Pyruvate Dehydrogenase Deficiency (PDCD) 

Updated: Aug 17, 2018
Author: Richard E Frye, MD, PhD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG 

Overview

Background

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. PDC metabolically converts pyruvate into acetyl-coenzyme A (ACoA), one of the first steps in the citric acid cycle (CAC). The CAC is a major biochemical process in the mitochondrial matrix that derives energy from several metabolic substrates, including carbohydrates, fatty acids, and amino acids. Malfunction of this cycle deprives the body of energy. In PDCD, pyruvate, which is derived from the breakdown of carbohydrates, is not converted into ACoA. This decreases the major substrate necessary for the CAC to function and results in an abnormal buildup of lactate and alanine, which are alternative metabolic products of pyruvate. Without function of the CAC, the mitochondria cannot produce energy for the cells to function. Lack of energy product and the buildup of unusable metabolites results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.

In PDCD, progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood and very rarely in adulthood. Symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood- and adult-onset forms of this disorder are often associated with intermittent periods of decompensation but normal or mildly delayed neurological development. Therapies are suboptimal for most forms of pyruvate dehydrogenase complex deficiency; although resolution of the lactic acidosis may occur, 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 in many but not all patients. 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. Leigh syndrome may be caused by mitochondrial defects other than PDCD.

Pathophysiology

Pyruvate dehydrogenase complex (PDC) converts pyruvate to ACoA, which is one of the two essential substrates needed to produce citrate (see the image below).[1]

This diagram shows a simplified version of the cit This diagram shows a simplified version of the citric acid cycle and shows the enzyme deficit. The dashed line indicates the blocked pathway and the size of the arrows indicates the relative flow of products. Because pyruvate does not proceed to acetyl-coenzyme A (CoA), it is shunted to other pathways that produce lactic acid and alanine.

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 ACoA; however, an energy deficit remains, especially in the central nervous system (CNS). 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 10 weeks' gestation. Maldevelopment of the corpus callosum is commonly observed in those with prenatal-onset types of PDCD.

Progressive neurological deterioration varies 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, whereas a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology is not usually observed in individuals with a later onset of PDCD.

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.

Epidemiology

Frequency

The incidence of PDCD is not known, but it is likely to be less than 1;50,000. It may be more common than appreciated, because this condition is potentially responsible for unexplained seizures, acidosis, and developmental delays in cases in which enzyme testing is not done, as well as unexplained Leigh syndrome with demonstrable CNS pathology. For X-linked cases, there is likely a 2 in 3 risk that the mother is an unexpressing carrier. For recessive cases, which are less common, there is a 1 in 4 recurrence risk. In-frame mutations of the X-linked E1 alpha gene have been shown for very mild cases.[2]

Mortality/Morbidity

Individuals with neonatal-onset and infantile-onset types of PDCD usually die during the first years of life.[3] Later childhood onset of the disease is usually, but not always, associated with survival into adulthood.

All children are born with some residual enzyme activity, because 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 is usually 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.

Affected males outnumber affected females, because the most common form of the PDCD is X-linked. Some female carriers may have mild symptoms. There is a wide range of presentation in the recessive forms of the disease, but most are milder than the X-linked form of the disease.

Race

PDCD does not appear to have a predilection for race/ethnicity.

Sex

Males are more commonly affected than females, because the most common form of the PDCD, that of the E1 alpha enzyme subunit, is X-linked. Some female carriers have mild to moderate symptoms because of variable X-chromosome inactivation. There is a wide range of presentation in the recessive forms of the disease, but many are equally as severe as the X-linked form of the disease.

West syndrome is more common in females with PDCD. Severe lactic acidosis with early demise and Leigh syndrome are more commonly observed in males with PDCD. Progressive neurological degeneration is also observed 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.

Prognosis

The prognosis of PDCD is proportional to residual PDC activity. In general, the lower the PDC activity, the earlier the onset and the more severe the disease progression. Since the most common form of the PDCD is X-linked recessive, carrier females can have a milder form of the disease, depending on variable X inactivation, whereas males with the X-linked form are more affected. Prognosis also significantly related to whether the form of PDCD is responsive to thiamine or lipoic acid.

