Pyruvate Dehydrogenase Complex Deficiency
Background: Pyruvate dehydrogenase complex deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.
Progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood. These symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood-onset forms of this disorder often are associated with intermittent periods of decompensation but normal neurological development. Therapies are suboptimal for other forms of PDCD; resolution of the lactic acidosis may occur, but cessation of the underlying progressive neurological damage is rare.
The key feature of this condition is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem. The group of disorders that result in this pathology are termed Leigh syndrome. Defects in one of many of the mitochondrial enzymes involved in energy metabolism may demonstrate similar brain pathology.
Pathophysiology: Pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-CoA, which is one of the two essential substrates needed to produce citrate (see Image 1). A deficiency in this enzymatic complex limits the production of citrate. Because citrate is the first substrate in the citric acid cycle, the cycle cannot proceed. Alternate metabolic pathways are stimulated in an attempt to produce acetyl-CoA; however, an energy deficit remains, especially in the central nervous system. The magnitude of the energy deficit depends on the residual activity of the enzyme.
Severe enzyme deficiencies may lead to congenital brain malformation because of a lack of energy during neural development. Morphological abnormalities occur before the 10th week of gestation. Maldevelopment of the corpus callosum commonly is observed in those with prenatal-onset types of PDCD.
Progressive neurological deterioration is variable in neonates with an apparently healthy brain. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum, with gray matter degeneration or necrotizing encephalopathy may occur in some individuals with PDCD, while a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology usually is not observed in those whose onset of PDCD is in childhood.
The most common form of PDCD is caused by mutations in the X-linked E1 alpha gene; all other causes are due to alterations in recessive genes.
Frequency:
Internationally: PDCD is a rare disorder. Several hundred cases of PDCD have been reported. Most mutations are sporadic, and the recurrence rate is very low. The true occurrence of this disorder is unknown because mild mutations of the E1 alpha enzyme subunit gene on the X chromosome may be asymptomatic, especially in females.
Mortality/Morbidity:
Individuals with neonatal- and infantile-onset types of PDCD usually die during the first years of life. Later childhood onset of the disease usually, but not always, is associated with survival into adulthood.
All children are born with some residual enzyme activity since a complete deficiency of PDC is incompatible with life. Infants with 15% or less PDC activity normally do not survive the newborn period. PDC activity greater than 25% is associated with less severe disease and usually is characterized by ataxia and mild psychomotor delay.
Some therapies may extend the lives of individuals who are severely affected with PDCD; however, the progressive nature of the neurological deterioration results in significant morbidity.
Sex:
Gender differences appear for dysfunction of the E1 alpha enzyme subunit, which is coded by the X chromosome. Heterozygous females can manifest severe symptoms, though males are typically affected to a much greater extent.
West syndrome is more common in females with PDCD.
Severe lactic acidosis with early demise and Leigh syndrome more commonly are observed in males with PDCD.
Progressive neurological degeneration is observed more commonly in females with PDCD.
Age:
Age of presentation varies from prenatal to early childhood and depends on the residual activity of the PDC.
Individuals with severe disease have prenatal onset with structural brain abnormalities.
Moderate disease presents in infants as psychomotor delay.
Individuals with less severe disease usually present in early childhood with intermittent lethargy or ataxia.
History: The presentation and progression of this disorder is highly variable.
Nonspecific but common symptoms of metabolic illnesses include the following:
Poor feeding
Lethargy
Rapid breathing (ie, tachypnea)
Developmental nonspecific signs of metabolic disease
Mental delays
Psychomotor delays
Growth retardation
Progressive neurologic symptoms of PDCD usually start in infancy but may be evident at birth or in later childhood. The following are signs of poor neurological development or degenerative lesions:
Poor acquisition or loss of motor milestones
Poor muscle tone
New onset seizures
Periods of incoordination (ie, ataxia)
Abnormal eye movements
Poor response to visual stimuli
Episodic dystonia is associated with a deficiency of the E2 subunit, while progressive dystonia appears to be associated with a deficiency in the E1-alpha subunit.
Early childhood-onset PDCD typically presents with intermittent periods of incoordination, especially during mild illnesses.
