Introduction:
Blass et al. first described pyruvate dehydrogenase complex (PDC) in 1970. The decarboxylation (removal of carbon) of pyruvate into acetyl-CoA is catalyzed by the pyruvate dehydrogenase complex (PDC). The alteration in any of the genes can cause PDC deficiency. PDC affects the central nervous system. There are few differences in symptoms for males and females due to differences in their genetic makeup of sex chromosomes. Females have more variable symptoms than males. A person having this deficiency may have high or low plasma lactate and pyruvate levels. However, it can be diagnosed by genetic tests, enzymatic assays, and blood tests. As per its treatment, healthcare has to manage its symptoms by supporting the patient's overall health, including different diets and therapies. This article will discuss causes, symptoms, and treatment.
What Is Pyruvate Dehydrogenase Deficiency?
Pyruvate dehydrogenase deficiency is an inborn error of mitochondrial (a powerhouse of the cell in the body) energy metabolism. Metabolism is the process of all chemical reactions taking place in our body. The pyruvate oxidation route in mitochondria bridges the various pathways of chemical reactions. Pyruvate dehydrogenase complex decarboxylates (removal of the carbon) pyruvate to acetyl coenzyme A. This reaction comprises three functional components and the regulatory PDC kinases and PDC phosphatases. The complexes of three functional components of enzyme 1 (pyruvate dehydrogenase), enzyme 2 (dihydrolipoamide transacetylase), enzyme 3 (dihydrolipoyl dehydrogenase), and one binding protein control the complex activity via phosphorylation/dephosphorylation.
Phosphorylation refers to adding phosphate, whereas dephosphorylation refers to removing phosphate from the compound. The body's low amount of pyruvate dehydrogenase complex is called pyruvate dehydrogenase deficiency. PDC deficiency in the majority of patients (around 77 %) occurs due to mutation (alteration in the gene) in the X-linked PDHA1, which encoded the enzyme 1 (E1). E1 catalyzes the first step of the reaction taking place during the cycle.
What Causes Pyruvate Dehydrogenase Deficiency?
Pyruvate dehydrogenase deficiency is caused due to alteration in the gene which encodes the enzyme responsible for the chemical reaction of PDC. Males are usually symptomatic, whereas females present variable symptoms due to X-inactivation in different tissues. The genetic makeup of sex chromosomes in males is XY, whereas, in females, it is XX. The remaining cases are caused by mutations in the genes encoding the remaining subunits: PDHB (Pyruvate dehydrogenase) encoding E1 (Enzyme 1) β (4.3 %), DLAT (dihydrolipoyl transacetylase) encoding E2 (Enzyme 2) (1.5 %), DLD (Dihydrolipoamide dehydrogenase deficiency) encoding E3 (Enzyme 3) (6.2 %), and PDHX (Pyruvate Dehydrogenase Complex) encoding E3 (Enzyme3) BP (10.7 %).
What Are the Symptoms Of Pyruvate Dehydrogenase Deficiency?
The clinical representation of pyruvate dehydrogenase deficiency is variable, ranging from a fatal lactic acidosis (a condition in which excess accumulation of lactic acid occurs in the body) and progressive neurological and neuromuscular degradation in the neonatal period (before birth) to chronological neurological dysfunction and neurodegenerative condition. Neurodegenerative condition refers to the degradation of the neurons or nervous system.
The following are the symptoms of pyruvate dehydrogenase deficiency:
-
Lactic acidemia (a condition in which excess lactic acid accumulates in the body due to inadequate removal of pyruvate or lactate).
-
Neurological dysfunction.
-
Hypotonia (a condition characterized by low muscle tone).
-
Seizures (a condition in which uncontrolled shaking movement of limbs occurs).
-
Ataxia (a condition in which impaired coordination of the muscles occurs).
-
Respiratory distress (like apnea and hypoventilation). Hyperventilation refers to a low breathing rate.
-
Facial dysmorphism (a condition in which facial features abnormalities occur).
-
Peripheral neuropathy is a disorder that damages the peripheral nerves, resulting in limb numbness and paralysis.
-
Structural and functional brain abnormalities.
How To Diagnose Pyruvate Dehydrogenase Deficiency?
The patients were suspected to be PDC deficient on the basis of clinical symptoms such as:
-
High plasma lactate (L) and pyruvate (P) levels.
-
low L/P ratio.
-
Impaired PDC activity.
Patients can be diagnosed by following investigations:
-
Genetic Test - X-linked mutation can be detected by a genetic test.
-
Enzymatic Assays - Enzymatic assays were performed either in circulating lymphocytes (white blood cells) or cultured fibroblasts. The suspected patients have positive results.
-
Blood Test - Blood samples were collected after overnight fasting by venipuncture. The elevated levels of plasma lactate and pyruvate dehydrogenase is detected.
What Are the Treatments of Pyruvate Dehydrogenase Deficiency?
The treatment of PDH focuses on managing the symptoms and supporting overall health. Here are some approaches used in the management of pyruvate dehydrogenase deficiency:
-
High-Fat and Low-Carbohydrate Diet: The ketogenic diet is a specialized eating plan that is the main treatment for PDH. This diet benefits the body by giving it an alternate energy source because it is high in fats and low in carbohydrates. By relying on fats instead of glucose, the body can bypass the deficient pyruvate dehydrogenase enzyme and generate energy through ketone bodies.
-
Thiamine (vitamin B1) Supplementation: Thiamine acts as a cofactor for the pyruvate dehydrogenase complex. Supplementing with thiamine can help enhance the activity of the remaining functional enzyme and improve energy metabolism. Thiamine supplementation is often administered in high doses.
-
Lipoic Acid Supplementation: Lipoic acid is another cofactor required for the pyruvate dehydrogenase complex. Supplementation with lipoic acid can help support the function of the enzyme and improve energy production. Lipoic acid is often given in the form of sodium dihydrolipoate.
-
Coenzyme Q10 Supplementation: Coenzyme Q10 plays a role in the electron transport chain, which is involved in energy production within cells. Supplementing with coenzymes, Q10 can help improve energy metabolism and alleviate some of the symptoms associated with PDH.
-
Physical Therapy and Supportive Care: Physical therapy and supportive care are important components of the treatment plan for PDH. These measures aim to optimize muscle function, improve mobility, and address any complications that may arise due to the condition.
Conclusion
Pyruvate Dehydrogenase Deficiency (PDH) is a rare genetic disorder that affects the body's ability to convert carbohydrates into energy. This disorder results from an absence or malfunction of the pyruvate dehydrogenase enzyme complex, which is essential for cellular energy synthesis. Research efforts are ongoing to better understand the underlying mechanisms of PDH deficiency and develop potential therapeutic interventions. Gene therapy and other emerging strategies hold promise for future treatment options.
