ATAXIA WITH LACTIC ACIDOSIS II
PC DEFICIENCY
leigh syndrome due to pyruvate carboxylase deficiency
Leigh syndrome due to PC deficiency
leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency
Ataxia with lactic acidosis type II
Ataxia with lactic acidosis type 2
Tsuchiyama et al. (1983) reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the ... - Prenatal Diagnosis Tsuchiyama et al. (1983) reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the cultured amniotic fluid cells obtained by amniocentesis were within normal limits. In a family at risk for PC deficiency, Robinson et al. (1985) confirmed the diagnosis in a fetus by enzyme assay and (3)H-biotin labeling of proteins in cultured fetal skin fibroblasts.
PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with ... PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. Patients in group B have decreased survival compared to group A, and usually do not survive beyond 3 months of age (Robinson et al., 1987). Group C is relatively benign. - North American Phenotype ('Group A') Tada et al. (1969) reported a family in which 2 sisters were presumably affected with the same physical and mental retardation. The proband had elevated serum alanine and pyruvate, normal SGPT and liver pyruvate decarboxylase (300502) activities, but decreased activity of pyruvate carboxylase. Hyperalaninemia was likely secondary to the increased level of pyruvate. Delvin et al. (1972) noted that 2 forms of pyruvate carboxylase exist in liver, one with a high Km and the other with a low Km for pyruvate. They reported a patient with abnormality of gluconeogenesis and elevated plasma levels of pyruvate, lactate, and alanine in which the low Km enzyme was deficient. Atkin et al. (1979) reported a child with lactic acidosis, severe mental and developmental retardation, and proximal renal acidosis. Laboratory studies showed severe hepatic, renal cortical, and cerebral deficiencies of pyruvate carboxylase activity. Postmortem neuropathologic examination revealed no signs of Leigh syndrome (256000), but developmental and degenerative lesions were observed. Oizumi et al. (1983) reported a patient with PC deficiency associated with renal tubular acidosis and cystinuria. Haworth et al. (1981) reported 2 unrelated Canadian Indian infants with PC deficiency. Both presented in infancy with metabolic acidosis. Laboratory findings included increased plasma lactate, pyruvate, glutamic acid, proline, and alanine, and low PC activity in skin fibroblasts and liver. Both survived until at least 2 years of age with severe mental retardation. Gilbert et al. (1983) reported a case of Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency. Carbone et al. (1998) studied 11 males and 6 females from several Canadian Indian populations. Presentation was at birth in 7, and 1 to 8.5 months in 10. Presenting signs included metabolic acidosis in 10, seizures in 5, respiratory distress in 4, pneumonia in 3, and hypotonia in 3. The clinical course was characterized by frequent lactic acidosis, severe developmental delay, and muscular hypotonia in 17, seizures in 8, hypoglycemia in 4, and other CNS involvement (clonus or athetosis) in 4. Eleven patients died between ages 3 months and 4.75 years; 6 were surviving at ages ranging from 3 months to 19 years. - 'French form' ('Group B') The second form of PC deficiency, reported particularly from France, presents early with lactic acidosis, but also shows elevated blood levels of ammonia, citrulline, proline, and lysine. In addition, there is an intracellular redox disturbance, with increased lactate/pyruvate and acetoacetate/beta-hydroxybutyrate ratios. Saudubray et al. (1976) reported 2 familial cases of neonatal congenital lactic acidosis with liver PC deficiency. Disease onset was immediately after birth, characterized by major neurologic symptoms, hyperammonemia, and hyperketonemia. Hyperlactic acidemia was associated with an increased lactate/pyruvate ratio and an increased acetoacetate/beta-hydroxybutyrate ratio. The authors suggested that the unusual metabolic pattern resulted from decreased oxaloacetate synthesis resulting from PC deficiency and impaired oxaloacetate-dependent mitochondrial redox shuttles. The disease course was rapidly fatal. Coude et al. (1981) and Bartlett et al. (1984) also reported patients with the group B type of PC deficiency. Robinson et al. (1984) reported 8 patients from 7 families from Canada with pyruvate carboxylase deficiency. Five were of full Amerindian descent, 2 were unrelated Caucasians, and 1 was the offspring of related Egyptian parents. All presented from soon after birth to age 5 months with chronic metabolic