The following respiratory symptoms are consistent with neurological disease and severe lactic acidosis:
Apnea
Dyspnea
Respiratory depression
Physical:
Low Apgar scores and small for gestational age are nonspecific signs of prenatal onset.
With poor feeding and lethargy out of proportion to a mild viral illness, consider metabolic disturbances, especially after bacterial infection has been ruled out.
Neurologic
Hypotonia, ataxia, choreoathetosis, and progressive encephalopathy are found in children with lactic acidosis.
Loss of cortical material can result in a positive Babinski reflex, absent deep tendon reflexes, tremors, or spastic diplegia or quadriplegia.
Prenatal or postnatal microcephaly may be found.
Ophthalmological examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary responses, and blindness.
Seizures vary in type from clonic-tonic to infantile spasms.
Episodic or progressive dystonia
Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.
Dysmorphology
A characteristic but uncommon dysmorphology has been described for infantile-onset PDCD. Features include narrow forehead, frontal bossing, wide nasal bridge, long philtrum, and anteverted nostrils. Structural brain lesions have also been reported.
In addition, a case of X-component deficiency has been described with trigonocephaly, supranasal lipoma, hypertelorism, thin upper lip, bilateral epicanthus, upward slant of the eyes, high palate, and pectus excavatum.
Causes:
The intramitochondrial pyruvate dehydrogenase complex is composed of 3 basic substrate-processing enzymes: a protein X and 2 regulatory enzymes. Thiamine pyrophosphate and lipoic acid are important PDC cofactors. Dysfunction in all 3 substrate-processing enzymes, as well as protein X and thiamine dependence of the E1 alpha enzyme, has been described; however, dysfunction of the E1 alpha enzyme subunit is most common.
The E1 alpha subunit gene is located at Xp22.2-p22.1. More than 90 mutations of the E1 alpha enzyme subunit impair either polypeptide stability or catalytic efficiency.
The gene for the E1 beta enzyme subunit of the PDC has been mapped to 3p13-q23; an isolated deficiency in E1 beta enzyme subunit has recently been documented.
A thiamine triphosphate synthesis inhibitor may cause PDC E1 enzyme thiamine dependence in some patients who present with Leigh syndrome.
A deficiency of lipoic acid, the E2 enzyme cofactor, has been described.
A deficiency of the E2 enzyme has been described.
The gene for the X protein of the PDC is located at 11p13 and has an autosomal recessive inheritance. Eleven cases of PDC X protein deficiency have been documented.
The E3 enzyme is mapped to 7q31-32 and has an autosomal recessive inheritance. The E3 enzyme is also active in the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes.
Other Problems to be Considered:
D-Lactic acidosis
Gluconeogenesis abnormalities
Mitochondrial electron transport chain disorders
Lab Studies:
Lactate and pyruvate levels
High blood lactate and pyruvate levels with or without lactic acidemia suggest an inborn error of metabolism at the mitochondrial level.
Cerebrospinal fluid also shows elevation of lactate and pyruvate (at times even in the absence of elevated blood levels).
In mild cases of PDCD, these levels may be elevated only slightly under normal conditions; elevated levels also may be found during periods of crisis.
The normal lactate-to-pyruvate ratio of approximately 10-15:1 is preserved.
Serum and urine analysis
Serum and urine amino acid analyses reveal hyperalaninemia.
Deficiency of the E3 enzyme also causes an elevation in branched-chain amino acids in the serum and alpha-ketoglutarate in the serum and urine.
Amino acid levels vary with the general metabolic state of the patient; a catabolic state, in which gluconeogenesis is activated and proteins are degraded, elevates many amino acids, leading to a nonspecific amino acid profile.
Hyperammonemia and nonspecific amino acid elevation are associated with E2 enzyme deficiency, which is more common during acute illnesses.
Thiamine pyrophosphate-adenosine triphosphate phosphoryl transferase inhibitor can be detected in urine or blood by a specific assay.
Other studies
Definitive diagnosis is made by showing abnormal enzyme function.
Functional assays can be performed on leukocytes, fibroblasts, or properly preserved tissue samples. PDC activity should be measured with and without thiamine in order to detect cases of thiamine responsive PCD.
