation (P0 = 0.048, Fisher exact probability). We measured native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in two patients (#1 and 2) using cultured lymphoblastoid cell lines which were transformed by EB virus and the results were normal. We also analyzed CSF citric acid intermediates from 7 RS patients including citric acid, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate. These concentrations were not significantly different from those control patients (N = 21). An elevated lactate level may be a clue to clarify the etiology of RS.
 ...
PMID:The Rett syndrome and CSF lactic acid patterns. 159 May 31

We report the clinical and autopsy findings in a young man of 18 with a chronic progressive disorder comprised of lactic acidosis, mental deterioration, and epileptic seizures which were sometimes accompanied by stroke-like episodes with transient hemiparesis and cortical blindness. He died of congestive heart failure. The autopsy showed lesions of the gray matter of the brain. Both the putamen and parieto-occipital cortex showed loss of neurons and proliferation of macrophages, astrocytes and vessels. There was marked loss of neurons in the inferior olives, and slight reduction of the number of Purkinje cells. Skeletal muscle studies revealed ragged-red fibers and structurally abnormal mitochondria. The heart was enlarged: accumulations of mitochondria occurred in the muscle fibers. The liver exhibited marked fatty degeneration. Biochemical analyses showed normal activities of pyruvate dehydrogenase in thrombocytes, pyruvate carboxylase in lymphocytes, biotinidase in serum as well as succinate dehydrogenase and cytochrome c oxidase. The features of this disorder differ in many respects from cases of mitochondrial encephalomyopathy previously reported and cannot be assigned to any specific disease entity.
 ...
PMID:Mitochondrial encephalomyopathy. A variant with heart failure and liver steatosis. 367 21

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.
 ...
PMID:Histological changes of muscle in a patient with pyruvate dehydrogenase deficiency. 623 Sep 47

Two patients, one dying at 25 days and one at 20 months had 'chronic' lactic acidaemia with a high lactate to pyruvate ratio. Both showed EEG abnormalities and seizure activity and both died of respiratory failure. Investigation of cultured skin fibroblasts from these patients revealed normal pyruvate dehydrogenase and pyruvate carboxylase activities but the cells showed a decreased ability to oxidase pyruvate which was returned to normal on the addition of methylene blue. Subsequent investigations revealed that the mitochondria from the patients' cells could oxidase pyruvate normally but that the cells had an abnormal NAD to NADH ratio under standard conditions of incubation. It was concluded that both children had a redox disequilibrium in the cytoplasmic compartment due to a problem in transporting reducing equivalents from the cytoplasmic to the mitochondrial compartments.
 ...
PMID:Lactic acidosis, neurological deterioration and compromised cellular pyruvate oxidation due to a defect in the reoxidation of cytoplasmically generated NADH. 688 92

Subacute necrotizing encephalomyelopathy (Leigh's syndrome) is a rare neurodegenerative disease in the adult. The precise metabolic defect is unknown, but abnormalities of a mitochondrial enzyme system related to cytochrome-c oxidase or pyruvate dehydrogenase are described. The clinical picture usually consists of an altered breathing pattern, oculomotor paralysis, other signs of cranial nerve dysfunction, ataxia, myoclonic jerks, nystagmus, generalized seizures, optic atrophy and demyelinating peripheral neuropathy. Hypopnea leads to CO2-retention with consecutive loss of consciousness demanding mechanical ventilation. Respiratory failure is the most frequent cause of death. Here we describe two patients with adult onset Leigh's syndrome and we discuss the longterm treatment strategies including vitamin B1 and CPAP mask.
 ...
PMID:[Adult Leigh syndrome. A rare differential diagnosis of central respiratory insufficiency]. 771 56

Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 alpha subunit showed normal results. In the 2 sons, complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.
 ...
PMID:Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity. 802 67

Disruption of early or late fetal brain development resulting in structural abnormalities may be associated with inborn errors of mitochondrial metabolism. It is common in patients with deficiency of pyruvate dehydrogenase activity and it has sporadically been described in patients with dysfunction of the tricarboxylic acid cycle. Mitochondrial respiratory chain disorders are not commonly known to interfere with early brain development. We describe here a girl with an encephalomyopathy likely to be due to a novel type of deficiency of cytochrome c oxidase (complex IV) activity that presented with severe hypotonia, myoclonic seizures, optic atrophy and elevated lactate concentration in cerebrospinal fluid shortly after birth. Cranial magnetic resonance imaging revealed hypoplasia of the cerebellum with rudimentary cerebellar hemispheres and relative sparing of the vermis. This case suggests that deficiency of cytochrome c oxidase and possibly respiratory chain disorders in general have to be considered in the differential diagnosis of cerebellar hypoplasia.
 ...
PMID:Cerebellar hypoplasia in respiratory chain dysfunction. 889 74

The finding that epileptic seizures alter blood-brain barrier (BBB) properties has stimulated interest into the possibility that phenotypic changes in brain endothelium may constitute a pathological initiator leading to seizures. Recent evidence obtained from epileptic patients undergoing cortical resection, demonstrated abnormal expression of glucose transporter molecules (GLUT1), while [18F]deoxyglucose PET studies demonstrated regions of decreased glucose uptake and hypometabolism in seizure foci. The properties of other 'nonexcitable CNS cells' are also altered in epileptic tissue, and glial cells from epileptic brain displayed diminished capacity for ionic homeostasis; voltage-dependent mechanisms were primarily affected, increasing reliance on energy-dependent mechanisms. Diminished ion homeostasis together with increased metabolic demand of hyperactive neurons may further aggravate the neuropathological consequences of BBB loss of glucose uptake mechanisms. Since ketone bodies can provide an alternative to glucose to support brain energy requirements, it is hypothesized that one of the mechanisms of the ketogenic diet in epilepsy may relate to increased availability of beta-hydroxybutyrate, a ketone body readily transported at the BBB. This hypothesis is supported by the fact that the ketogenic diet is the treatment of choice for the glucose transporter protein syndrome and pyruvate dehydrogenase deficiency, both associated with cerebral energy failure and seizures.
 ...
PMID:Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. 1058 72

Leigh syndrome is a heterogenous neurologic disease characterized by seizures, developmental delay, muscle weakness, respiratory abnormalities, optic abnormalities, including atrophy and ophthalmoplegia, and progressive cranial nerve degeneration with early onset in infants and children. Diagnosis can be confirmed by characteristic pathologic findings of necrosis in the basal ganglia, thalamus, and brainstem. Severe dysfunction of mitochondrial energy metabolism is generally present and involved in the etiology of this degenerative central nervous system disease. At the molecular level, a number of point mutations have been located in mitochondrial DNA genes, including ATPase6 and tRNA(Lys) genes, and in nuclear genes encoding subunits of oxidative enzymes, such as pyruvate dehydrogenase. Biochemically these mutations are responsible for enzymatic defects in either respiratory complexes (I, IV, or V) or pyruvate dehydrogenase. We describe here the first case of Leigh syndrome with marked depletion of mitochondrial DNA levels in skeletal muscle and abnormal activities in skeletal muscle of mitochondrial respiratory complexes I, III, IV, and V.
 ...
PMID:Mitochondrial DNA depletion in Leigh syndrome. 1195 36


1 2 3 Next >>