Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients

Abstract

Background The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype–phenotype correlations. Results The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.

Loss of Oligodendrocytes in Mouse Model of Pyruvate Dehydrogenase Complex Deficiency and Partial Reversal by Phenylbutyrate Treatment

“…The mechanism by which PB produces its restorative effects were illustrated in the studies of Ferriero, et al which demonstrated PB-induced marked dephosphorylation of the PDHα in the brain, liver and the muscle tissues [17] and further discussed in [48]. PB is known also as a histone deacetylase inhibitor and this could potentially play a role in upregulation of OLG and OLG progenitors in the current study of PDC-deficient mice.…”

Ambiguous Presentations of Pyruvate Dehydrogenase Deficiency: Combined Case Studies

“…The presentation of symptomatic patients varies -from lactic acidosis that occurs when a patient is under physiologic stress to deranged infantile brain development [6,10,11]. Nevertheless, treatment for acute PDH deficiency and long-term management entail supplementing the following cofactors: thiamine, carnitine and lipoic acid [12].…”

“…Literature corroborates the infamous triad of WE: confusion, ophthalmoplegia and ataxia [5]. Patients with PDH deficiency may share similar neurological deficits [6]. Even so, the initial complaints for both metabolic disorders are rather vague and may demand a variety of investigations -most of which will be normal or entirely inconclusive.…”

Treatable Hyperkinetic Movement Disorders Not to Be Missed

“…Pyruvate dehydrogenase deficiency is caused by mutations in genes coding for the mitochondrial pyruvate dehydrogenase complex that has a crucial role in cellular metabolism (PDHA1 in most cases, more rarely PDHA2, PDHX, or DLAT) (190)(191)(192). Most patients present with severe early-onset encephalopathy, whereas others may present with prominent movement disorders, mainly static and/or paroxysmal dystonia or episodic ataxia.…”