Individuals with mild deficiencies in the E1 enzyme of the pyruvate dehydrogenase complex have a better prognosis than those with deficiencies in the E2 and E3 pyruvate dehydrogenase complex enzymes.

Prediction of prognosis is unclear because of the small number of children with pyruvate dehydrogenase complex deficiency studied and the large number of mutations involved. Complications include Leigh syndrome, seizures, and CNS deterioration in many patients with pyruvate dehydrogenase deficiency, and there is a high morbidity and mortality rate.[3]

In most cases of neonatal-onset and infantile-onset of pyruvate dehydrogenase complex deficiency, 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 pyruvate dehydrogenase complex deficiency.[4]

Dichloroacetate appears to produce biochemical correction of pyruvate dehydrogenase complex deficiency in many cases, but resolution of neurologic symptoms is exceptional. Structural CNS abnormalities likely cannot be reversed with successful biochemical treatment.

Dichloroacetate may have greater efficacy with particular mutations of the E1 subunit.

In general, treatment of individuals with pyruvate dehydrogenase complex deficiency 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 pyruvate dehydrogenase complex deficiency 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 pyruvate dehydrogenase complex deficiency and the caregivers regarding the factors that may elicit a crisis and the early signs of decompensation.

Patient support groups for mitochondrial disorders include United Mitochondrial Disease Foundation and MitoAction.

 

Presentation

History

The presentation and progression of pyruvate dehydrogenase complex (PDC) deficiency (PDCD) widely varies.[5, 6]

Nonspecific but common symptoms of metabolic illnesses include the following:

  • Poor feeding
  • Lethargy
  • Rapid breathing (ie, tachypnea)

Developmental nonspecific signs of metabolic disease include the following:

  • Developmental 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 (regression) of motor milestones
  • Poor muscle tone
  • New onset seizures
  • Periods of incoordination (ie, ataxia)
  • Abnormal eye movements
  • Poor response to visual stimuli
  • Episodic dystonia: Associated with E2 subunit deficiency
  • Progressive dystonia: Associated with E1-alpha subunit deficiency

Early childhood-onset pyruvate dehydrogenase complex deficiency 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

An acute form resembling Guillain-Barré syndrome with limb weakness has been described.

Physical

Birth

Low Apgar scores and small for gestational age are nonspecific signs of prenatal onset.

Infectious

With poor feeding and lethargy out of proportion to a mild viral illness, consider metabolic disturbances, especially after bacterial infection has been ruled out and especially in the presence of acidosis.

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 pyruvate dehydrogenase complex deficiency. 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 PDC 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 been documented.

A thiamine triphosphate synthesis inhibitor may cause PDC E1 enzyme thiamine dependence in some patients who present with Leigh syndrome.

A post-translational modification in which EGFR-PTK-mediated tyrosine-phosphorylation of the E1ss protein led to enhanced ubiquitination followed by proteasome-mediated degradation has been described.[7]

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.

 

DDx

Diagnostic Considerations

Pyruvate carboxylase deficiency presents with similar chemical and central nervous system findings as pyruvate dehydrogenase complex deficiency. Enzyme testing is required to distinguish between the two conditions.

Other conditions to consider in the differential diagnosis include the following:

  • D-Lactic acidosis

  • Gluconeogenesis abnormalities

  • Mitochondrial electron transport chain disorders

Differential Diagnoses

 

Workup

Laboratory Studies

The following studies are indicated in pyruvate dehydrogenase complex (PDC) deficiency (PDCD):

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 pyruvate dehydrogenase complex deficiency, blood lactate and pyruvate levels may be elevated only slightly or not at all under normal conditions; elevated levels are usually found during periods of crisis.

A recent study suggests that the lactate-to-pyruvate ratio is only diagnostically useful to differentiate pyruvate dehydrogenase complex deficiency from other forms of congenital lactic acidosis at higher lactate levels (>5 mmol/L).[8]

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. Pyruvate dehydrogenase complex activity should be measured with and without thiamine in order to detect cases of thiamine-responsive pyruvate dehydrogenase complex deficiency.

Blood and fibroblast enzyme tests 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 grows if obtained within 2 days of death.

Imaging Studies

MRI

MRI shortly after birth may reveal 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 reveal 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 reveal discrete lesions restricted to the globus pallidus.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) of the brain reveals high lactate levels in individuals with pyruvate dehydrogenase complex deficiency.

