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Results for “Pyruvate Dehydrogenase Complex Deficiency Disease”

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At least 127 records · Page 7Linked to original sources
PubMed1996

Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation.

The mitochondrial DNA (mtDNA) point mutation T8993G has been associated with maternally inherited Leigh syndrome (MILS) when very abundant (> 95%). MILS patients are usually severely affected and die in early infancy. In 1993, a novel T8993C point mutation was described in a juvenile form of Leigh syndrome (LS) characterized by a less aggressive clinical course. We describe four unrelated T8993C patients who had diverse, relatively mild, clinical manifestations. Polymerase chain reaction-restriction fragment length polymphorphism analysis showed that the heteroplasmic T8993C point mutation was very abundant in several tissues from all four patients (94.2 +/- 1.5%) but was less copious in blood from 20 maternal relatives. ATP production in mitochondria isolated from skin fibroblasts in three patients was normal, whereas in one patient it was decreased to 20-35% of controls. These findings suggest that the T8993C mutation is less severe than the more common T8993G mutation.

Adenosine Triphosphate↗
PubMed1997

Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 x 10(-4) mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patient's older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 alpha subunit revealed a C-->G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1 alpha gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.

DNA↗
PubMed1993

X chromosome inactivation and the diagnosis of X linked disease in females.

In studies of female patients with suspected deficiency of the E1 alpha subunit of the pyruvate dehydrogenase complex, we have found that X inactivation ratios of 80:20 or greater occur at sufficient frequency in cultured fibroblasts to make exclusion of the diagnosis impossible in about 25% of cases. Pyruvate dehydrogenase E1 alpha subunit deficiency is an X linked inborn error of metabolism which is well defined biochemically and is unusual in that most heterozygous females manifest the condition. The diagnosis is usually established by measurement of enzyme activity and the level of immunoreactive protein and these analyses are most commonly performed on cultured fibroblasts from the patients. Skewed patterns of X chromosome inactivation make it impossible to exclude the diagnosis if the normal X chromosome is expressed in the majority of cells. While most of the observed variation appears to be the expected consequence of random X inactivation, it may be further exaggerated by sampling and subsequent expansion of the cells for analysis.

Cells, Cultured↗
PubMed2006

Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children.

OBJECTIVE: Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS: Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME: There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor delta-aminolevulinate. CONCLUSIONS: In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.

Acidosis, Lactic↗
PubMed1993

Neuropathological findings of a patient with pyruvate dehydrogenase E1 alpha deficiency presenting as a cerebral lactic acidosis.

Neuropathological findings are reported of a 6-month-old female child with a "cerebral" lactic acidosis. A mutation in the pyruvate dehydrogenase (PDH) E1 alpha gene was found. Gross examination of the brain revealed a severe thinning of the cerebral parenchym, a marked hydrocephalus sparing the aqueduct and fourth ventricle, agenesis of the corpus callosum and heterotopic noduli of gray matter in subependymal regions. Microscopical examination showed heterotopic inferior olives, absent pyramids and focal neuroglial overgrowth into meninges. In addition some heterotopia of Purkinje cells and dysplasia of the dentate nuclei were observed. There was a marked vascular proliferation with many thin-walled, congestive vessels in the cerebral and cerebellar white matter, and to a lesser extent in the striatum. To our knowledge these cerebellar and vascular abnormalities have not been reported before in patients with "cerebral" lactic acidosis. The combination of these neuropathological findings might be characteristic for PDH deficiency and more specifically for its E1 alpha subtype. Neuropathological examination could lead to the retrospective diagnosis of PDH E1 alpha deficiency in those cases where biochemical investigations were not or incompletely performed. This may have potential implications for genetic counseling.

Acidosis, Lactic↗
PubMedDate not supplied

Isolated capillary proliferation in Leigh's syndrome.

An infant with hypotonia and recurrent apneic spells died with a diagnosis of pyruvate dehydrogenase deficiency and showed typical pathological changes of Leigh's syndrome at postmortem. Despite the prominence of symptoms suggesting dysfunction of brainstem respiratory centers during life, lesions were not found in the upper medulla. However, quantitative morphometric analysis demonstrated abnormal capillary hyperplasia in the region including and between the nucleus ambiguus and nucleus tractus solitarius. There was an average area of 8.0 +/- 2.5 x 10(6) mm2 occupied by capillaries per 0.75 mm2 field in the patient's brainstem, compared with 4.6 +/- 1.6 x 10(6) mm2 and 5.5 +/- 1.4 x 10(6) mm2 in two age-matched controls (p < 0.01). We speculate that capillary hyperplasia is a pathological marker of chronically impaired oxidative metabolism in the central nervous system in metabolic disease.

Brain↗
PubMed1988

In utero central nervous system damage in pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase deficiency is among the most common causes of congenital lactic acidosis. We describe siblings with congenital lactic acidosis due to a deficiency of pyruvate dehydrogenase complex. The findings of computed tomography and pathologic studies suggest that central nervous system damage had occurred in utero. These observations have implications for treatment and outcome in patients with enzymatic defects causing congenital lactic acidosis.

Brain↗
PubMed1994

Aberrant splicing of exon 6 in the pyruvate dehydrogenase-E1 alpha mRNA linked to a silent mutation in a large family with Leigh's encephalomyelopathy.