acidosis, and 4 had at least 1 episode of hypoglycemia. Six patients died by age 2 years (range 10 days to 2 years), and the 2 living patients were mentally and physically retarded. Using (3)H-biotin labeling and (35)S-streptavidin to detect biotin-containing proteins, and immunodetection with PC antibodies, Robinson et al. (1984) distinguished 2 groups of patients: group 'A' synthesized PC subunits with a normal molecular mass and recognized by antibodies against PC, but showed very little enzymatic activity, (termed CRM(+ve) or type I), whereas group 'B' had no detectable PC subunits and no protein recognized by the antibody (termed CRM(-ve), or type II). The 2 patients with CRM(-ve) results, the Egyptian patient and 1 of the Caucasian patients, had additional biochemical features, including hyperammonemia, citrullinemia, lysinemia, and altered redox states (in 1 patient) similar to the features of patients reported in France. These 2 patients also died early (10 days and 7 weeks) and had hepatomegaly due to excessive fat storage. Robinson et al. (1984) concluded that the 2 subtle types of PC deficiency result from 2 different mutations in the PC gene, 1 that synthesizes an inactive protein and 1 that results in lack of protein expression. In a follow-up study of cultured skin fibroblasts from 16 patients with either French or American PC deficiency, Robinson et al. (1987) confirmed that the North American cases are associated with the presence of a mature biotin-containing protein of the correct molecular weight. Three families with the French presentation had absence of immunoreactive PC protein and PC mRNA; however, another 3 families with the French presentation had evidence of protein production as well as PC mRNA. Robinson et al. (1987) concluded that when a PC enzyme is produced in French cases, it has no activity. Pineda et al. (1995) reported an infant with what they termed the 'French' type of pyruvate carboxylase deficiency, with somewhat less severity. The initial neonatal symptoms were respiratory distress, severe metabolic acidosis, and a tendency to hypoglycemia. At age 6 months, he presented with acute neurologic symptoms, lactic acidosis, and hyperammonemia, and died of pneumonia, cardiac failure, and renal insufficiency. Pyruvate carboxylase deficiency was confirmed by enzymatic studies. Postmortem analysis showed periventricular cysts and diffuse hypomyelination. Brun et al. (1999) reported brother and sister with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was less than 2% of control. The lesions were detected at a time of maximal periventricular metabolic demand. Brun et al. (1999) postulated that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. The authors noted that discovery of cystic periventricular leukomalacia on cerebral ultrasound at birth in a newborn presenting with primary lactic acidemia is highly suggestive of PC deficiency. - 'Benign' type ('Group C') Van Coster et al. (1991) reported a 7-year-old girl with metabolic and biochemical features of the North American type of PC deficiency who had a benign disease course with preservation of motor and mental abilities. She had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, which were well-managed by rehydration and bicarbonate therapy. PC activity was 1.8% of normal, and she was CRM(+ve). The authors commented on the unique phenotypic expression in this patient. Schiff et al. (2006) reported a patient with atypical PC deficiency and long survival. He presented at 3 days of age with acute ketoacidosis, tachypnea, and hypotonia. Laboratory studies showed lactacidemia with normal plasma amino acids and ammonia. After successful treatment, he was discharged with an increased lactate-to-pyruvate ratio and avoidance of fasting was advised. During the first 2 years of life, he had mild psychomotor delay and failure to thrive with intermittent acute decompensation. PC activity in cultured skin fibroblasts was severely decreased, leading to the correct diagnosis. Brain MRI at age 18 months showed bilateral high signal intensities in frontoparietal subcortical white matter. At the time of the report, he was 9 years old and showed mild and global psychomotor delay with dysarthria and dysgraphia. Treatment included biotin, L-carnitine, sodium bicarbonate, sodium citrate, and avoidance of fasting. Schiff et al. (2006) noted that relatively long survival into childhood is not a frequent finding for this usually very severe disease.
In 5 patients with PC, Monnot et al. (2009) noted that type B was consistently associated with at least 1 truncating mutation, whereas type A always resulted from 2 missense mutations.
