Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency

Abstract

Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs multiple, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder. We sought to evaluate the diagnostic sensitivity and variability of the various PDC enzyme assays in females and males at the Center for Inherited Disorders of Energy Metabolism (CIDEM). CIDEM data were filtered by lactic acidosis and functional PDC deficiency in at least one cell/tissue type (blood lymphocytes, cultured fibroblasts or skeletal muscle) identifying 186 subjects (51% male and 49% female), about half were genetically resolved with 78% of those determined to have a pathogenic PDHA1 mutation. Assaying PDC in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1, was highly sensitive irrespective of gender; 97% (95% confidence interval [CI]: 90%–100%) and 91% (95% CI: 82%–100%) in females and males, respectively. In contrast to the fibroblast-based testing, the lymphocyte- and muscle-based testing were not sensitive (36% [95% CI: 11%–61%, p = 0.0003] and 58% [95% CI: 30%–86%, p = 0.014], respectively) for identifying known PDC deficient females with pathogenic PDHA1 mutations. In males with a known PDHA1 mutation, the sensitivity of the various cell/tissue assays (75% lymphocyte, 91% fibroblast and 88% muscle) were not statistically different, and the discordance frequency due to the specific cell/tissue used for assaying PDC was 0.15 ± 0.11. Based on this data, a practical diagnostic algorithm is proposed accounting for current molecular approaches, enzyme testing sensitivity, and variability due to gender, cell/tissue type used, and successive repeat testing.

A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

“…Similarly in cultured fibroblasts, average (n = 2) activated and inactivated PDC activity was 33% and 37% of control mean, respectively (Table ), with one inactivated value in fibroblasts being low (15%) and another low‐normal (59%). We have observed discordance with successive repeat of fibroblast‐based PDC testing in males in about 5% of cases (n = 70) tested and the reason for this remains unclear. Activity of dihydrolipoamide dehydrogenase (the E3 component of PDC and another mitochondrial reference enzyme) was normal in both blood lymphocytes and cultured fibroblasts (Table ).…”

“…Epilepsy (16%‐57%), hypotonia (46%‐89%), and developmental delay (57%‐83%) are other common findings in subjects with PDC deficiency . PDC deficiency is sub‐classified into at least three groups, primary‐specific, primary‐generalized, and secondary PDC deficiencies . Primary‐specific PDC deficiency due to mutations in primary specific genes including PDHA1 , PDHB , DLAT , PDHX , PDP1 , PDP2 , and PDPR , constitute 70% to 90% of PDC activity deficiencies, with those due to X‐linked PDHA1 mutations representing >80% of genetically defined primary‐specific deficiencies .…”

“…[30][31][32]34 PDC deficiency is sub-classified into at least three groups, primary-specific, primary-generalized, and secondary PDC deficiencies. 29 Primary-specific PDC deficiency due to mutations in primary specific genes including PDHA1, PDHB, DLAT, PDHX, PDP1, PDP2, and PDPR, constitute 70% to 90% of PDC activity deficiencies, with those due to X-linked PDHA1 mutations representing >80% of genetically defined primary-specific deficiencies. 5,29 The clinical consequences of defects of primary-specific PDC gene products are not qualitatively distinct because each of these defects have the common biochemical effect of impairing function of the overall complex.…”

Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes

“…PDC de ciency diagnosis is extremely challenging due to a phenotypic presentation that can be observed in many other disorders, especially those causing altered mitochondrial metabolism (6,21,22). Given this context, we aimed to present the rst report on Portuguese PDC de cient patients combining information on the associated clinical, biochemical, enzymatic and genotypic spectra.…”

A Case of Early Diagnosis of Pyruvate Dehydrogenase Complex Deficiency: The Use of Next-Generation Sequencing

“…In the past, 1-14C-pyruvate-based assay of PDC in blood lymphocytes, cultured fibroblasts or skeletal muscles were used for diagnosis of PDHD. With the development of nextgeneration sequencing (NGS) technique, genetic testing is also being used in the diagnosis of PDHD (5). Nevertheless, it is difficult to make a diagnosis of PDHD in neonatal period.…”