Pyruvate dehydrogenase (PDH)-E1 alpha deficiency has recently been studied at the molecular-genetic level. The gene is situated on the X chromosome. We report on an unusual mutation in a familial E1 alpha deficiency. In fibroblasts, PDH deficiency was diagnosed in a young infant presenting with Leigh's encephalomyelopathy and in a maternal nephew with episodes of "malaises." In the two affected children as well as their mothers we found a silent mutation in exon 6 of the PDH-E1 alpha and an aberrant splicing of exon 6 in some of the cDNA clones. This case emphasizes the need for both genomic and cDNA analysis in cases where a PDH-E1 alpha deficiency is strongly suspected.

Base Sequence↗
PubMed1991

Deficiency of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation.

Defects of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation are important causes of disease. Defects of pyruvate dehydrogenase may present in early childhood with severe CNS changes or, as lactic acidosis or later with ataxia. Defects of fatty acid oxidation may present with hypoglycaemic coma, myopathy, liver disease with encephalopathy, cardiomyopathy or sudden infant death. The investigation of both these groups of disorders is difficult and depends upon a combination of biochemical and molecular biology techniques.

Fatty Acids↗
PubMed1996

Leigh syndrome: clinical features and biochemical and DNA abnormalities.

We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, ie, 80% in the tightly defined group and 41% in the "Leigh-like" group. Eleven patients had mitochondrial DNA point mutations (nucleotide [nt] 8993 T to G, nt 8993 T to C, or nt 8344 A to G) and 1 Leigh-like patient had a heteroplasmic deletion. Twenty-nine patients had enzyme defects, ie, 13 respiratory chain complex I, 9 complex IV, and 7 pyruvate dehydrogenase complex (PDHC). Complex I deficiency is more common than recognized previously. Six PDHC-deficient patients had mutations in the X-chromosomal gene encoding the E1alpha subunit of PDHC. Parental consanguinity suggested autosomal recessive inheritance in two complex IV-deficient sibships. We found no strong correlation between the clinical features and basic defects. An assumption of autosomal recessive inheritance (frequently made in the past) would have been wrong in nearly one-half (11 of 28 tightly defined and 18 of 41 total patients) of those in whom a cause was found. A specific defect must be identified if reliable genetic counseling is to be provided.

Brain↗
PubMed1992

Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet.

A one-year-old boy suffering from intermittent lactic acidosis, muscular hypotonia, horizontal gaze paralysis and spasticity in both legs had low activity of the pyruvate dehydrogenase complex associated with low amounts of immunoreactive E 1 alpha and E 1 beta. Leigh syndrome was diagnosed on the basis of the clinical and biochemical abnormalities and the typical lesions observed on MRI of the brain. Treatment with a ketogenic diet was associated with clinical and biochemical amelioration. A striking improvement of the cerebral lesions was observed by neuro-imaging.

Brain↗
PubMed1982

Glutamate dehydrogenase deficiency in spinocerebellar degenerations.

Glutamate dehydrogenase (GDH) activity in leukocytes and platelets in spinocerebellar degenerations (SCD) was determined. In the same subject, GDH activity was higher and more reproducible in platelets than in leukocytes. GDH was decreased significantly in olivopontocerebellar atrophy (OPCA) (Ca. 30% decrease). Pyruvate dehydrogenase (PDH) in platelets showed non specific decreased activity in SCD and amyotropic lateral sclerosis. Energy metabolism in cerebellum may be diminished in some types of ataxia, and glutaminergic neurons may be more affected in OPCA than in other SCD.

Adult↗
PubMed1999

[Genetic counseling and prenatal diagnosis in mitochondrial diseases].

Since mitochondrial diseases lead frequently to severe phenotypes and are often hereditary, there is a need for genetic counselling of the affected families. The specific features of mitochondrial genetics, however, hamper straightforward definition of recurrence risks as in Mendelian diseases. Empirical risks were recently provided for MELAS and MERRF syndromes and for Leber hereditary optic neuropathy. In MELAS and MERFF, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome are in general sporadic disorders without increased recurrence risks in the offspring. As Leigh syndrome is found with maternal, autosomal recessive or X chromosomal transmission, the definition of the molecular defect is crucial for genetic counselling. Prenatal diagnosis was reported only in one case of mitochondrial disease so far, and in our opinion it remains questionable because of the uncertain correlation of the proportion of mutant DNA in chorionic villi and in clinically relevant tissues such as brain.

Adolescent↗
PubMed2002

Renal manifestations of congenital lactic acidosis.

Congenital lactic acidoses (CLAs) constitute a group of rare inborn errors of mitochondrial metabolism in which cellular energy failure is the defining biochemical abnormality. We report the principal manifestations of renal dysfunction in 35 children with CLA caused by defects in either the pyruvate dehydrogenase multienzyme complex or one or more components of the respiratory chain. The most prominent renal abnormalities included bicarbonaturia, phosphaturia, hypercalciuria, complete Fanconi's syndrome, proteinuria, and decreased glomerular filtration rate. These data were compared with those from 79 previously published cases. Clinical manifestations of renal dysfunction in CLA are common and may be the first presenting sign of the disease. The glomerulus and proximal renal tubule appear to be the anatomic sites most vulnerable to abnormal mitochondrial energy transduction. We propose that the primary defect in mitochondrial energy metabolism, together with the consequent intracellular accumulation of lactate and hydrogen ions, precipitates a state of tissue injury that, unless interrupted, becomes self-perpetuating and ultimately leads to renal cell death.

Acidosis, Lactic↗