The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients

Abstract

Context: Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration and, usually, death during childhood. There has been no recent comprehensive analysis of the natural history and clinical course of this disease.

Objective: We reviewed 371 cases of PDC deficiency, published between 1970 and 2010, that involved defects in subunits E1α and E1β and components E1, E2, E3 and the E3 binding protein of the complex.

Data sources and extraction: English language peer-reviewed publications were identified, primarily by using PubMed and Google Scholar search engines.

Results: Neurodevelopmental delay and hypotonia were the commonest clinical signs of PDC deficiency. Structural brain abnormalities frequently included ventriculomegaly, dysgenesis of the corpus callosum and neuroimaging findings typical of Leigh syndrome. Neither gender nor any clinical or neuroimaging feature differentiated the various biochemical etiologies of the disease. Patients who died were younger, presented clinically earlier and had higher blood lactate levels and lower residual enzyme activities than subjects who were still alive at the time of reporting. Survival bore no relationship to the underlying biochemical or genetic abnormality or to gender.

Conclusions: Although the clinical spectrum of PDC deficiency is broad, the dominant clinical phenotype includes presentation during the first year of life; neurological and neuromuscular degeneration; structural lesions revealed by neuroimaging; lactic acidosis and a blood lactate:pyruvate ratio ≤ 20.

Fig. 1

A. Central role of PDC in cellular energetics. B. PDC multi-enzyme complex. Abbreviations: TCA, tricarboxylic acid; e⁻, electrons; E1, pyruvate decarboxylase; E2, dihydrolipoamide transactylase; E3, dihydrolipoamide dehydrogenase; TPP, thiamine pyrophosphate; Lip, lipoate (reduced and oxidized).

Fig. 2

Brain imaging findings in 186 patients with PDC deficiency. Abbreviation: BS, brain stem.

Fig. 3

Outcome of 371 patients with PDC deficiency. There were 294 patients in whom death or survival was documented at the time of reporting and 77 patients whose outcome was unknown at the time of reporting.

Fig. 4

Outcome of 187 patients with PDC deficiency due to an identified biochemical and/or molecular genetic defect in E1α.