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1/35. Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.

    A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor. ( info)

2/35. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings.

    This paper describes the molecular characterization of two male siblings displaying the complex (Type B) form of pyruvate carboxylase (PC) deficiency in which severe neonatal lactic acidosis and redox abnormalities results in death within the first few weeks of life. The two male siblings were found to be compound heterozygous for a TAGG deletion at the exon15/intron15 splice site (IVS15 2-5delTAGG) and a dinucleotide deletion in exon 16 (2491-2492delGT) of the PC gene. We also demonstrate through RT-PCR and sequencing of aberrant transcripts that the IVS15 2-5delTAGG results in the retention of intron 15 during pre-mRNA splicing. In addition, both deletions are predicted to result in a frameshift to generate a premature termination codon such that the encoded mRNA could be subject to nonsense mediated decay. ( info)

3/35. pyruvate carboxylase deficiency--insights from liver transplantation.

    pyruvate carboxylase deficiency, complex form, presents in early infancy with lethal metabolic acidosis, resulting from ketoacidosis and lactic acidemia. Renal tubular acidosis, hyperammonemia, and citrullinemia complete the picture. In an infant with this disease, large amounts of glucose ameliorated the ketoacidosis, but worsened the lactic acidosis. Orthotopic hepatic transplantation completely reversed the ketoacidosis and the renal tubular abnormality and ameliorated the lactic acidemia. Concentrations of glutamine in cerebrospinal fluid were low and did not improve with liver transplantation. ( info)

4/35. pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy.

    A six-day-old girl was referred for severe hepatic failure, dehydratation, axial hypotonia, and both lactic acidosis and ketoacidosis. biotin-unresponsive pyruvate carboxylase deficiency type B was diagnosed. Triheptanoin, an odd-carbon triglyceride, was administrated as a source for acetyl-CoA and anaplerotic propionyl-CoA. Although this patient succumbed to a severe infection, during the six months interval of her anaplerotic and biochemical management, the following important observations were documented: (1) the immediate reversal (less than 48 h) of major hepatic failure with full correction of all biochemical abnormalities, (2) on citrate supplementation, the enhanced export from the liver of triheptanoin's metabolites, namely 5 carbon ketone bodies, increasing the availability of these anaplerotic substrates for peripheral organs, (3) the demonstration of the transport of C5 ketone bodies-representing alternative energetic fuel for the brain-across the blood-brain barrier, associated to increased levels of glutamine and free gamma-aminobutyric acid (f-GABA) in the cerebrospinal fluid. Considering that pyruvate carboxylase is a key enzyme for anaplerosis, besides the new perspectives brought by anaplerotic therapies in those rare pyruvate carboxylase deficiencies, this therapeutic trial also emphasizes the possible extended indications of triheptanoin in various diseases where the citric acid cycle is impaired. ( info)

5/35. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation.

    pyruvate carboxylase (PC) is a key enzyme for gluconeogenesis and anaplerotic pathways in brain. PC deficiency is a rare autosomal recessive neurometabolic disorder with three described characteristic presentations. We report a patient with atypical clinical and neuroradiological aspects. He survived from neonatal lactic acidemia and is alive at 9 years of age with a mild developmental delay. A brain MRI performed by the age of 18 months disclosed an unusual subcortical leucodystrophic process. ( info)

6/35. pyruvate carboxylase deficiency: a benign variant with normal development.

    The devastating nature of a pyruvate carboxylase deficiency is underscored by the uniformly fatal outcome of the neonatal (French) type and the severely disabling and ultimately fatal outcome of the infantile (North American) type. We report a 7-y-old girl with metabolic and biochemical features of the North American phenotype. Remarkably, the clinical course has been benign with preservations of motor and mental abilities. The residual enzyme activity in cultured skin fibroblast homogenates was 1.8% and cross-reacting material was present in normal abundance and electrophoretic mobility. She has had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, and undetectably low aspartate concentrations. These crises have been managed by rehydration and bicarbonate therapy. We are unable to provide a satisfactory explanation for the uniquely benign clinical course that has been experienced by this patient. ( info)

7/35. Congenital lactic acidosis due to pyruvate carboxylase deficiency: absence of an inhibitor of TPP-ATP phosphoryl transferase.

