Difficulties in diagnosing pyruvate dehydrogenase complex deficiency based on clinical and biochemical data: series of clinical case reports

Pyruvate dehydrogenase complex deficiency (PDC) is a mitochondrial disease associated with a violation of pyruvate metabolism and leading to a decrease in ATP production. PDC is responsible for the decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by changes in any of the genes encoding its subunits. The clinical phenotype is very variable, mainly the central nervous system is affected. Diagnosis of the disease can cause significant difficulties due to the rarity of the pathology, the lack of specificity of clinical symptoms and pronounced clinical polymorphism. The purpose of this research was to describe and discuss the clinical, biochemical and genetic data of six recently observed patients with PDC deficiency who were identified in Russia. Authors have analyzed the clinical manifestations of a rare progressive pathology from the group of mitochondrial diseases caused by pathogenic variants of the nuclear X-linked PDHA1 gene (encodes the alpha subunit of pyruvate dehydrogenase) in six patients aged 8 to 120 months old. By the time of examination in the hospital the main clinical symptoms included as follows: delayed psychomotor development, epileptic seizures, severe delay in psychomotor development and - in a single patient - depression of consciousness to coma, the status of epileptic seizures and an unfavorable outcome. In all patients, magnetic resonance imaging (MRI) of the brain revealed changes as follows: cortical atrophy in all 6 patients, basal ganglia lesion in three cases, congenital brain defects in 3 patients and multicystic lesion in a single patient. All children had high lactate levels. Pathogenic variants of the PDHA1 gene were detected in all 6 children and on this basis the diagnosis was confirmed. As a result of treatment, 5 of the 6 children showed moderate positive dynamics as follows: a decrease in the frequency of epileptic seizures and lactate in the blood, improvement in psychomotor development and - in a single patient - a fatal outcome as a result of late diagnosis and rapidly progressing clinical symptoms. Conclusion: Authors have described the clinical characteristics of PDC in recent cases such as: age of manifestation, the disease course nature, results of molecular genetic studies. Clinical polymorphism in patients with this rare pathology was shown as well. The Article may be of great help to pediatricians, neurologists and geneticists in improving the diagnosis of PDC deficiency.