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

[pyruvate dehydrogenase deficiency]

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 (E 1 )alpha subunit have been reported previously : H 44 R , R 88 S , G 8 9 S , R 263 G , and V 389 fs . All five mutations are in a region outside the thiamine pyrophosphate (TPP )-binding region of the E 1 alpha 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 E 1 alpha subunit revealed a point mutation (F 2 05 L and L 216 F ) within the TPP-binding region in exon 7 .

Diseases
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Diseases presenting "clinical improvement" symptom

pyruvate dehydrogenase deficiency

wiskott-aldrich syndrome

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