    Two children are described who suffered from episodes of metabolic acidosis and progressive mental and motor deterioration. The patients showed periodic elevation of blood lactate, pyruvate and alanine, which was accompanied by vomiting, hypotonia or convulsions. The concentrations of lactate and pyruvate in cerebrospinal fluid were found to be increased. Liver biopsies revealed a decrease in pyruvate carboxylase activity and normal pyruvate decarboxylase activity. No inhibitor of TPP-ATP phosphoryl transferase was detected in urine from the patients. These findings suggest that congenital lactic acidosis due to pyruvate carboxylase deficiency is probably a different disease entity from Leigh's encephalomyelopathy. A possible mechanism of brain damage caused by a defect in pyruvate carboxylase is postulated. ( info)

8/35. pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.

    A child with lactic acidosis, severe mental and developmental retardation, and proximal renal tubular acidosis is presented. biopsy and autopsy studies show severe hepatic, renal cortical, and cerebral deficiencies in pyruvate carboxylase (EC activity. The patient had 1.81 /- 0.20 units/g fresh weight at biopsy and 0.75 /- 0.07 units/g fresh weight hepatic pyruvate carboxylase activity at autopsy compared with 10.9, 11.3, and 9.5 units/g fresh weight in two autopsy and one biopsy controls, respectively. The patient's renal cortical pyruvate carboxylase activity at autopsy was 0.008 /- 0.004 units/g fresh weight compared with 5.05 units/g in the autopsy control. The patient had no detectable (less than 0.018 units/g fresh weight) cerebral pyruvate carboxylase activity at autopsy compared with 0.44, 0.53, and 0.695 units/g in the autopsy cerebrum of one human and two rhesus monkeys, respectively. pyruvate dehydrogenase complex, phosphoenolpyruvate carboxykinase (PEPCK, EC, and fructose-1,6-bisphosphatase (EC activities were in the normal range. The patient's urine pH was above 7.9 when the total serum CO2 was greater than 7.8 mM. However, the patient was able to acidify the urine to pH 5.1 when the total serum CO2 was 1.6 mM. The neuropathologic examination of the brain at autopsy revealed no sign of Leigh's disease, although developmental and degenerative lesions were observed. This is the first reported patient with a primary deficiency in hepatic, renal, and cerebral pyruvate carboxylase deficiency in whom the neuropathologic lesions, distinct from those of Leigh's disease, and proximal renal tubular acidosis have both been documented. ( info)

9/35. pyruvate carboxylase deficiency: acute exacerbation after ACTH treatment of infantile spasms.

    pyruvate carboxylase deficiency results in congenital lactic acidosis. We report the significant finding in a child with infantile spasms controlled with adrenocorticotrophin hormone (ACTH) but who then developed severe lactic acidosis; pyruvate carboxylase deficiency was subsequently diagnosed. Blood lactate, pyruvate, and alanine levels were elevated, as well as cerebrospinal fluid alanine. plasma alanine concentration was doubled by ACTH therapy. fibroblasts contained extremely low pyruvate carboxylase activity. The patient died at 12 weeks of age after recurrent episodes of profound acidosis. At autopsy, the brain manifested cystic degeneration and demyelination. pyruvate carboxylase deficiency is associated with neonatal onset of acidosis, delayed development, seizures, hypotonia, recurrent profound acidosis, and early death. The dramatic rise in plasma alanine content coincident with ACTH therapy suggest that ACTH played a role in precipitating the catastrophic metabolic acidosis. ( info)

10/35. Biochemical and histologic pathology in an infant with cross-reacting material (negative) pyruvate carboxylase deficiency.

    An infant with the acute neonatal form of pyruvate carboxylase deficiency (cross-reacting material negative) presented with severe intractable lactic acidosis within 4 h after birth. He also had hyperammonemia, hypercitrullinemia, and hyperlysinemia. plasma glutamine was not elevated. He had a rapidly deteriorating clinical course with severe liver dysfunction, repeated septicemia and seizures; he was comatose and was on a ventilator throughout; death occurred at 8 wk of age. skin fibroblast study confirmed the enzyme deficiency. Detailed biochemical parameters and histopathology of the brain and liver are presented. The evidence from this infant suggests that disturbances of intracellular oxaloacetate levels as a result of the primary enzyme defect might also contribute to deficiency in ATP generation which may explain the various other biochemical changes and liver pathology. ( info)
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