A Korean Female Patient with Thiamine-responsive Pyruvate Dehydrogenase Complex Deficiency Due to a Novel Point Mutation (Y161C)in the PDHA1 Gene

Abstract

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1α subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1×10-3 mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP.

Thiamine-Responsive and Non-responsive Patients with PDHC-E1 Deficiency: A Retrospective Assessment

“…Similarly, patient 12 had substantial residual PDHC activity in cultured cells but undetectable activity in skeletal muscle, possibly due to different levels of TPP in tissue versus culture media or to other factors affecting PDHC stability in different cell types. Such pitfalls have been previously described (Di Rocco et al 2000;Lee et al 2006). Interpretation of results is further complicated in female patients, where enzyme activity reflects the impact of X inactivation (e.g.…”

“…A number of patients have been reported as thiamine responsive but have mutations involving amino acid residues that are located well away from the TPP-binding site. These include p.Val71Ala and p.Cys101Phe (Naito et al 2002b), p.Tyr161Cys (Lee et al 2006), p.Tyr243Ser (Benelli et al 2002), p.Arg263Gly (Bachmann-Gagescu et al 2009) and other C-terminal residues (Narisawa et al 1992). At present, there is no structural explanation as to why these should influence TPP binding.…”

“…However, its efficacy has been variable (Weber et al 2001). The administration of thiamine is an additional treatment that can potentially be effective, given its role as a cofactor (as TPP) of the enzyme-complex activity (Di Rocco et al 2000;Lee et al 2006;Barnerias et al 2010;Giribaldi et al 2012).…”

“…Thus, it is likely that not all patients are correctly diagnosed and therefore the exact prevalence of PDHC deficiency is not known (Barnerias et al 2010;Patel et al 2012). Moreover, thiamineresponsive patients might be missed, because enzyme analysis is usually performed with high TPP concentrations and will not show a decreased PDHC enzyme activity in these patients (Di Rocco et al 2000;Naito et al 2002a;Lee et al 2006). Amongst patients with thiamine-responsive PDHC deficiency, several different mutations have been found; the majority located in the PDHA1 gene, encoding the E1a subunit, some in the region encoding the TPPbinding site, some outside the TPP-binding site (Naito et al 1994(Naito et al , 2002aBenelli et al 2002;Debray et al 2008).…”

Therapeutic Strategies for Mitochondrial Disorders

“…[18][19][20] Thiamine seems to be particularly effective in patients with PDG deficiency. [21][22][23] In several studies, thiamine has been administered together with other cofactors, why the effect of thiamine in monotherapy cannot be reliably assessed from these studies. 24 …”