Pyruvate dehydrogenase deficiency

Microcephaly and a normal head size

PDCD is generally presented in one of two forms. The metabolic form appears as lactic acidosis. The neurological form of PDCD contributes to hypotonia, poor feeding, lethargy and structural abnormalities in the brain.[4] Patients may develop seizures and/or neuropathological spasms. These presentations of the disease usually progress to mental retardation, microcephaly, blindness, and spasticity.[5][6][7]

Females with residual pyruvate dehydrogenase activity will have no uncontrollable systemic lactic acidosis and few, if any, neurological symptoms. Conversely, females with little to no enzyme activity will have major structural brain abnormalities and atrophy. Males with mutations that abolish, or almost abolish, enzyme activity presumably die in utero because brain cells are not able to generate enough ATP to be functionally viable. It is expected that most cases will be of mild severity and have a clinical presentation involving lactic acidosis.[8] Male infants that reach full term display more severe symptoms than females, and exhibit high mortality within the first few years of life [9][7]

Prenatal onset may present with non-specific signs such as low Apgar scores and small for gestational age. These cases display hydrocephalus, and thinning of the cerebral tissue.[7] Metabolic disturbances may also be considered with poor feeding and lethargy out of proportion to a mild viral illness, and especially after bacterial infection has been ruled out.[5] PDH activity may be enhanced by exercise, phenylbutyrate and dichloroacetate.

The clinical presentation of congenital PDH deficiency is typically characterized by heterogenous neurological features that usually appear within the first year of life. In addition, patients usually show severe hyperventillation due to profound metabolic acidosis mostly related to lactic acidosis. Metabolic acidosis in these patients is usually refractory to correction with bicarbonate.[10]

The following table lists common symptoms of pyruvate dehydrogenase deficiency.[3]

Aerobic respiration is the process of converting energy in the form of glucose into ATP, the primary currency of energy used by cells to fuel biochemical processes and support growth. The first phase of respiration is glycolysis, a series of ten biochemical reactions in the cytoplasm that convert glucose into pyruvate. Pyruvate is then transported into mitochondria, where it is converted by the pyruvate dehydrogenase complex into acetyl-CoA, the starting substrate of the Krebs cycle. When PDC activity is reduced or abolished by mutation, pyruvate levels rise. Excess pyruvate is then converted into lactic acid by lactate dehydrogenase. Lactic acid enters the blood stream, causing acidification in a condition known as lactic acidosis.

Glycolysis

Citric acid cycle with aconitate 2

The most commonly seen form of PDCD is caused by mutations in the X-linked E1 alpha gene, PDHA1,[11] and is approximately equally prevalent in both males and females. However, males are more severely affected than heterozygous females. This can be explained by x-inactivation, as females carry one normal and one mutant gene. Cells with a normal allele active can metabolize the lactic acid that is released by the PDH deficient cells. They cannot, however, supply ATP to these cells and, therefore, phenotype depends largely on the nature/severity of the mutation.[5][8]

More rarely, mutations occur in the E2 (dihydrolipoyl transacetylase) or the E3 (dihydrolipoyl dehydrogenase) subunits of the PDC enzymatic complex, DLAT and DLD genes respectively. In these cases, PDCD displays autosomal recessive inheritance, affecting males and females equally.[12]

In cases where PDCD is a result of a mutation in a gene other than PDHA1, it is most commonly known to be due to mutations in the following four genes, PDHB, DLAT, PDHX and PDP1. All of these genes, like the PDHA1 gene are responsible for coding for a specific subunit of the pyruvate dehydrogenase complex. The PDHB gene is responsible for the coding of the E1 beta subunit of the pyruvate dehydrogenase complex. The DLAT gene is responsible for the coding of the E2 subunit, and the PDP1 is responsible for producing the PDH phosphatase catalytic subunit that catalyzes PDH dephosphorylation. This dephosphorylation activates the complex. The final gene that could be responsible for this disease is the PDHX gene, which codes for the E3 binding protein which is responsible for binding E3 dimers to the E2 subunit of the complex.[13]

MRI of head(brain)- cerebral atrophy can be detected by such a method[14]

Pyruvate dehydrogenase deficiency can be diagnosed via the following methods:[14]

• Blood test (Lactate and pyruvate levels)
• Urine analysis
• Magnetic resonance spectroscopy
• MRI

Direct treatment that stimulates the pyruvate dehydrogenase complex (PDC), provides alternative fuels, and prevents acute worsening of the syndrome.[15] However, some correction of acidosis does not reverse all the symptoms. CNS damage is common and limits a full recovery.[7] Ketogenic diets, with high fat and low carbohydrate intake have been used to control or minimize lactic acidosis and anecdotal evidence shows successful control of the disease, slowing progress and often showing rapid improvement.[16] Ketogenic baby formulas such as Nutricia KetoCal are available.[17] With the ketogenic diet, ATP is synthesized by the catabolism of fatty acids rather than glucose, which produces the ketone bodies, 3-beta-hydroxybutyrate, acetoacetate, and acetone. Ketone bodies serve as an alternate source of energy for the body and the brain.[16] Preliminary data from PDHD patients on the ketogenic diet indicate that in milder cases, there is a reduction in the frequency of seizures, abnormal EEG readings, ataxia and abnormal sleeping patterns, and extension of remission periods. More severe cases are less responsive to the ketogenic diet, but have displayed modest improvement of gross and fine motor skills, speech and language development and development of social skills.[16] The ketogenic diet has several long term drawbacks, including pancreatitis, sialorrhea and obstipation to vomiting. Patients must be monitored regularly for blood lactate levels, transaminase and plasma ketone levels.[16]

There is some evidence that dichloroacetate reduces the inhibitory phosphorylation of pyruvate dehydrogenase complex and thereby activates any residual functioning complex. Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability. However, treatment with dichloroacetate does not improve neurological damage.[5] Oral citrate is often used to treat acidosis.[18]

Clinical trials to improve scientific and medical understanding of PDCD are underway. More information is located at ClinicalTrials.gov.[19]

Pyruvate dehydrogenase deficiency is extremely rare, with ~500 reported cases in the medical literature. Due to the rarity and unfamiliarity of the disease, it is likely underdiagnosed[7] (Shin et al., 2017).

• Citric acid cycle
• Branched-chain alpha-keto acid dehydrogenase complex
• Anti-mitochondrial antibody