In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). Two brothers of Micmac origin had a transversion mutation in the PC ... In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). Two brothers of Micmac origin had a transversion mutation in the PC gene (608786.0002). Carrier frequency was estimated to be as high as 1 in 10 in some groupings. In 2 brothers with type B PC deficiency, Carbone et al. (2002) identified compound heterozygosity for 2 mutations in the PC gene (608786.0005; 608786.0006). Monnot et al. (2009) identified 9 novel mutations in the PC gene (see, e.g., 608786.0007-608786.0009) in 5 unrelated patients with PC deficiency: 3 had the more severe type B PC, and 2 had type A. PC activity in cultured fibroblasts was undetectable in all patients. Three mutations were frameshift, predicted to introduce a premature termination codon, 1 was an in-frame deletion, and 5 were missense substitutions. Although most PC mutations were suggested to interfere with biotin metabolism, none of the patients was biotin-responsive.
Carbone et al. (1998) noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a ... Carbone et al. (1998) noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a founder group in southern Ontario approximately 300 B.C. It had been suggested that there could be one or more disease-causing mutations in the PC gene that are unique to the 'Algonkian-speaking peoples' of North America.
Pyruvate carboxylase (PC) deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. ...
DiagnosisClinical Diagnosis Pyruvate carboxylase (PC) deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. The three clinical presentations of PC deficiency:Type A: infantile or North American formType B: severe neonatal or French formType C: intermittent/benign formTestingBiochemical testing − abnormalities by PC deficiency typeType A. Infantile-onset mild to moderate lactic acidemia; normal lactate-to-pyruvate ratio despite acidemia [Robinson 2000, Wang et al 2008] Type B. Increased lactate-to-pyruvate ratio; increased acetoacetate to 3-hydroxybutyrate ratio; elevated blood concentrations of citrulline, proline, lysine, and ammonia; low concentration of glutamine [Nelson et al 2000, García-Cazorla et al 2006, Wang et al 2008]Type C. Episodic metabolic acidosis with normal citrulline plasma concentrations and elevated lysine and proline plasma concentrations [Wang et al 2008] Abnormalities by analyteNote: For each of the following analytes the abnormal values overlap among types A, B, and C. Normal values differ by laboratory.Lactate and pyruvate. The lack of PC enzyme activity causes the accumulation of pyruvate in the plasma, which is subsequently converted into lactate by the enzyme lactate dehydrogenase, causing an elevated plasma concentration of lactic acid. Elevated blood lactate concentrations (5.5-27.8 mmol/L; normal range 0.5-2.2) are characteristically found in PC deficiency type A (2-10 mmol/L), type B (>10 mmol/L), and type C (2-5 mmol/L). Blood pyruvate concentrations are usually elevated in PC deficiency type B (0.14-0.90 mmol/L; normal range 0.04-0.13), resulting in an elevated lactate-to-pyruvate ratio (>20). The ratio is usually normal in PC deficiency type A and C (<20). Amino acids. In serum and urine: high alanine, citrulline, and lysine; low aspartic acid and glutamine. Amino acid concentrations vary with the general metabolic state of the individual. Hyperalaninemia as a result of pyruvate shunting Hypercitrullinemia and hyperlysinemia caused by the block in the urea cycle secondary to a low aspartic acid Low aspartic acid and glutamine as a result of deficiency in the oxaloacetate precursor Ketonemia. 3-hydroxybutyrate and acetoacetate concentrations are increased in blood. In PC deficiency type B, the ratio of acetoacetate to 3-hydroxybutyrate is increased, reflecting a low NADH-to-NAD ratio inside the mitochondria. Lack of oxaloacetate prevents the liver from oxidizing acetyl-CoA derived from pyruvate and fatty acids. The expanded acetyl-CoA pool results in hepatic ketone body synthesis [De Vivo et al 1977]. Hypoglycemia. Oxaloacetate deficiency limits gluconeogenesis. Note: Hypoglycemia is not a consistent finding despite the fact that PC is the first rate-limiting step in gluconeogenesis.Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.Cerebrospinal fluid (CSF) Elevated lactate and pyruvate concentrations Markedly reduced glutamine concentrationElevated glutamic acid and proline concentrations PC enzyme assay. In PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls [Wang et al 2008]. Similar abnormalities are noted in lymphoblasts. Muscle PC activity is quite low in control tissue.Molecular Genetic Testing Gene. PC is the only gene in which mutations are known to cause PC deficiency. Clinical testingSequence analysis of PC promoters and coding region detects mutations in 95% of affected individuals including the most common PC mutations (p.Ala610Thr, p.Arg631Gln, and p.Ala847Val).Deletion/duplication analysis. The usefulness of deletion/duplication testing has not been demonstrated, as no deletions or duplications of PC have been reported to cause pyruvate carboxylase deficiency.Table 1. Summary of Molecular Genetic Testing Used in Pyruvate Carboxylase DeficiencyView in own windowGene SymbolTest MethodMutations Detected 1Mutation Detection Frequency by Test Method 2Test AvailabilityPCSequence analysisSequence variants 395%Clinical Deletion/ duplication analysis 4Deletion/ duplication of one or more exons or the whole gene 5Unknown1. The presence of mosaicism may complicate molecular testing; see Genotype Phenotype Correlations, Table 2, and Wang et al [2008]. 2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. No deletions or duplications involving PC have been reported to cause pyruvate carboxylase deficiency. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. The diagnosis of PC deficiency rests on the following: Detection of characteristic abnormalities in serum concentrations of amino acids, organic acids, glucose, and ammonia Deficiency of PC enzyme activity assayed in fibroblasts and other tissues Identification of PC mutations by sequence analysisCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in PC.
