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PubMed1984

Pyruvate dehydrogenase activity is not deficient in the brain of three autopsied cases with Leigh disease (subacute necrotizing encephalomyelopathy, SNE).

In autopsied brain tissue from three cases with Leigh disease (subacute necrotizing encephalomyelitis, SNE) and controls, the activity of pyruvate dehydrogenase complex (PDHC) was determined under different conditions. It was found to be at the control level or increased, but not deficient. The activities of succinate dehydrogenase, fumarase, succinate cytochrome c reductase, cytochrome c oxidase, and glutamate dehydrogenase were measured as additional mitochondrial markers and showed no essential differences between SNE and control tissue. The metabolic defect in SNE remains unknown. According to the literature, the defect may be localized to the mitochondrial systems. However, the reported results indicate that it cannot be ascribed to PDHC function. Extensive biochemical studies are necessary for understanding of the pathogenesis in the fatal genetic metabolic disease.

Adenosine Triphosphate↗
PubMed1994

Leigh syndrome: pyruvate dehydrogenase defect. A case with peripheral neuropathy.

Pyruvate dehydrogenase deficiency is one of the most common causes of encephalopathy associated with lactic acidosis and is known to account for congenital lactic acidosis, recurrent ataxia, and infantile Leigh syndrome. Hitherto, however, peripheral neuropathy has not been regarded as a presenting symptom of pyruvate dehydrogenase deficiency. Here, we report on a boy who presented peripheral neuropathy with severe limb hypotonia, absent deep-tendon reflexes, and reduced motor nerve conduction velocities at 8 months of age. Persistent hyperpyruvicemia with normal lactate/pyruvate molar ratios in plasma were highly suggestive of a pyruvate dehydrogenase deficiency, and the determination of pyruvate dehydrogenase activity in circulating lymphocytes led to the diagnosis of pyruvate decarboxylase (PDH-E1) deficiency in the proband. Based on this observation, we suggest that pyruvate dehydrogenase deficiency should be considered in the diagnosis of peripheral neuropathy in infancy, especially when associated with persistent hyperpyruvicemia, normal lactate/pyruvate molar ratios in plasma, and recurrent episodes of drowsiness and hypotonia of unknown origin.

Brain↗
PubMed1985

Thiamine-responsive inborn errors of metabolism.

Three different inherited disorders are known in which thiamine may exert a beneficial effect: maple syrup urine disease (MSUD), lactic acidaemia and the syndrome of megaloblastic anaemia with sensorineural deafness and diabetes mellitus. The amounts of thiamine which were used for long-term treatment varied from 20 to 2400 mg day-1. Additional treatment, such as the reduction of dietary branched chain amino acids in MSUD, could not be omitted in some cases. It has been shown that the vitamin improves the stability of the branched chain ketoacid decarboxylase, although some weeks may be needed to observe the in vivo effect of treatment. A prolonged trial with high doses of thiamine should always be given.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1984

Fluorescent analysis of alpha-keto acids in serum and urine by high-performance liquid chromatography.

A procedure for rapid separation and microquantitative determination of various alpha-keto acids in serum and urine was developed. The procedure used reverse-phase high-performance liquid chromatography of the alpha-keto acids after derivatization into fluorescent quinoxalines by reaction with o-phenylenediamine. Deproteinization of serum with tungstic acid or methanol facilitated a constant recovery of alpha-keto acids. The useful range of analysis of seven alpha-keto acids by isocratic chromatography was from 10 to 250 pmol. The fluorescence emission was measured at 410 nm with excitation at 350 nm. The data obtained from samples of patients with chronic pyruvic acidemia and maple syrup urine disease, confirmed the usefulness of the method in clinical applications. A slightly modified procedure was needed for the analysis of oxaloacetic acid and phenylpyruvic acid.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

[Diagnostic criteria in classical infantile subacute necrotizing encephalomyelopathy (Leigh's disease)].

