Case Report: A novel hemizygous missense PDHA1 variant in a Vietnamese boy with pyruvate dehydrogenase E1-alpha deficiency

Abstract

A pyruvate dehydrogenase complex deficiency causes a reduction in adenosine triphosphate production and energy insufficiency, leading to neurological disorders. An abnormal E1-alpha protein originating from the PDHA1 gene with pathogenic variants is unable to communicate with E1-beta for the formation of the E1 enzyme, decreasing pyruvate dehydrogenase complex activity. In this study, we report a Vietnamese boy with lethargy, severe metabolic acidosis, increased serum lactate, hyperalaninemia, lactic acidosis, and globus pallidus lesions. Whole-exome sequencing and variant filtering identified a hemizygous missense variant NM000284.4 (PDHA1): c.479T>G (p.Phe160Cys) in the patient. The variant c.479T>G caused a single nucleotide substitution on exon 5 and was predicted to be a disease-causing variant in the in silico analyses. We present the first report with a genetic analysis of a Vietnamese patient with pyruvate dehydrogenase E1-alpha deficiency (PDHAD). Sanger sequencing demonstrated that the patient inherited the variant from his mother who harbored the variant in a heterozygous state, but no PDHAD symptoms were observed in her. In addition, a prenatal test of the patient's mother revealed a fetus with a normal genotype. Furthermore, the patient's father and sister both carried a normal allele. Based on the American College of Medical Genetics criteria, the variant c.479T>G was predicted to be a likely pathogenic variant. Using the combination of the patient's genotype and phenotype, he was definitively diagnosed with pyruvate dehydrogenase E1-alpha deficiency. Our findings expand the mutational spectrum of neurological disorders and provide the scientific basis for genetic counseling for the patient's family.

Keywords: PDHA1; Vietnamese; missense variant; pyruvate dehydrogenase E1-alpha deficiency; whole-exome sequencing.

Figure 1

Magnetic resonance imaging of the brain (a) and timeline of medical events (b) of the proband. (a) Magnetic resonance imaging of the brain at 15 months of age showing globus pallidus lesions (hypointensity in the T1W image, and hyperintensity in the T2W image and FLAIR image). (b) The numbers in the arrow represent the months. The proband was small for his gestational age (GA), and presented with three episodes of acute lactate acidosis at 10, 13, and 15 months of age. At 24 months of age, whole blood was collected for genetic testing including whole-exome sequencing (WES) and Sanger sequencing. Two months later, a molecular diagnosis was achieved for the proband. However, at 25 months of age, the proband presented with tachypnea and coma and died at home.

Figure 2

A PDHA1 variant was confirmed by Sanger sequencing. (a) A DNA sequencing electropherogram in the patient's family, the variant NM000284.4 (PDHA1): c.479T > G (p.Phe160Cys) was hemizygous in the patient. The mother carried the variant in a heterozygous state, while the father, sister, and fetus harbored normal alleles. (b) The alignment of multiple PDHA1 amino acid sequences showed the highly conserved amino acid at the Phe160 position.