Blood and fibroblasts are the easiest to obtain, but mosaicism can cause normal enzymatic activity in leukocytes and fibroblasts, requiring a tissue biopsy if the diagnosis is strongly suspected.
A skin sample will grow if obtained within 2 days of death.
Imaging Studies:
Magnetic resonance imaging
Magnetic resonance imaging (MRI) shortly after birth may show ventricular dilation, cerebral atrophy, hydranencephaly, partial or complete absence of the corpus callosum, absence of the medullary pyramids, or abnormal and ectopic inferior olives.
MRI of infants with progressive neurological symptoms may show symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum, or generalized hypomyelination.
Individuals with a deficiency in the E2 subunit may demonstrate discrete lesions restricted to the globus pallidus.
Magnetic resonance spectroscopy
Magnetic resonance spectroscopy (MRS) of the brain shows high lactate levels in individuals with PCDC.
N-acetylaspartate and choline levels are consistent with hypomyelination.
Medical Care:
Direct treatment that stimulates the pyruvate dehydrogenase complex, provides alternative fuels, and prevents acute worsening of the syndrome. Correction of acidosis does not reverse all the symptoms. Central nervous system damage is common and limits recovery of normal function.
Cofactor supplementation with thiamine, carnitine, and lipoic acid is the standard of care. The cases of PDCD that are responsive to these cofactors respond to supplementation, especially thiamine. Some evidence suggests that high doses of thiamine may be most effective in some mutations causing thiamine-responsive PDCD. However, administration of all of these cofactors to all patients with PDCD is typical in order to optimize PDC function.
Ketogenic diets (with restricted carbohydrate intake) have been used to control lactic acidosis with minimal success.
Dichloroacetate reduces the inhibitory phosphorylation of PDC. Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability. Studies with human fibroblast have demonstrated that certain gene deletions are more response to dichloroacetate than others. Other lactic acidemias have been treated successfully with this compound; however, long-term use is associated with reversible peripheral neuropathy and elevation in liver transaminases. Coadministration of thiamine appears to protect against neuropathy in animals. Because of the largely unknown benefit of this compound, it remains an investigational drug.
Oral citrate often is used to treat acidosis.
Consultations:
Evaluation by an expert in metabolic and genetic disease is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.
Genetic counseling for the parents of the individual with PDCD is important in order to estimate the recurrence risk for future pregnancies.
Progressive renal failure is common in PDCD. A nephrologist should be consulted if signs of renal failure are evident.
Anesthesia can be complicated by PDCD. An anesthesiologist should be consulted prior to procedures that require anesthesia.
Diet:
Limit carbohydrate administration to 3-4 mg/kg/min to prevent lactate buildup. The appropriate carbohydrate intake depends on the residual enzyme activity and must be titrated individually.
Ketogenic diets
Ketogenic diets minimize the carbohydrate content and maximize the daily intake of fat content.
Fat intake should account for 65-80% of the caloric intake, with protein accounting for about 10% of the caloric intake and carbohydrate caloric intake making up the balance.
Manipulate the percent of dietary fat and carbohydrate calories to provide an appropriate lactic acid level.
Although the ketogenic diet may reduce the blood lactic acid level and extend lifespan, central nervous system metabolic abnormalities persist, as evidenced by high lactic acid levels in the cerebrospinal fluid and progressive neurological degeneration.
The vulnerability of the central nervous system is a result of its dependence on glucose as a fuel.
Drug Category: Cofactors -- Organic substances required by the body in small amounts for various metabolic processes. They are essential for new cell growth and division. Used clinically for the prevention and treatment of specific deficiency states.