Subacute necrotizing encephalomyelopathy (SNE; Leigh's disease), though a defined entity in neuropathological and morphological terms, is characterized by high clinical heterogenity. SNE of infancy can be defined and diagnosed on the basis of clinical symptoms more readily than juvenile and adult forms. Four patients with SNE displayed combinations of recurrent vomiting, difficulty in swallowing, failure to thrive, impairment of ocular innervation, muscle tone regulation and central regulation of respiration. These symptoms, particularly in combination, point to a disorder of the brainstem and basal ganglia. In addition, all four patients were suffering from lactic acidosis. Other possible indicators, but not in all 4 patients, were abnormal CT brain scans, impaired nerve conduction velocity, elevated CSF protein levels and enlarged mitochondria in muscle cells. Abnormal brainstem auditory evoked potentials have proved to be one of the best criteria for early diagnosis of brainstem lesions. Enzyme assays of pyruvate degradation in cultured skin fibroblasts revealed diminished activity of the pyruvate dehydrogenase complex in one patient (52 pmol/mg protein x min; median range 313, 82-917, n: 58). This paper summarizes the findings and proposes primary and secondary criteria of assistance in establishing an initial clinical diagnosis of infantile SNE. As no common pathogenetic mechanisms have yet been recognized and no uniform diagnostic markers are yet available, the diagnosis still requires confirmation by histological examination of brain and brainstem, as was the case with all four patients presented.

Brain↗
PubMed2000

Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency.

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease in children. Clinical symptoms can vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies result from mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1). The major factors that contribute to the clinical variation in E1alpha deficiency and its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X-inactivation in females. To date, 37 different missense/nonsense and 39 different insertion/deletion mutations have been identified in the E1alpha subunit gene of 130 patients (61 females and 69 males) from 123 unrelated families. Insertion/deletion mutations occur preferentially in exons 10 and 11, while missense/nonsense mutations are found in all exons. In males, the majority of missense/nonsense mutations are found in exons 3, 7, 8 and 11, and three recurrent mutations at codons R72, R263 and R378 account for half of these patients with missense/nonsense mutations (25 of 50). A significantly lower number of females is found with missense/nonsense mutations (25). However, 36 females out of 55 affected patients have insertion/deletion mutations. The total number of female and male patients is thus almost the same, although a difference in the distribution of the type of mutations is evident between both sexes. In many families, the parents of the affected patients were studied for the presence of the PDHA1 mutation. The mutation was never present in the somatic cells of the father; in 63 mothers studied, 16 were carriers (25%). In four families, the origin of the new mutation was determined to be twice paternal and twice maternal.

Amino Acid Sequence↗
PubMed1993

Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex.

Human PDH complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. In an investigation at the level of the gene into ten cases of PDH complex (E1) deficiency, we found that all had mutations in the coding sequence of the X-linked E1 alpha gene while the E1 beta coding sequence was normal. Six of these patients (three males, three females) had missense mutations resulting in a changed amino acid residue in the E1 alpha subunit at positions amino acid 148 (in two siblings), 170, 202, 234 and 263 of the mature protein. Two of the females had one normal E1 alpha gene and one with a deletion at the sites of tandem repeats of AGTAAGA and TAT respectively. The two remaining females also had one normal E1 alpha gene and one with an insertion. Both insertions, one of 2 bp and one of 4 bp, occurred in DNA hotspots normally associated with deletions. Only two of these ten mutations have been reported in other patients previously. In the five cases (including the two siblings) where parent DNA was available, only in one case could the same mutation be found in the patient as well as the maternal genomic DNA.

Amino Acid Sequence↗
PubMed1999

[Molecular basis of vitamin-responsive inborn errors of metabolism].

In inborn errors where the defective enzyme had a cofactor requirement it was found that the administration of large amounts of the vitamin resulted in a clinical and biochemical improvement. A mutation that imposes an exaggerated requirement for a vitamin affects the apoenzyme directly, the conversion of a vitamin into coenzyme, or the attachment of vitamin to the apoenzyme. Direct proof has so far been provided that molecular defects in the said gene underlie both the vitamin-responsive and vitamin-nonresponsive forms. HCS deficiency is an exception, all HCS-deficient patients being responsive to biotin administration. We examined the relationship between the kinetic characteristics of HCS mutants and the clinical and biochemical features of the HCS deficient patients.

Carbon-Nitrogen Ligases↗
PubMed1989

Metabolic myopathies: evaluation by graded exercise testing.