Most individuals with pyruvate carboxylase (PC) deficiency present with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Hypoglycemia is an inconsistent finding. ...
Natural History Most individuals with pyruvate carboxylase (PC) deficiency present with failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Hypoglycemia is an inconsistent finding. Three types of PC deficiency have been recognized, based on clinical presentation.Type A (infantile form) is characterized by infantile onset with mild metabolic acidosis, delayed motor development, intellectual disability, failure to thrive, apathy, hypotonia, pyramidal tract signs, ataxia, nystagmus, and convulsions. Episodes of acute vomiting, tachypnea, and acidosis are usually precipitated by metabolic or infectious stress. Most affected children die in infancy or early childhood, although some may survive to maturity. Older individuals function at a lower-than-average level and need special care and schooling [Carbone et al 1998, Wang et al 2008].Type B (severe neonatal form) was first described in France by Saudubray et al [1976]. Affected infants present with biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (including high-amplitude tremor and dyskinesia), and bizarre ocular behavior.Motor development is severely retarded and affected individuals have intellectual disability [García-Cazorla et al 2006, Wang et al 2008]. Although the majority of affected infants die within the first three months of life [García-Cazorla et al 2006], two are alive at ages nine and 20 years, likely because of mosaicism [Wang et al 2008] (see Genotype-Phenotype Correlations).Type C (intermittent/benign form) is characterized by normal or mildly delayed neurologic development and episodic metabolic acidosis. Five affected individuals have been reported [Van Coster et al 1991, Stern et al 1995, Vaquerizo Madrid et al 1997, Arnold et al 2001, Wang et al 2008]. The first individual described had normal mental and motor development at age 12 years despite several earlier episodes of metabolic acidosis [Van Coster et al 1991]. Brain MRI. Symmetric cystic lesions and gliosis in the cortex, basal ganglia, brain stem, or cerebellum; generalized hypomyelination; and hyperintensity of the subcortical fronto-parietal white matter were described in some individuals with type A. Ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts have been reported in some individuals with type B [García-Cazorla et al 2006]. Magnetic resonance spectroscopy (MRS). Brain MRS shows high levels for lactate and choline, and low levels for N-acetylaspartate.Pathophysiology. The glutamine-glutamate cycle in astrocytes requires a continuous supply of oxaloacetate provided by the reaction catalyzed by PC enzyme activity.
Type A. Seven mutations (p.Arg62Cys, p.Arg631Gln, p.Ala847Val, p.Val145Ala, p.Arg451Cys, p.Ala610Thr, and p.Met743Ile) have been identified in five individuals [Wang et al 2008]. ...
