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Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex
Ha Kyung Shin1, George Grahame2, Shawn E McCandless3
1School of Medicine, Case Western Reserve University (CWRU), Cleveland, OH, USA.
Insights
Pyruvate dehydrogenase complex (PDC) deficiency diagnosis is crucial for children with lactic acidemia. Fibroblast enzyme assays are highly sensitive for detecting PDC deficiency, regardless of sex, aiding in accurate diagnosis and management.
Area of Science:
- Biochemistry and Metabolism
- Genetics and Molecular Biology
- Pediatric Medicine
Background:
- Pyruvate dehydrogenase complex (PDC) deficiency is a primary cause of lactic acidemia in children.
- Accurate diagnosis is vital for effective clinical management and therapeutic strategies.
- Current diagnostic approaches include genetic and enzymatic testing, but their efficacy requires systematic investigation.
Purpose of the Study:
- To evaluate the diagnostic sensitivity and variability of PDC enzyme assays in males and females.
- To compare the efficacy of different cell/tissue types (lymphocytes, fibroblasts, muscle) for PDC deficiency testing.
- To propose a diagnostic algorithm considering enzyme assay sensitivity, genetic factors, and patient demographics.
Main Methods:
- Analysis of data from 186 subjects with lactic acidosis and functional PDC deficiency at the Center for Inherited Disorders of Energy Metabolism (CIDEM).
- Filtering subjects based on lactic acidosis and PDC deficiency in blood lymphocytes, cultured fibroblasts, or skeletal muscle.
- Evaluation of diagnostic sensitivity of PDC enzyme assays across different cell types and genders, particularly for PDHA1 mutations.
Main Results:
- Cultured fibroblast PDC assays demonstrated high sensitivity (97% in females, 91% in males) for PDHA1-related deficiency.
- Lymphocyte and muscle assays showed lower sensitivity, especially in females (36% and 58%, respectively).
- In males with PDHA1 mutations, sensitivities of lymphocyte (75%), fibroblast (91%), and muscle (88%) assays were not significantly different.
Conclusions:
- Fibroblast-based PDC enzyme assays are highly sensitive and reliable for diagnosing PDHA1-related deficiency in both sexes.
- Lymphocyte and muscle assays exhibit lower sensitivity and greater variability, necessitating careful interpretation.
- A proposed diagnostic algorithm integrates molecular testing, enzyme assay sensitivity, and cell-type specific variations for improved diagnostic accuracy.
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 generalized, 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 for testing, and successive repeat testing.