Exertional muscle pain and fatigue are common complaints; some patients with these symptoms have a metabolic myopathy. We have performed graded exercise testing with analysis of expired ventilation on 13 individuals with various kinds of metabolic myopathies. Their results differed from normal and reflected the underlying biochemical abnormality. Patients with disorders of the mitochondrial electron transport chain demonstrated marked limitations in aerobic metabolism and a greatly reduced maximum oxygen consumption. During intense exertion, normal individuals increase carbon dioxide generation due to buffering of lactic acid. This did not occur in patients with McArdle disease, in whom the respiratory exchange ratio (carbon dioxide production/oxygen consumption) did not rise above 1.0 at maximum exercise. These results indicated a deficit in anaerobic metabolism. Pyruvate dehydrogenase complex allows pyruvate produced from carbohydrate metabolism to enter the citric acid cycle. Patients with this enzyme deficiency showed an initially normal pattern followed by an abrupt cessation in carbohydrate dependent aerobic metabolism at higher work loads. During high-intensity exercise, progressive anaerobic metabolism was not accompanied by additional oxygen consumption. Finally, results from a patient with carnitine palmitoyl transferase deficiency revealed an early dependence on carbohydrate metabolism. The ventilatory threshold occurred at a low percentage of maximal oxygen consumption, reflecting the limited availability of lipid substrates for aerobic metabolism. Detection of some muscle metabolic abnormalities can be made on small biopsy specimens. However, definitive diagnosis of the defect nearly always requires studies on fresh or frozen muscle tissue obtained by an open biopsy. The decision on how the tissue should be processed and which metabolic studies should be performed frequently needs to be made before the biopsy is obtained. Thus, a noninvasive method to initially characterize patients with potential metabolic disorders is useful. Exercise testing with expired gas analysis can indicate the presence of a metabolic myopathy and results can then be used to direct the appropriate biochemical evaluations.

Adolescent↗
PubMed1990

MR findings in patients with subacute necrotizing encephalomyelopathy (Leigh syndrome): correlation with biochemical defect.

MR studies were correlated with biochemical results in nine children who presented with lactic acidosis and/or abnormal MR findings in the basal ganglia. Neurologic development was delayed in all nine children. Seven of these patients were diagnosed as having subacute necrotizing encephalomyelopathy (SNE, or Leigh syndrome) on the basis of history, clinical findings, and biochemical studies; of the remaining two, one had congenital lactic acidosis and the other had familial bilateral striatal necrosis with no known biochemical correlate. Although the clinical presentation of these patients was similar, we found distinctive MR abnormalities in characteristic locations in the seven patients with SNE, with or without detectable specific mitochondrial enzyme deficiency in cultured skin fibroblast assays. In our case studies of SNE patients with detectable enzyme deficiency states, defects in pyruvate dehydrogenase complex and cytochrome c oxidase have been found. The MR finding of note in SNE is the remarkably symmetrical involvement, most frequently of the putamen. In our study, lesions were also commonly found in the globus pallidus and the caudate nucleus, but never in the absence of putaminal abnormalities. Other areas of involvement included the paraventricular white matter, corpus callosum, substantia nigra, decussation of superior cerebellar peduncles, periaqueductal region, and brainstem. In patients who present with lactic acidosis and whose MR findings show symmetrical abnormalities in the brain, but with sparing of the putamen, the diagnosis of SNE is in doubt.

Acidosis, Lactic↗
PubMed1999

Adult leigh syndrome: treatment with intravenous soybean oil for acute central respiratory failure.

This study reports a 38-year-old woman with adult Leigh syndrome associated with partial deficiency of the pyruvate dehydrogenase complex. The patient had intermittent diplopia, loss of vision, dystonia, central respiratory failure and unconsciousness with lactic acidosis. Treatment with an intravenous ketogenic emulsion resulted in rapid clinical and biochemical improvement. In patients with acute respiratory failure under these circumstances, intravenous ketogenic emulsion therapy is worth consideration.

Acute Disease↗
PubMed1991

Characteristic changes on brain CT in a case of Leigh encephalopathy with deficiency of pyruvate dehydrogenase.

A girl aged 23 months of Leigh encephalopathy with pyruvate dehydrogenase complex (PDHC) deficiency was reported. Brain CT scan showed atrophy of the frontal and parietal cortex, low density in the midbrain and putamina, and rounded caudatum. CT change was showed from rounded to atrophic caudatum during a three-month period. The rounded caudatum may be an early CT finding in Leigh encephalopathy.

Brain↗