Genotype-Phenotype Correlations Type A. Seven mutations (p.Arg62Cys, p.Arg631Gln, p.Ala847Val, p.Val145Ala, p.Arg451Cys, p.Ala610Thr, and p.Met743Ile) have been identified in five individuals [Wang et al 2008]. Type B. Complex missense mutations, deletions, and splice donor site mutations occur in homozygotes, compound heterozygotes, and individuals with mosaicism (see Table 2) [Wang et al 2008]. Type C. A heterozygous mutation (p.Ser266Ala) and somatic mosaic mutation (p.Ser705X) were observed in the first individual described [Wang et al 2008], and compound heterozygosity for the mutations p.Thr569Ala and Leu1137Valfs*1170 was observed in the second individual described [Wang et al 2008]. Mosaicism was found in five individuals [Wang et al 2008, Table 3 (type A: #6; type B: #2, #5, and #7; type C: #1)]. Four had prolonged survival; the fifth (type B: #7) died from unrelated medical complications. Homozygous mutations. The deaths of the more severely affected individuals with type B correlated with homozygous mutations, which produced very low amounts (2% and 3%) of fibroblast PC protein [Wang et al 2008, Table 3].
Biotinidase deficiency results from the inability to recycle endogenous biotin and to use protein-bound biotin from the diet. Biotin binds to propionyl-coenzyme A-carboxylase, pyruvate carboxylase (PC), beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase. Deficiency affects all biotinylated enzymes and can present in the neonatal period or later in infancy with neurologic symptoms such as lethargy, seizures with metabolic acidosis, hearing loss, alopecia, and perioral/facial dermatitis. It can be effectively treated with biotin. ...
Differential DiagnosisBiotinidase deficiency results from the inability to recycle endogenous biotin and to use protein-bound biotin from the diet. Biotin binds to propionyl-coenzyme A-carboxylase, pyruvate carboxylase (PC), beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase. Deficiency affects all biotinylated enzymes and can present in the neonatal period or later in infancy with neurologic symptoms such as lethargy, seizures with metabolic acidosis, hearing loss, alopecia, and perioral/facial dermatitis. It can be effectively treated with biotin. In the untreated state, profound biotinidase deficiency during infancy is usually characterized by neurologic and cutaneous findings that include seizures, hypotonia, and rash, often accompanied by hyperventilation, laryngeal stridor, and apnea. Older children may also have alopecia, ataxia, developmental delay, sensorineural hearing loss, optic atrophy, and recurrent infections. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress. Biotinidase deficiency is caused by mutations in BTD. Individuals with profound biotinidase deficiency have lower than 10% of mean normal serum biotinidase activity; individuals with partial biotinidase deficiency have 10%-30% of mean normal serum biotinidase activity. Biotinidase deficiency is inherited in an autosomal recessive manner. Pyruvate dehydrogenase complex (PDHC) deficiency results from deficiency of either one of three catalytic components (E1, E2, and E3) or the regulatory component of PDHC (pyruvate dehydrogenase phosphate phosphatase). The diagnosis of PDHC deficiency is suspected in individuals with lactic acidemia who have a progressive or intermittent neurologic syndrome including: poor acquisition or loss of motor milestones, poor muscle tone, new onset seizures, periods of incoordination (i.e., ataxia), abnormal eye movements, poor response to visual stimuli, and episodic dystonia. Blood and CSF lactate concentrations are elevated and are associated with elevations of blood and CSF concentrations of pyruvate and alanine. Unlike PC deficiency, PDH deficiency usually presents with a normal lactate-to-pyruvate ratio in plasma. Typically, the CSF lactate elevations are higher than those in the blood, giving rise to the term “cerebral lactic acidosis.” Brain MRI may show varying combinations of ventricular dilatation; cerebral atrophy; hydrocephaly; partial or complete absence of the corpus callosum; absence of the medullary pyramids; abnormal and ectopic inferior olives; symmetric cystic lesions; gliosis in the cortex, basal ganglia, brain stem, or cerebellum; or generalized hypomyelination. Brain MRS shows:High lactate concentrations, giving rise to the term “cerebral lactic acidosis”N-acetylaspartate and choline concentrations consistent with