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A cognitively normal PDH-deficient 18-year-old man carrying the R263G mutation in the PDHA1 gene
R Bachmann-Gagescu1, J Lawrence Merritt, S H Hahn
1Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Insights
Pyruvate dehydrogenase deficiency (PDHD) can present variably. This case highlights an exceptional outcome with normal cognition in an 18-year-old despite a common PDHA1 mutation, R263G.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pyruvate dehydrogenase (PDH) deficiency is a metabolic disorder impacting the link between glycolysis and the citric acid cycle.
- Mutations in the PDHA1 gene are the most common cause, leading to a spectrum of neurological symptoms.
- Clinical presentation ranges from severe neonatal acidosis to chronic encephalopathy, with variable genotype-phenotype correlations.
Observation:
- A case of PDH deficiency due to a common PDHA1 mutation (R263G) is presented in an 18-year-old.
- This patient exhibits an exceptional clinical outcome, with normal cognition and brain MRI.
- Previous cases with the R263G mutation typically presented with intellectual disability or Leigh syndrome.
Findings:
- The R263G mutation in PDHA1 can be associated with a much milder phenotype than previously recognized.
- Effective management, including a ketogenic diet and specific supplements, may contribute to favorable outcomes.
- This case expands the known clinical spectrum of PDH deficiency.
Implications:
- The variability in PDH deficiency necessitates individualized patient management and counseling.
- Further research is needed to understand the factors influencing the diverse clinical presentations.
- This case underscores the importance of considering a broad differential diagnosis for neurological symptoms.
Abstract:
Pyruvate dehydrogenase (PDH) is a crucial multienzyme system linking glycolysis to the tricarboxylic acid cycle by catalysing the decarboxylation of pyruvate to acetyl-CoA. Deficiency in pyruvate dehydrogenase is most commonly secondary to mutations in the X-linked PDHA1 gene encoding the E1 alpha subunit. There is a wide range of clinical presentations from severe neonatal lactic acidosis to chronic encephalopathy (Leigh syndrome). In recent years, a small subset of patients was recognized with less severe involvement, presenting initially only with intermittent symptoms, mainly of ataxia. Most of these patients remain stable for a number of years before developing progressive neurological deterioration around puberty at the latest. There does not appear to be a reliable correlation between genotype, phenotype, or enzyme activity. This makes counselling in a clinical setting challenging. We report a case with a previously known common mutation in PDHA1 (R263G) with an excellent outcome at 18 years of age. Previous patients with this mutation have presented with mental retardation and/or Leigh syndrome, while our patient's clinical outcome is exceptional. He is cognitively normal and has normal brain MRI. His management includes a stringent carbohydrate-free diet, as well as supplementation with thiamine, carnitine and vitamin E. This case further broadens the clinical spectrum, including now an example of a cognitively normal adult with PDH deficiency.
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