Drug Name |
Biotin -- Essential cofactor for several important enzymes, including an alternative pathway for pyruvate. Vitamin H is a synonym. |
Pediatric Dose |
1-5 mg/kg/d PO/IV divided bid |
Contraindications |
Documented hypersensitivity |
Interactions |
Anticonvulsants (eg, phenytoin, primidone, carbamazepine, phenobarbital) may decrease absorption, thus reducing blood levels of biotin |
Pregnancy |
C - Safety for use during pregnancy has not been established. |
Precautions |
None reported |
Drug Name |
Thiamine (Thiamilate) -- Important cofactor for the pyruvate dehydrogenase complex E1 enzyme. Some disorders are responsive to simple supplementation. |
Pediatric Dose |
50-100 mg/kg/d PO/IV divided qid |
Contraindications |
Documented hypersensitivity |
Interactions |
Incompatible with alkaline or neutral solutions |
Pregnancy |
A - Safe in pregnancy |
Precautions |
Pregnancy category C for doses exceeding RDA; caution when administering thiamine IV (deaths have resulted from IV use); administer before or together with dextrose-containing fluids in suspected thiamine-deficiency; protect oral product from light |
Drug Category: Enzyme activator -- Dichloroacetate sodium (DCA) is the only drug found to activate the enzyme complex.
Drug Name |
Dichloroacetate sodium -- A compound believed to activate the pyruvate dehydrogenase complex by inhibiting the inactivating kinase. This decreases lactate production and promotes pyruvate oxidation. |
Adult Dose |
30-100 mg/kg/d IV divided bid |
Pediatric Dose |
30-100 mg/kg/d IV divided bid |
Contraindications |
Documented hypersensitivity |
Interactions |
Limited data exist; inhibits glucose synthesis, caution with coadministration of hypoglycemic agents |
Precautions |
Polyneuropathy has been reported with long-term administration; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; monitor for metabolic acidosis and hypoglycemia |
Drug Category: Alkalinizing agents -- Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs. Citric acid mixtures may also be used. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.
Drug Name |
Bicarbonate sodium -- Can be used to correct the acidosis in chronic and acute settings. |
Adult Dose |
Acute: 1-2 mEq/kg IV over 20 min; infusion can be repeated up to q30min prn in an emergency setting; however, careful monitoring of blood pH must be obtained |
Pediatric Dose |
Acute: Administer as in adults |
Contraindications |
Alkalosis, hypernatremia, severe pulmonary edema, hypocalcemia, and unknown abdominal pain |
Interactions |
Inactivates catecholamines, calcium salts, and atropine when mixed together; has been shown to decrease the therapeutic levels of methotrexate, tetracyclines, and salicylates because of urinary alkalinization |
Pregnancy |
C - Safety for use during pregnancy has not been established. |
Precautions |
May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; administer with extravasation precautions |
Drug Name |
Citrate mixtures (Bicitra, Oracit, Cytra-K) -- Several mixtures of citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate. |
Adult Dose |
1-3 mEq/kg/d PO tid/qid to control chronic acidosis |
Pediatric Dose |
2-5 mEq/kg/d PO tid/qid to control chronic acidosis |
Contraindications |
Severe renal impairment; acute dehydration |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
May cause hypocalcemia, hypernatremia, and/or hyperkalemia, depending on the formulation used; individually base formulation with consideration of other supplementation and the ability of the patient to tolerate sodium or potassium loads |
Prognosis:
Individuals with mild deficiencies in the E1 enzyme of the PDC have a better prognosis than those with deficiencies in the E2 and E3 PDC enzymes.
Prediction of prognosis is unclear because of the small number of children with PDCD studied and the large number of mutations involved.
In most cases of neonatal- and infantile-onset of PDCD, a poor prognosis remains, even when the lactic acidosis is treated successfully. Although lactic acidosis appears to be controlled by thiamine supplementation in individuals who respond to thiamine, the neurological outcome may be poor.
One case report describes cessation of neurological demyelination with the ketogenic diet; however, the ketogenic diet has not been reported to be of significant neurologic benefit to other patients with PDCD.
Dichloroacetate appears to produce biochemical correction of PDCD in many cases, but resolution of neurologic symptoms is exceptional. It is doubtful that structural CNS abnormalities can be reversed with successful biochemical treatment.
Dichloroacetate may have greater efficacy with particular mutations of the E1 subunit.
In general, treatment of individuals with PDCD is most beneficial if started early. Although successful treatment is rare, some cases have been reported.
Although the recurrence rate for subsequent pregnancies is low, test future gestations for PDCD because of the possibility of germline mosaicism. Enzyme activity of cultured chorionic villus cells can be determined in time to make an early diagnosis. Inaccuracies in the diagnosis of the female fetus arise from X chromosome inactivation.
