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PCDC summary

Pyruvate dehydrogenase complex (PDC) deficiency is a mitochondrial neurodegenerative

illness. PDC transforms pyruvate to acetyl-coenzyme A (ACoA), a citric acid cycle step (CAC).

Carbohydrates, fatty acids, and amino acids found in the mitochondrial matrix provide energy to

the CAC. The malfunction of this cycle drains energy. Pyruvate cannot be converted to ACoA

when PDCD is present. As a result, the main CAC substrate is decreased, and the alternative

pyruvate metabolic products lactate and alanine are abnormally accumulated. Mitochondria

cannot produce cell energy without CAC. Lack of energy products and accumulation of useless

metabolites result in generalized symptoms during times of illness, stress, or high carbohydrate

intake. PDCD patients typically experience progressive neurological symptoms in infancy,

though they might appear at birth or later in adulthood. Developmental delay, sporadic ataxia,

poor tone in the muscles, and seizures are all symptoms.

Childhood- and adult-onset versions of this illness generally have occasional

decompensation but normal or modestly delayed neurological development. Most pyruvate

dehydrogenase complex deficiencies have inadequate therapies; lactic acidosis may resolve, but

neurological impairment seldom stops. One of the main symptoms is gray matter degeneration

with necrosis and capillary growth in the brainstem. This pathology is described by Leigh

syndrome.

Pyruvate is transformed into ACoA, a citrate substrate, by the pyruvate dehydrogenase

complex (PDC).
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This enzymatic complex restricts citrate synthesis. The citric acid cycle can't proceed

since citrate is the first substrate. Alternate metabolic pathways are stimulated to create ACoA,

but a central nervous system energy shortage remains (CNS). Enzyme residual activity

determines the energy deficit. Enzyme deficits during neural development can induce congenital

brain malformations. Before ten weeks, morphological problems occur. Prenatal-onset PDCD

often causes corpus callosum maldevelopment. Neonates with a healthy brain can develop

neurodegeneration. In contrast to Leigh syndrome, which results in gliosis of the brainstem and

basal ganglia with capillary development, PDCD can induce cystic lesions, hypomyelination, and

gliosis of the cortex or cerebellum. Later-onset PDCD patients rarely have neuropathology.

Although PDCD incidences are unknown, they may be more frequent than anticipated

since they can produce unexplained seizures, acidosis, developmental delays in instances without

enzyme testing, and Leigh syndrome with CNS pathology. In X-linked situations, the mother is a

2-in-3 carrier. 1 in 4 recessive instances recur. Very mild examples feature in-frame E1 alpha

mutations. Neonatal-onset and infantile-onset PDCD are frequently fatal. [3] Later childhood

onset is often connected with adult survival. As PDC deficiency is deadly, all infants are born

with some residual enzyme activity. Infants with PDC activity of 15% or less do not survive.
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PDC activity greater than 25% is associated with a milder illness characterized by ataxia

and a minimal psychomotor delay. People with severe PDCD may live longer with certain

medications, although neurodegeneration causes major morbidity. X-linked PDCD affects more

males than females. Carriers may have minimal symptoms. Recessive variants of the disease are

milder than the X-linked version.

Because the E1 alpha enzyme subunit is X-linked, males are more typically impacted.

Variable X-chromosome inactivation causes mild-to-moderate symptoms in female carriers.

Many recessive versions are as severe as the X-linked form. PDCD females often have West

syndrome. PDCD males often have severe lactic acidosis and Leigh syndrome. PDCD females

experience neurodegeneration. Prenatal to early childhood presentation depends on PDC activity.

Severe illness causes fetal brain abnormalities. Psychomotor delay in babies indicates moderate

illness. The less severe illness causes occasional lethargy or ataxia in childhood.

