Pyruvate dehydrogenase E1-alpha deficiency is the most frequent form of pyruvate dehydrogenase deficiency (PDHD). The signs and symptoms usually first appear shortly after birth and include; lactic acidosis, psychomotor retardation, hypotonia, seizure, ataxia and other signs of neurological dysfunction. The exact prevalence is unknown, however more than 200 patients have been described. It was noted that male patients are more severely affected the female patients.Some patients have structural brain lesions. Dignosis can be made by measuring the level of lactic acid and pyrovate in on to perform enzyme assay and molecular genetic testing. Clinically, check for signs of central nervous system dysfunctions. Treatments include cofactor supplementation with thiamine, carnitine, and lipoic acid in order to optimize the function of pyruvate dehydrogenase complex. The correction of lactic acidosis does not restore the damaged CNS.
Mutations in the PDHA1 gene cause Pyruvate dehydrogenase E1-alpha deficiency. PDHA1 gene is located on the short arm of chromosome X. The E1 component of the PDH complex catalyzes the thiamine pyrophosphate (TPP)-dependent decarboxylation of pyruvate. Moreover, E1 alpha-subunit contains a conserved TPP binding motif. Several mutations have been identified in this gene.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organelle disorders were identified in 18 out of 248 of diagnosed subjects. Among them, 3 cases from 2 families were found to have PDH deficiency; additionally, 4 cases from 4 families were found to have congenital lactic acididemia. The incidence is estimated at 2 per 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with IEM in whom mutational pathogenicity was confirmed, 1 patient harboring a deleterious variant of PDHA1 was diagnosed with pyruvate dehydrogenase E1-alpha deficiency. The patient clinically presented with low fibroblastic succinate dehydrogenase activity and CNS structural anomalies indicative of Leigh syndrome.
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