hypomyelinationPDHC enzyme activity assay, immunoblotting analysis, and sequence analysis of two of the genes known to be associated with this disorder (PDHA1 [pyruvate dehydrogenase E1 deficiency] and DLAT [pyruvate dehydrogenase E2 deficiency]) can help make the diagnosis [DiMauro & De Vivo 1999]. Most pathogenic mutations involve the X-linked gene PDHA1, which encodes the E1 alpha subunit.Respiratory chain disorder may result from mutations in nuclear genes or mitochondrial genes that encode any one of the five enzyme complexes. Lactate and pyruvate concentrations are elevated, and the lactate/pyruvate ratio is elevated, often above 20. Biopsied skeletal muscle may reveal ragged-red fibers, cytochrome c-oxidase negative fibers, and succinate dehydrogenase intensely positive fibers. These histologic abnormalities are commonly seen with nuclear DNA mutations causing intergenomic signaling defects and mitochondrial DNA mutations affecting protein synthesis genes. Brain MRI may reveal distinctive abnormalities, as described with Leigh disease or mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [DiMauro & Schon 2007]. Nuclear gene mutations are inherited in an autosomal recessive or dominant manner; mitochondrial DNA mutations are inherited as maternal, non-Mendelian traits.Krebs cycle disorders are rare and the enzymyopathies are partial. Lactate and pyruvate concentrations are elevated and the lactate/pyruvate ratio is normal. Urine organic acid profile may reveal distinctive elevation of fumaric acid or other Krebs cycle intermediates, reflecting the site of the enzyme deficiency (see Organic Acidemias).Gluconeogenic defects may be aggravated clinically by fasting. Blood lactate, pyruvate, and alanine concentrations are classically elevated with clinical symptoms, and blood glucose concentration is low, indicating glycogen depletion and gluconeogenic pathway block. Ketone bodies are elevated, reflecting a physiologic response to fasting, stress, and hypoglycemia.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).PC deficiency type A (infantile form)PC deficiency type B (severe neonatal form)PC deficiency type C (intermittent/benign form)
To establish the extent of disease in an individual diagnosed with pyruvate carboxylase (PC) deficiency, the following are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with pyruvate carboxylase (PC) deficiency, the following are recommended:Blood, urine, and CSF measures of organic and amino acids; brain MRI and MRS analysis Evaluation by a pediatric neurologist skilled in metabolic and genetic disorders to confirm the diagnosis, guide the treatment, and determine the prognosis Genetic counseling for the parents regarding the risk of recurrence in future pregnanciesTreatment of ManifestationsTreatment focuses on providing alternative energy sources, hydration, and correction of the metabolic acidosis during acute decompensation. Stimulating residual PC enzyme activity is an important goal for long-term stable metabolic status. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment [DiMauro & De Vivo 1999].“Anaplerotic therapy” is based on the concept that an energy deficit in these diseases could be improved by providing alternative substrate for both the citric acid cycle and the electron transport chain for enhanced ATP production [Roe & Mochel 2006].Citrate supplementation reduces the acidosis and provides substrate for the citric acid cycle [Ahmad et al 1999]. Aspartic acid supplementation allows the urea cycle to proceed and reduces the plasma and urine ammonia concentrations but has no effect on the neurologic disturbances as the aspartate does not enter the brain freely [Ahmad et al 1999].Biotin supplementation is given to help optimize the residual PC enzyme activity but is usually of little use. Triheptanoin, an odd-carbon triglyceride, providing a source for acetyl-CoA and anaplerotic propionyl-CoA, has been tried in one individual with biotin-unresponsive PC deficiency type B with immediate reversal (<48 h) of major hepatic failure and full correction of all biochemical abnormalities [Mochel et al 2005]. Triheptanoin provides C5-ketone bodies that can cross the blood-brain barrier, therefore providing substrates for the brain. Dietary intervention with triheptanoin is the only therapeutic approach that showed improvement of brain metabolism. However, this observation needs to be confirmed in additional patients. Orthotopic liver