Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency.

[pyruvate dehydrogenase deficiency]

The pyruvate dehydrogenase (PDH ) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl-CoA . We report four novel PDHA 1 mutations in patients with pyruvate dehydrogenase deficiency . Analysis of PDH activity showed decreased activity in fibroblasts from all four patients , around 16 -52 % of mean control , similar to what has been found in previous studies . Two of the mutations were missense mutations : c .616 G >A (p .Glu 206 Lys ) and c .457 A >G (p .Met 153 Val ), one was a 3 bp in -frame deletion : c .429 _431 delAGG (p .Gly 143 del ), and one was a 65 bp duplication : c .900 -6 _958 dup 65 . cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication . The small amount of normal transcript likely explains the survival of the patient , who was a boy . The duplication and one of the missense mutations were associated with decreased amounts of E (1 )Î± And E (1 )Î² protein on western blot analysis , whereas the other two mutations were associated with normal amounts . This study adds four novel mutations to the around 90 reported mutations in PDHA 1 (HGMD PDHA 1 mutation database ). The phenotypes of patients with PDH deficiency have been divided into three groups : a neonatal form with severe lactic acidosis , a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia , and an infantile form with hypotonia , lethargy , onset of seizures or dystonia , psychomotor retardation , in some cases Leigh -like lesions and mild to moderate hyperlactataemia . The four patients reported here all belong to the latter group , which is the largest .

Diseases
Validation

Diseases presenting "dehydrogenase deficiency" symptom

adrenomyeloneuropathy

krabbe disease

pyruvate dehydrogenase deficiency

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