From the Guidelines
Inborn errors of metabolism that lead to lactic acidosis include pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial respiratory chain disorders, and disorders of gluconeogenesis such as glucose-6-phosphatase deficiency, as identified in recent studies 1. These disorders typically present in infancy or early childhood with symptoms including poor feeding, lethargy, developmental delay, seizures, and hypotonia.
Key Disorders
- Pyruvate dehydrogenase deficiency, which prevents the conversion of pyruvate to acetyl-CoA, causing pyruvate to accumulate and convert to lactate
- Pyruvate carboxylase deficiency
- Mitochondrial respiratory chain disorders
- Disorders of gluconeogenesis such as glucose-6-phosphatase deficiency Laboratory findings show elevated lactate levels in blood and cerebrospinal fluid, with a high lactate-to-pyruvate ratio.
Management Strategies
- Supportive care
- Dietary modifications (such as ketogenic diet for pyruvate dehydrogenase deficiency)
- Cofactor supplementation (thiamine, biotin, or coenzyme Q10 depending on the specific disorder)
- Treatment of acute metabolic crises with intravenous fluids, bicarbonate for severe acidosis, and removal of toxic metabolites Early diagnosis through newborn screening or targeted genetic testing is crucial for implementing appropriate treatment and improving outcomes, as emphasized in recent guidelines 1.
From the Research
Inborn Errors of Metabolism Leading to Lactic Acidosis
- Lactic acidosis can be caused by several inborn errors of metabolism, including pyruvate dehydrogenase complex deficiency (PDCD) 2, 3, 4, 5.
- PDCD is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism, and it is the most common genetic disorder leading to lactic acidosis 4.
- Other inborn errors of metabolism that can lead to lactic acidosis include pyruvate carboxylase deficiency, phosphoenolpyruvate carboxykinase deficiency, and dihydrolipoyl dehydrogenase deficiency 5.
Clinical Presentation and Diagnosis
- The clinical presentation of lactic acidosis can vary, but common symptoms include hypotonia, developmental delay, and respiratory distress 2, 3.
- Diagnosis of PDCD and other inborn errors of metabolism can be made through a combination of clinical evaluation, laboratory tests, and genetic analysis 2, 3, 5.
- Laboratory tests may include measurement of lactate and pyruvate levels, as well as assays for enzyme activity 2, 3, 5.
Treatment and Management
- There is no effective treatment for PDCD, but management strategies may include dietary modifications, vitamin supplements, and pharmacological interventions such as dichloroacetate and phenylbutyrate therapy 2, 4.
- Phenylbutyrate has been shown to increase PDHC enzyme activity and reduce phosphorylated E1α in brain, muscle, and liver, and it may be a potential treatment for PDCD and other forms of primary and secondary lactic acidosis 4.
- Early recognition and treatment of lactic acidosis are critical to preventing long-term complications and improving outcomes 2, 3, 4.