Mild Phenotype in a Male with Pyruvate Dehydrogenase Complex Deficiency Associated with Novel Hemizygous In-Frame Duplication of the E1α Subunit Gene (PDHA1)

Abstract

Pyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that occurs most commonly due to mutations in the X-linked E1α subunit gene (PDHA1). We report a novel duplication of PDHA1 associated with a mild phenotype in a 15-year-old boy who was diagnosed with PDHC deficiency at 4 years of age following a history of seizures and lactic acidosis. The novel c.1087_1119 mutation in exon 11 resulted in an in-frame duplication of 11 amino acids. Measurements of PDHC activity in cultured skin fibroblasts were low, corresponding to 18.6 and 11.6% of the mean with respect to prior controls, whereas the E1 PDH component was absent. He has borderline intellectual functioning and maintains normal lactate levels on a ketogenic diet in between relapses due to illness. Review of the literature reveals wide variation of clinical phenotype in patients with mutations of the E1α subunit gene (PDHA1). There appears to be a higher incidence of normal or borderline intellectual ability in individuals who have insertions or deletions that are in-frame versus those that are out-of-frame. Furthermore, there is no correlation between mean residual PDH activity and phenotype in these patients.

Keywords

pyruvate dehydrogenase - complex deficiency - lactic acidosis - ataxia - neuropathy

• References

• 1 Chun K, MacKay N, Petrova-Benedict R , et al. Mutations in the X-linked E1 α subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet 1995; 56 (3) 558-569
• 2 Lissens W, De Meirleir L, Seneca S , et al. Mutations in the X-linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000; 15 (3) 209-219
• 3 Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab 2012; 105 (1) 34-43
• 4 Quintana E, Gort L, Busquets C , et al; PDH Working Group. Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clin Genet 2010; 77 (5) 474-482
• 5 Ostergaard E, Moller LB, Kalkanoglu-Sivri HS , et al. Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency. J Inherit Metab Dis 2009; 32 (Suppl. 01) S235-S239
• 6 Huntsman RJ, Sinclair DB, Bhargava R, Chan A. Atypical presentations of leigh syndrome: a case series and review. Pediatr Neurol 2005; 32 (5) 334-340
• 7 DeBrosse SD, Okajima K, Zhang S , et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab 2012; 107 (3) 394-402
• 8 Fujii T, Garcia Alvarez MB, Sheu KF, Kranz-Eble PJ, De Vivo DC. Pyruvate dehydrogenase deficiency: the relation of the E1 alpha mutation to the E1 beta subunit deficiency. Pediatr Neurol 1996; 14 (4) 328-334
• 9 Cameron J, Levandovskiy V, MacKay N, Tein I, Robinson BH. Deficiency of pyruvate dehydrogenase caused by novel and known mutations in the E1α subunit. Am J Med Genet 2004; 131A: 59-66
• 10 Endo H, Hasegawa K, Narisawa K, Tada K, Kagawa Y, Ohta S. Defective gene in lactic acidosis: abnormal pyruvate dehydrogenase E1 α-subunit caused by a frame shift. Am J Hum Genet 1989; 44 (3) 358-364