Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity.

Abstract

We have diagnosed dihydrolipoamide dehydrogenase (DLD) deficiency in two male second cousins, who presented with markedly different clinical phenotypes. Patient 1 had a recurrent encephalopathy, and patient 2 had microcephaly and lactic acidosis. Their presentation is unusual, in that the DLD subunit deficiency had little effect on pyruvate dehydrogenase complex activity, but caused a severe reduction in the activities of other enzymes that utilize this subunit. We have identified two mutations in the DLD gene in each patient. The second cousins have one novel mutation in common resulting in a substitution of isoleucine for threonine (I47T), which has not been previously reported in the literature. Patient 1 has a second mutation that has been reported to be common in the Ashkenazi Jewish population, G229C. Patient 2 has a second mutation, E375K, which has also been previously reported in the literature. Enzyme kinetic measurements on patient fibroblasts show that under certain conditions, one heteroallelic mutation may have a higher K(m). This may account for the differing clinical phenotypes. These findings have important repercussions for other patients with similar clinical phenotypes, as DLD activity is not normally measured in cases with normal PDHc activity.

• Authors: Jessie M Cameron, Valeriy Levandovskiy, Neviana Mackay, Julian Raiman, Deborah L Renaud, Joe T R Clarke, Annette Feigenbaum, Orly Elpeleg, Brian H Robinson
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 140 Issue 14 Pg. 1542-52 (Jul 15 2006) ISSN: 1552-4825 [Print] United States
• PMID: 16770810 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2006 Wiley-Liss, Inc.

Chemical References

• Protein Subunits
• Pyruvate Dehydrogenase Complex
• DNA
• Dihydrolipoamide Dehydrogenase

Topics

• Acidosis, Lactic (enzymology, genetics)
• Amino Acid Substitution
• Base Sequence
• Brain Diseases, Metabolic (enzymology, genetics)
• Child
• Child, Preschool
• DNA (genetics)
• Dihydrolipoamide Dehydrogenase (chemistry, deficiency, genetics)
• Female
• Fibroblasts (enzymology)
• Heterozygote
• Humans
• In Vitro Techniques
• Kinetics
• Male
• Microcephaly (enzymology, genetics)
• Models, Molecular
• Phenotype
• Point Mutation
• Protein Subunits
• Pyruvate Dehydrogenase Complex (chemistry, genetics, metabolism)