N -acetylaspartate and choline levels are consistent with hypomyelination.

Histologic Findings

Histologic findings of Leigh syndrome may be found in an autopsy examination.

 

Treatment

Medical Care

Consider pyruvate dehydrogenase complex (PDC) deficiency (PDCD) in all patients with lactic acidosis and central nervous system (CNS) findings; failure to do so may lead to a second, similarly affected child.

Direct treatment that stimulates the PDC provides alternative fuels and prevents acute worsening of the syndrome. Correction of acidosis does not reverse all the symptoms. CNS 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 thiamine and lipoic acid cofactors to all patients with PDCD is done to optimize PDC function, and carnitine is given to facilitate fatty acid transport into mitochondria and to potentially increase cellular ATP production.

Thiamine-responsive cases are more likely in children who are diagnosed at older than 1 year, and high-dose thiamine (400 mg/day) should be continued in patients who are responsive clinically and chemically.[9]

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.

Oral dichloroacetate administered for 6 months was found to be well tolerated and blunted the postprandial increase in circulating lactate but did not improve neurologic or other clinical measures.[10]

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.

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 is often used to treat acidosis.

Transfer the patient to a major medical center that takes care of complex metabolic cases is recommended if this specialized care cannot be provided.

Consultations

Evaluation by an expert in metabolic and genetic disease is generally helpful 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 oral carbohydrate intake depends on the residual enzyme activity and must be individually treated. It may be as low as 10-20 carbohydrate calories per kg carbohydrate.

A ketogenic diet may be indicated. 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, CNS metabolic abnormalities persist, as evidenced by high lactic acid levels in the cerebrospinal fluid and progressive neurological degeneration.

The vulnerability of the CNS is a result of its dependence on glucose as a fuel. However, the brain will change glucose to lipid energy sources after a few days of a ketogenic diet.

Long-Term Monitoring

Provide close follow-up for children with pyruvate dehydrogenase complex deficiency. Closely monitor lactate levels.

To help evaluate dietary manipulations and to ensure compliance, have caregivers of children with pyruvate dehydrogenase complex deficiency complete a dietary log.

Advise caregivers of individuals with pyruvate dehydrogenase complex deficiency to always carry an informational statement that describes pyruvate dehydrogenase complex deficiency and the appropriate medical treatment for the disorder in an emergency setting.

Further Inpatient Care

Acute decompensation during acute pyruvate dehydrogenase complex (PDC) deficiency (PDCD) requires admission and management of acidosis with intravenous bicarbonate.

 

Guidelines

Guidelines Summary

The following consensus mitochondrial guidelines may be useful:

  • Diagnosis and management of mitochondrial disease [11]
  • Patient care standards for primary mitochondrial disease [12]
 

Medication

Medication Summary

Cofactor supplementation with thiamine, carnitine, and lipoic acid is the standard of care. The cases of pyruvate dehydrogenase complex deficiency (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 pyruvate dehydrogenase complex deficiency. However, administration of all of these cofactors to all patients with pyruvate dehydrogenase complex deficiency is typical in order to optimize pyruvate dehydrogenase complex function.

Cofactors

Class Summary

Organic substances required by the body in small amounts for various metabolic processes. They are essential for new cell growth and division. They are used clinically for the prevention and treatment of specific deficiency states.

Biotin

Essential cofactor for several important enzymes, including an alternative pathway for pyruvate. Vitamin H is a synonym.

Thiamine (Thiamilate)

Important cofactor for the pyruvate dehydrogenase complex E1 enzyme. Some disorders are responsive to simple supplementation.

Lipoic acid

Vitamin cofactor for E2 subunit of the pyruvate dehydrogenase complex. Cases have been described as responsive to lipoic acid supplementation.

Enzyme activator

Class Summary

Dichloroacetate sodium is the only drug found to activate the enzyme complex.

Dichloroacetate sodium

A compound believed to activate the PDC by inhibiting the inactivating kinase. This decreases lactate production and promotes pyruvate oxidation.

Alkalinizing agents

Class Summary

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.

Sodium bicarbonate

Can be used to correct the acidosis in chronic and acute settings.

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.