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

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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.

Highlights

► We reviewed 371 cases of pyruvate dehydrogenase complex deficiency. ► We defined the dominant clinical and biochemical phenotype. ► The various biochemical etiologies of the disease had similar clinical courses.

Introduction

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the rate-limiting step in the aerobic glucose oxidation and is thus integral to cellular energetics [1], [2] (Fig. 1). It comprises multiple copies of three enzymatic subunits: pyruvate dehydrogenase (E1), dihydrolipoamide transacetylase (E2), and dihydrolipoamide dehydrogenase (E3), as well as an E3 binding protein (BP). The E1 component is a heterotetramer of 2 alpha and 2 beta subunits. The gene for the E1α subunit is located on the X chromosome and all proteins of the complex are nuclear encoded. Rapid regulation of the complex is regulated mainly by reversible phosphorylation of the E1α subunit [3] that is mediated by a family of PDC kinases (PDK) and phosphatases (PDP) [4], [5].

Although over 40 years have elapsed since the first description of a congenital deficiency of the PDC [6], the incidence and prevalence of this life-threatening condition remain unknown. Several excellent earlier reviews exist of the clinical and biochemical characteristics or of the molecular genetic etiologies of PDC deficiency [2], [7], [8], [9]. However, there has been no recent comprehensive analysis of the natural history of the disease, nor attempts to discern phenotypic differences or predictable outcomes based on biochemical defects or mutations in specific components of the complex. Here we summarize the clinical, biochemical and genetic findings contained in published reports and personal experience of 371 individual cases of PDC deficiency. We sought associations among various pathological indices that could provide new insight into the pathobiology and clinical course of this disease.

Section snippets

Source material

We reviewed all English language publications under “pyruvate dehydrogenase deficiency” and deficiency of each individual subunit and component of the complex listed in PubMed and Google Scholar from 1970 through December, 2010. Additional publications were found by reviewing the references included in articles not identified by the search engines. We also included information on a previously unpublished case of PDC E1α deficiency.

Definition of PDC deficiency

To be included a report had to provide a quantitative assessment

Results

We found 159 full-length, peer-reviewed publications of 392 case reports of patients with PDC deficiency from the first reported case in 1970–2010. A few papers reported complimentary details of the same patient [6], [24], [32], [38], [40], [41], [45], [47], [49], [66], [69], [75], [77], [80], [83], [84], [96], [97], [103], [105], [112], [114], [129]. Twenty-one cases were omitted from our analysis, owing to lack of explicit enzymological or molecular genetic confirmation of disease [12], [13],

Discussion

PDC deficiency has been considered one of the most common biochemically proven causes of congenital lactic acidosis [2]. Our review of 371 cases of biochemically and/or genetically established PDC deficiency supports this notion. Regardless of which subunit or component of the complex is defective, most patients present within the first few months of life with both clinical and biochemical evidence of disease. The dominant presenting phenotype of PDC deficiency includes impairment of

Conclusions

In summary, our analysis of 371 cases of proven PDC deficiency found that neither gender nor any biochemical or clinical feature differentiates the various enzymological or molecular genetic etiologies of the disease. The clinical spectrum of PDC deficiency is broad, but typically presents in early childhood with neurodevelopmental and neuromuscular compromise. Hyperlactatemia is a frequent, but not universal, finding early in the disease process, is associated with a blood lactate:pyruvate

Acknowledgments

This work was supported by NIH grants , , and by the University of Florida's Clinical and Translational Science Institute. We thank Ms. Kathryn St. Croix for editorial assistance.

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