Individuals with an E2 subunit deficiency may have a mild phenotype.
Patient Education:
Educate the patient with PDCD and the caregivers regarding the factors that may elicit a crisis and the early signs of decompensation.
Pyruvate Carboxylase Deficiency
Background: Pyruvate carboxylase deficiency (PCD) is a rare disorder that causes developmental delay and failure to thrive starting in the neonatal or early infantile period. PCD results in malfunction of the citric acid cycle and gluconeogenesis, thereby depriving the body of energy; the former biochemical process derives energy from carbohydrates, while the latter produces carbohydrate fuel for the body when carbohydrate intake is low.
Metabolic acidosis caused by an abnormal lactate production is associated with nonspecific symptoms such as severe lethargy, poor feeding, vomiting, and seizures, especially during periods of illness and metabolic stress. Progressive neurologic symptoms, starting in the neonatal or early infantile period, include developmental delay, poor muscle tone, abnormal eye movements, or seizures. Therapies can ameliorate the biochemical abnormalities but cannot undo the progressive neurologic damage.
Pathophysiology: Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that converts pyruvate to oxaloacetate. Oxaloacetate is one of two essential substrates needed to produce citrate, the first substrate in gluconeogenesis (Image 1). This deficit in oxaloacetate affects metabolism in 4 major ways.
The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from proceeding.
The precursor of oxaloacetate, pyruvate, is shunted towards alternate metabolic pathways, leading to an increase in lactic acid, alanine, and acetylcoenzyme A (acetyl-CoA). Acetyl-CoA cannot produce citrate without oxaloacetate and is shunted to produce ketone bodies.
Gluconeogenesis cannot proceed without oxaloacetate, resulting in hypoglycemia during times of prolonged fasting. Tissues that are solely dependent on glucose for fuel, such as the brain, are severely compromised during fasting states. Because cells cannot use the citric acid cycle to produce energy, energy is extracted from glucose exclusively through glycolysis. The highly inefficient process of glycolysis causes glucose to be degraded at a very high rate, resulting in a glucose deficit, thereby compounding the problem.
Aspartic acid, which is derived from oxaloacetate, is required for the urea cycle. A decrease in aspartic acid production reduces ammonia disposal and leads to increased serum ammonia levels.
Frequency:
In the US: PCD is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset PCD is more common in the United States. An increased incidence has been documented among certain populations, most notably native North American Indians who speak the Algonquin dialect. A founder effect has been postulated.
Internationally: Neonatal onset PCD has a greater incidence in France.
Mortality/Morbidity:
Most patients die within the first 6 months of life.
PCD is a progressive disorder that manifests in the neonatal or infantile period. Some therapies may reduce the biochemical dysfunction. However, progressive neurologic deterioration results in significant morbidity. Most patients die within the first 6 months of life.
The severe energy deficit in the central nervous system causes neurologic symptoms and congenital brain malformation due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration is variable. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum with gray matter degeneration or necrotizing encephalopathy occur in some infants. Others develop Leigh syndrome, which is a gliosis of the brainstem and basal ganglia with capillary proliferation and characteristic changes on CT and MRI scanning.
Age:
Age of presentation varies from the prenatal period to early infancy.
Severe disease has prenatal onset with congenital brain abnormalities.
Less severe cases manifest in early infancy.
History:
Birth: Low Apgar scores and small size for gestational age are nonspecific symptoms of metabolic disturbance during gestation.
General: The development of poor feeding, vomiting, and lethargy are nonspecific but common symptoms of metabolic illnesses. If these symptoms are instigated by a mild viral illness and are more severe than would be expected, a metabolic disturbance should be considered, especially after a bacterial infection has been ruled out.
Development: Mental, psychomotor, and/or growth retardation are nonspecific symptoms of metabolic disease.
Neurologic: Poor acquisition or loss of motor milestones, new-onset seizures, episodic incoordination, abnormal eye movements, and poor response to visual stimuli are signs of poor neurologic development or degenerative disease.