transplantation has reversed the biochemical abnormalities in two patients [Nyhan et al 2002].Prevention of Primary ManifestationsEducate parents about the factors that elicit a crisis and the early signs of decompensation.Carry an informational statement regarding the child's disorder and the appropriate treatment in an emergency setting.Minimize intercurrent infections as environmental stressors.SurveillanceMonitor lactate levels regularly. Agents/Circumstances to AvoidAvoid the following:Fasting The ketogenic diet, which precipitates life-threatening metabolic acidosis Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementPregnancy in a woman with PC deficiency has not been reported. However, women with the benign form (Type C) could become pregnant; such a pregnancy should be closely monitored for any metabolic derangements including dehydration and acidosis. Therapies Under InvestigationThiamine and lipoic acid could optimize PDHC activity, which could help reduce the plasma and urine pyruvate and lactate concentrations through an alternate route of pyruvate metabolism. Theoretically, this intervention could increase the acetyl-CoA pool and worsen the ketonemia.Thiamine was tried in an individual with PC deficiency who was found to be responsive. Two sisters with PC deficiency, severe intellectual disability and motor retardation, and Leigh syndrome improved clinically and biochemically after treatment with thiamine and lipoic acid. The precise molecular diagnosis in these cases is uncertain.Based on reports from the literature [Nyhan et al 2002, Mochel et al 2005], it has been suggested that a combination of orthotopic liver transplantation and anaplerotic diet be used in order to obtain both (i) long-term metabolic stability and (ii) improvement/correction of brain energy metabolism, myelination, and neurotransmission.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Pyruvate Carboxylase Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPC11q13.2Pyruvate carboxylase, mitochondrialPC homepage - Mendelian genesPCData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Pyruvate Carboxylase Deficiency (View All in OMIM) View in own window 266150PYRUVATE CARBOXYLASE DEFICIENCY 608786PYRUVATE CARBOXYLASE; PCMolecular Genetic Pathogenesis Pyruvate carboxylase (PC) [EC 6.4.1.1] is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways. PC catalyzes the conversion of pyruvate to oxaloacetate (Figure 1). FigureFigure 1. Diagrammatic representation of metabolic pathway affected by PC deficiency. The PC enzyme is indicated by the red oval; the dotted arrow lines represent absent pathways. Normal allelic variants. Many normal allelic variants have been reported. Most are in the untranslated regions (UTR) and introns. Three normal allelic variants are in the coding region (see Table 2). PC contains 20 coding exons and four non-coding exons at the 5’-UTR [Wang et al 2008]. All four non-coding exons are involved in alternative splicing, resulting in three tissue-specific PC transcripts carrying the same coding region: variant 1 (4004bp, NM_000920.3), variant 2 (3959 bp, NM_022172.2), and variant 3 (4192bp, NM_001040716.1) (Figure 2). Southern blotting of human genomic DNA showed that PC exists in a single copy and no pseudogenes are detected. FigureFigure 2. PC structure and three transcript variants. The coding exons of PC are represented by rectangles with different symbols and Arabic numbers on the top. The four untranslated exons (UEs) are labeled UE1-UE4 (top left). The arrows before UE1, UE2, (more...)Pathologic allelic variantsTable 2. Selected PC Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change (Alias 1)Reference SequencesNormalc.2286C>Gp.= 2(Arg762Arg)NM_000920.3 NP_000911.2c.2619C>Tp.= 2(Asn873Asn)c.2874G>Tp.= 2(Gly958Gly)c.227A>Tp.His76Leu 3c.1054G>Tp.Ala352Ser 3Pathologicc.184C>Tp.Arg62Cysc.796T>Ap.Ser266Alac.434T>Cp.Val145Alac.1351C>Tp.Arg451Cysc.1705A>Gp.Thr569Alac.1828G>Ap.Ala610Thrc.1892G>Ap.Arg631Glnc.2114C>Ap.Ser705X 4c.2229G>Tp.Met743Ilec.2540C>Tp.Ala847Val3499-3500delCTp.Leu1137ValfxX1170 5 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions 2. p.= designates that protein has not been analyzed, but no change is expected3. Presumed normal allelic variants, but not yet reported in individuals with PC deficiency.4. Indicates the mosaic state of this allele5. Wang et al [2008]Table 3. PC Genotypes and PC Level and ActivityView in own windowCase ID#PC TypeDNA Nucleotide 1 ChangeProtein Amino Acid Change 2PC Amount 3PC Activity 41Cc.