Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region

Abstract

The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit. We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7.

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

“…None of the mutations that have been well defined as causing "thiamine-responsive" PDHC deficiency have involved amino acid residues that are directly involved in TPP binding; most are adjacent to the binding site and probably alter the position of the actual side chains that interact with the cofactor, weakening their binding. There are two groups of these: p. Ile87Met (present report), p.Arg88Ser (Marsac et al 1997), p.Arg88Cys (Fujii et al 2006) and p.Gly89Ser (Naito et al 1999) on one side and p.Phe205Leu (Naito et al 2002a), p.Met210Val (Tripatara et al 1999), p.Trp214 (Lissens et al 2000), p.Leu216Phe (Naito et al 2002a) and p. Pro217Leu (also denoted as Pro188Leu) (Hemalatha et al 1995) on the other. 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.…”

“…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).…”

“…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). At present, it is not known whether thiamine-responsive patients present differently from those not responsive to thiamine and what doses of the vitamin are required to gain significant therapeutic benefits.…”

The Role of Thiamine in Autism

“…Genetic defects in pyruvate dehydrogenase complex (PDHC) are known to cause lactic acidosis, neurological deficits, and premature death [26]. Patients with these defects show reduced activity of PDHC and PDH E 1 α subunit and decreased affinity of PDHC for TPP [127][128]. Thiamine treatment is very effective in some PDHCdeficient patients [128][129].…”

“…Patients with these defects show reduced activity of PDHC and PDH E 1 α subunit and decreased affinity of PDHC for TPP [127][128]. Thiamine treatment is very effective in some PDHCdeficient patients [128][129]. Thiamine regulates the expression of enzymes that require thiamine as a cofactor and thiamine deficiency has been shown to reduce the mRNA levels of transketolase and PDH [130].…”