Respiratory: A history of apnea, dyspnea, or respiratory depression is consistent with neurologic disease or severe lactic acidosis.
Physical:
Neurologic
Hypotonia, ataxia, tremors, and choreoathetosis are consistent with PCD.
Progressive motor pathway degeneration results in a present Babinski sign and spastic diplegia or quadriplegia.
Ophthalmologic examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary response, and blindness.
Prenatal microcephaly or postnatal microcephaly also may be evident on physical examination.
Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.
Causes:
The gene that encodes PC has been localized to bands 11q13.4-q13.5.
An autosomal recessive inheritance pattern is characteristic.
Neonatal PCD is associated with complete absence of messenger ribonucleic acid (mRNA) and the PC enzyme protein.
Infantile-onset PCD is associated with a residual enzyme activity less than 2% of normal levels.
Other Problems to be Considered:
Gluconeogenesis abnormalities
Fatty acid beta-oxidation deficiencies
Leigh encephalopathy
Pyruvate dehydrogenase complex deficiency
Phosphoenolpyruvate carboxykinase deficiency
2-Ketoglutarate dehydrogenase deficiency
Dihydrolipoamide dehydrogenase deficiency
Fumarase deficiency
Lab Studies:
Lactate and pyruvate levels
High blood lactate and pyruvate with or without a lactic aciduria suggests an inborn error of energy metabolism.
An increased lactate-to-pyruvate ratio is characteristic of citric acid cycle disorders.
This ratio may be particularly elevated during periods of crisis, such as illness or metabolic stress.
Hypoglycemia
Hypoglycemia during fasting results from greatly reduced gluconeogenesis.
Period of fasting required to produce symptoms is much shorter in PCD than other disorders.
Amino acid levels
Measurement of serum amino acids reveals hyperalaninemia, hypercitrullinemia, hyperlysinemia, and low aspartic acid levels.
Hyperalaninemia is due to the pyruvate shunting.
Hypercitrullinuria and hyperlysinemia results from a metabolic block in the urea cycle due to a low aspartic acid.
Low aspartic acid is due to the deficiency in the oxaloacetate precursor.
Amino acid levels vary with the general metabolic state of the patient. If the patient is in a catabolic state, proteins are degraded, resulting in the elevation of many amino acids and a nonspecific amino acid profile.
Other studies
Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.
Abnormal enzyme function can be detected by functional assays performed on leukocytes, fibroblasts, or properly preserved tissue samples.
The severe form of PCD can be diagnosed by demonstrating the absence of PC mRNA or specific cross-reacting material.
Cerebrospinal fluid shows an elevation of lactate and pyruvate.
Cerebrospinal fluid glutamine is markedly reduced, while glutamic acid and proline levels are elevated.
Imaging Studies:
MRI
MRI in the neonatal period may show ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.
MRI in infants with progressive neurologic symptoms may show symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum and/or generalized hypomyelination.
Magnetic resonance spectroscopy (MRS): Brain MRS shows high lactate levels, as well as levels of N-acetylaspartate and choline consistent with hypomyelination.
Histologic Findings: Histologic examination of the liver may reveal lipid droplet accumulation.
Central nervous system neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes.
Medical Care:
Treatments are aimed at stimulating the pyruvate dehydrogenase complex (PDC) and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment.
The PDC can provide an alternative pathway for pyruvate metabolism PDC activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help reduce the pyruvate and lactate levels.
Biotin supplementation is given to help optimize the residual enzyme activity but is usually of little use.
Citrate supplementation reduces the acidosis and provides the needed substrate in the citric acid cycle.
Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.
One patient reportedly was successfully treated with a continuous nocturnal gastric drip feeding of uncooked cornstarch.
Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.
Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.
Consultations:
Evaluation by an expert in metabolic and genetic disorders is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.
Genetic counseling for the parents is important in order to determine the risk of recurrence in future pregnancies.
Diet:
Diet has a small effect on outcome.
A high-carbohydrate, high-protein diet may help to maintain an anabolic state and prevent activation of gluconeogenesis.
Drug Category: Enzyme activator -- Dichloroacetate (DCA) sodium is the only drug found to activate the enzyme complex.