[796T>G; =] + [=; 2114C>A, =] p.[S266A; =] + [=; S705X, =]86%1.9%2Bc.[1892G>A, =; =] + [=; 2493_2494delGT, =]p.[R631Q, =; =] + [=; V831Vfs*832,=]8%03Bc.[321+1G>T] + [321+1G>T]p.[V105_K107del] + [V105_K107del]3%04Bc.[806G>A] + [806G>A] p.[R269Q] + [R269Q]2%5%5Bc.[467G>A; 496G>A; 1892G>A, =; 2540C>T, =] + [467G>A; 496G>A; =; =] p.[R156Q; V166I; R631Q, =; A847V, =] + [R156Q; V166I; =; =]44%1.9%6Ac.[184C>T; 1892G>A ; 2540C>T] + [=; 1892G> A, =; 2540C> T, =] p.[R62C; R631Q; 847V] + [=; R631Q, =; A847V, =]49%6%7Bc.[1892G>A; 2540C>T] + [1892G>A, =; 2540C>T, =] 6p.[R631Q; A847V] + [R631Q, =; A847V, =] 17%17%8Cc.[1705A>G; =] + [=; 3409-3410delCT]p.[T569A; =] + [=; L1137Vfs*1170]N/A1%9 5Ac.[434T>C] + [434T>C]p.[V145A] + [V145A]Barely detectable7%-25%10 5Ac.[1351C>T] + [1351C>T]p.[R451C] + [R451C]~100%7%11 5Ac.[1828G>A] + [1828G>A]p.[A610>T] + [A610T]~100%1%-4%12 5Ac.[2229G>T] + [2229G>T]p.[M743I] + [M743I]~100%1%-4%13 5Bc.[2493_2494delGT] + [2473+2-2473+5delTGCA]p.[V831Vfs*832] + [E825Gfs*846]~01%-4%Adapted from Wang et al [2008]1. Nomenclature follows the recommendations for the description of sequence variants [www.hgvs.org/mutnomen/recs.html, www.hgvs.org/mutnomen, www.hgvs.org/mutnomen/checklist.html [den Dunnen & Antonarakis 2000, den Dunnen & Paalman 2003]. The coding sequence is NM_000920.3. Nucleotide +1 is the A of the ATG translation initiation codon. In brief, nucleotide changes in a single allele are listed between brackets as c.[434T>C] and changes in each allele as c.[434T>C] + [434T>C]. Nomenclature for mosaic cases is complex. Two different nucleotides found at one position on one chromosome are described as c.[2114C>A, =] (where “=” indicates the normal variant); more than two different substitutions are separated by a semicolon as c.[796T>G; =] + [=; 2114C>A, =]. Refer to www.hgvs.org/mutnomen/examplesDNA.html for more information.2. Note: Changes are deduced based on the findings in DNA level. “0” indicates no protein; “=” indicates WT protein synthesized. The single-letter abbreviation for amino acids is used in this table; see Quick Reference for an explanation. Nomenclature for amino acid changes follows the same general format as described above for nucleotide changes. 3. The PC /MCC +PCC ratios in individuals with PC are normalized to the ratio in normal control.4. The PC activity is expressed as the ratio of patient/control.5. #10 and #13 were reported by Carbone et al [1998] and Carbone et al [2002]; #11 and #12 were reported by Wexler et al [1998].6. Nomenclature indicates the mosaic state of the two substitutions 1892G>A and 2549C>T in this allele. Together, with the other allele, these substitutions are more abundant than the ‘=’ (wild-type) in this individual.Normal gene product. The protein consists of 1178 amino acids with a molecular weight of approximately 125 kd. It consists of a homotetramer of polypeptides, each covalently bound to a biotin molecule and processing both the catalytic and regulatory functions. PC (EC 6.4.1.1, PC) normally serves an anaplerotic function by replenishing the Krebs cycle and intermediates the conversion of pyruvate into oxaloacetate in response to elevated acetyl-coenzyme A levels (Figure 1). The anaplerotic function of PC is important for the biosynthesis of neurotransmitters in the central nervous system, as well as energy metabolism. PC also controls the first step of hepatic gluconeogenesis and is important in lipogenesis. The enzyme is localized within the mitochondrial matrix in many tissues. Expression is highest in the liver, kidney, adipose tissue, pancreatic islets, and lactating mammary gland. Expression is moderate in brain, heart, and adrenal gland, and least in white blood cells and skin fibroblasts [Jitrapakdee & Wallace 1999].Abnormal gene product. In some individuals with missense mutations, the protein is expressed but lacks activity or has only residual activity. Nonsense, splice-site, and frameshift mutations identified to date result in quick degradation of mRNA. The mutagenesis studies of p.Ala610Thr, identified in Ojibwa with type A PC deficiency in a retroviral expression system have shown that the mutation may affect the stability of the protein, resulting in decreased steady-state levels of expression, and affect the secondary structure of the protein during the import process, thereby inhibiting proper translocation into the mitochondria.