Diagnostic Strategy for PDHC Deficiency

Metabolism Disease Project: Diagnostic Strategy for PDHC Deficiency Pyruvate Dehydrogenase Complex Deficiency is an X-linked and autosomal recessive disease that occurs in the mitochondria, where the enzyme complex is located (De Meirleir et al, 1993). The pyruvate dehydrogenase complex (PDHC) consists of three subunits: El (pyruvate dehydrogenase), E2( dihydrolipoyl transacetylase), and E3 (dihydrolipoyl dehydrogenase). Mutations in the PDHC Ela gene (~80% of cases), El p gene, E2 gene, E3 gene, and pyruvate dehydrogenase phosphatase in the X-chromosome have been identified as genetic causes of this condition (De Meirleir et al, 2000). Mutations in these genes affect the PDC by either influencing its effectiveness, or the synthesis of PDH itself. Despite multiple possible sources of genetic mutations, the prognosis of PDHC is not related to the genetic mutations. Consequently, the determination of PDHC must be made by testing afflicted metabolites in PDCD. The main function of the pyruvate dehydrogenase complex is catalyzing the synthesis of the cofactor ADH and the starting molecule for the TCA cycle, acetyl-CoA, from pyruvate, the main product of glycolysis. Moreover, pyruvate serves as a convergence point of the catabolism of many other macromolecules including some lipids, proteins, and amino acids into the citric acid cycle and eventually produces ATP. A deficiency of the pyruvate dehydrogenase complex will cause increased production of lactate (lactic acidosis) instead of acetyl-CoA from glucose, thereby lowering the efficiency of energy production (Saudubray et al, 2016, p.192). Given the importance of PDC, symptoms of PDC deficiency usually present within the first year of birth (Patel et al, 20 I 2). A reduction of ATP production efficiency most prominently affects the brain in afflicted patients, resulting in neurological developmental disorders such as early-onset seizures, developmental delay, and ventricular dilatation due to the lack of cellular energy (De Meirleir et al, 1993). Since patients who developed these symptoms usually have increased lactate and pyruvate in their blood and cerebrospinal fluid, a good target to diagnose afllicted patients are lactic acid levels, particularly within the brain. Therefore, one of our diagnostic strategies will be to measure lactate levels in the blood, urine, and cerebrospinal fluid. In addition, to further confirm the diagnosis of PDHC, we will test for alanine levels in the blood serum and cerebrum fluid (De Meirleir et al, 1993). This will be the best amino acid to test for as it catabolizes to pyruvate directly during metabolism. So, accumulation of pyruvate due to a non-functioning pyruvate dehydrogenase complex will lead to a buildup in alanine as the conversion of alanine to pyruvate will be paused due to negative feedback regulation. In some patients, the blood lactate and alanine levels can appear to be normal and only show the characteristic abnormal increase after an oral carbohydrate load, such as a meal high in carbohydrates, and the excretion of excess alanine can occur only after experiencing acute episodes (Saudubray et al, 2016, p.193). False-negative results from the lactate and alanine measurements might lead to misdiagnosis, which could delay treatments. Therefore, for a more accurate diagnosis of PDHC deficiency, it is important to collect multiple blood samples from a patient under different dietary conditions, especially when the patient is severely ill and the blood becomes difficult to obtain. In addition, neuroimaging such as MRI is highly recommended for patients experiencing acute episodes of metabolic decompensation since the brain lesion caused by PDHC deficiency can be transient and reversible (Giribaldi et al, 2012).