Drug Name |
Sodium dichloroacetate -- Used to treat lactic acidosis. This is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation. |
Adult Dose |
30-100 mg/kg/d IV divided bid |
Pediatric Dose |
Administer as in adults |
Contraindications |
Documented hypersensitivity |
Interactions |
Reduces urate clearance and may counteract the effect of uricosuric drugs |
Pregnancy |
C - Safety for use during pregnancy has not been established. |
Precautions |
Sedation is common; stimulates myocardial contractility; may elevate serum transaminases; polyneuropathy has been reported with long-term administration of DCA; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; DCA is currently an investigational agent and is not commercially available; it is only available through an investigational protocol at this time |
Drug Category: Alkalinizing agents -- Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs.
Drug Name |
Bicarbonate sodium -- Bicarbonate can be used to correct the acidosis in chronic and acute settings. |
Adult Dose |
Acidosis during acute attacks: 1-2 mEq/kg IV over 20 min; infusion can be repeated up to q30min prn in an emergency setting but careful monitoring of blood pH must be obtained |
Pediatric Dose |
Acidosis during acute attacks: Administer as in adults |
Contraindications |
Alkalosis; hypernatremia; severe pulmonary edema; hypocalcemia; unknown abdominal pain |
Interactions |
Sodium bicarbonate inactivates catecholamines, calcium salts, and atropine when mixed together; shown to decrease therapeutic levels of methotrexate, tetracyclines, and salicylates due to urinary alkalinization |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; avoid extravasation; carefully monitor arterial or venous blood pH with IV infusion; response to bicarbonate should be checked 10-20 min after infusion; guide repeat treatment with bicarbonate by clinical change in the patient's condition along with laboratory values; take particular care when using with neonates because of increased risk of intraventricular hemorrhage |
Drug Name |
Citrate solutions (Bicitra, Polycitra) -- Several solutions containing citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate. |
Adult Dose |
Chronic acidosis: 1-3 mEq/kg/d PO divided tid/qid |
Pediatric Dose |
Chronic acidosis: 2-5 mEq/kg/d PO divided tid/qid |
Contraindications |
Severe renal impairment; acute dehydration |
Interactions |
Urine alkalinization may decrease serum levels of lithium, chlorpropamide, methenamine, methotrexate, salicylates, or tetracyclines; urine alkalinization may increase serum levels of flecainide, quinidine, or sympathomimetics |
Pregnancy |
B - Usually safe but benefits must outweigh the risks. |
Precautions |
May cause hypokalemia, hypernatremia, and/or hyperkalemia depending on the formulation used; formulation should be individually based with consideration of other supplementation and the ability of the patient to tolerate sodium or potassium loads |
Further Inpatient Care:
Acute decompensation during illness requires admission and management of the acidosis with hydration and intravenous bicarbonate. The patient must be supplied with adequate carbohydrates.
Further Outpatient Care:
Lactate levels should be monitored closely.
A dietary log should be completed to help evaluate dietary manipulations and to ensure compliance.
An informational statement that describes the child's disorder and the appropriate medical treatment for the disorder in an emergency setting should be carried by the parents at all times.
Prognosis:
Although diet manipulation and supplementation of substrates and cofactors can reverse some of the biochemical abnormalities, neurologic abnormalities typically progress, and demise within the first 6 months of life is the rule.
Enzyme activity of cultured chorionic villus cells can be determined in time to allow for early prenatal diagnosis.
Patient Education:
The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.
For excellent patient education resources, please refer to eMedicinehealth.
Medical/Legal Pitfalls:
Several other metabolic encephalopathies can manifest with the same signs and symptoms as PCD. Exclude other disorders of the citric acid cycle, such as PDC deficiency and other mitochondropathies. Biotinidase deficiency is also important to exclude because it is potentially treatable.
MRI brain abnormalities can be essential to the diagnosis of an energy deficiency syndrome such as PCD but may not develop early in the disease course. Thus, repeat MRI scans at regular intervals in children who display signs and symptoms consistent with an energy deficiency syndrome.
Urine organic acids may be nonspecific or may only demonstrate abnormalities during times of stress. Thus, this test may need to be repeated several times for a meaningful result.