Protein X and two regulatory enzymes make up the intramitochondrial PDC. PDC

cofactors thiamine pyrophosphate and lipoic acid. The dependence on E1 alpha and the three

substrate-processing enzymes protein X, thiamine, and E1 alpha have all been described;

however, E1 alpha subunit dysfunction is the most frequent. E1 alpha is encoded by the Xp22.2-

p22.1 gene. The stability or catalytic efficiency of polypeptides is reduced by over 90 E1 alpha

mutations. There has been a deficiency in the E1 beta enzyme component of PDC.

A thiamine triphosphate synthesis inhibitor in Leigh syndrome patients may produce

PDC E1 enzyme thiamine dependency. Tyrosine-phosphorylation of E1ss by EGFR-PTK

resulted in enhanced ubiquitination and proteasome-mediated degradation. Lipoic acid, an

enzyme cofactor, is deficient. E2 enzyme deficiency documented. Autosomal recessive

inheritance maps E3 to 7q31-32. Alpha-ketoglutarate dehydrogenase and branched-chain

ketoacid dehydrogenase are both carried out by E3.

PDCD is a serious medical condition that requires definitive testing to diagnose. Two of the

most important diagnostic tests are lactate/pyruvate levels and serum urine testing.

Lactate/pyruvate levels, when tested together, can help identify whether or not PDCD is present.

Serum and urine testing are also important for diagnosing PDCD as they can detect markers for the

condition that may not be found with lactate/pyruvate levels alone. With or without lactic

acidemia, elevated blood lactate and pyruvate levels indicate a mitochondrial metabolic error.

Blood lactate and pyruvate levels may be little or not at all elevated in typical situations in

moderate cases of pyruvate dehydrogenase complex impairment. According to recent studies, the

lactate-to-pyruvate ratio is only useful for diagnosing pyruvate dehydrogenase complex

impairment at higher lactate levels (>5 mmol/L).

Hyperalaninemia is seen in serum and urine. Deficiency of the E3 enzyme raises serum

branched-chain amino acids and urine alpha-ketoglutarate. Multiple amino acids are increased in

catabolic conditions, resulting in an unspecific amino acid profile. The absence of the E2 enzyme

is associated with hyperammonemia and a rise in nonspecific amino acids. Thiamine

pyrophosphate-adenosine triphosphate phosphoryl transferase inhibitor is found in blood or urine

using a test. Consume no more than 3–4 mg/kg/min of carbohydrates to reduce lactate buildup.

Individualize carbohydrate intake based on residual enzyme activity. 10-20 carbohydrate calories

per kilogram.

Considering ketogenic diets, limit carbohydrates and emphasize fat. Fat should make up

65-80% of calorie intake, protein 10%, and carbs the rest. To keep lactic acid levels constant,

modify your diet's fat and carbohydrate intake. The high levels of lactic acid in cerebrospinal
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fluid and the slow decline in neurological function show that CNS metabolic abnormalities

persist even while the ketogenic diet lowers blood lactic acid and lengthens lifespan. CNS

susceptibility is due to glucose dependency. After a few days on a ketogenic diet, the brain

switches from glucose to lipids.

Treatment of PDCD involves a combination of dietary modification, medications, lifestyle

changes, and nutrient supplementation. Thiamine, carnitine, and lipoic acid are usually

supplemented as a part of the treatment regimen, depending on the deficiency present. Cofactor

supplementation, particularly thiamine, is effective in some cases, with high dosages successfully

treating certain mutations that cause thiamine-responsive pyruvate dehydrogenase complex

deficiency. Additionally, dietary modifications such as avoiding high fructose corn syrup, limiting

sugar and carbohydrates, and increasing protein intake can be beneficial in some cases.

Cofactors are small organic molecules essential for a wide range of metabolic processes.

They help to facilitate the growth and division of cells and are clinically used to prevent and treat

deficiencies that can arise if cofactors are deficient. Some of the most important cofactors for

cellular metabolism are Biotin (vitamin H), Thiamine, lipoic acid, and Sodium dichloroacetate

(activator), which is part of the pyruvate dehydrogenase complex. It is important to note that each

of these cofactors has a distinct role in regulating cell metabolism, making them vital for cell

survival.
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References

https://emedicine.medscape.com/article/948360-print