Main causes of the pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex deficiency is usually caused by a deficiency of one or more enzymes or cofactors (such as thiamine) that are needed for an important chemical reaction in the cells of the body.


These enzymes or cofactors are part of the pyruvate dehydrogenase complex and normally convert (or aid in converting) a chemical called pyruvate to another chemical called acetyl-coenzyme A (CoA), which is one of two important chemicals the body needs to make citrate for the cells.


Because pyruvate cannot be converted to acetyl-CoA, there is too much pyruvate in the cells, which then undergoes lactic fermentation instead of Kreb's cycle. Hence lactic acid, instead of citrate, is produced from the pyruvate. Without the body undergoing Kreb cycle, there is insufficient amount of energy being produced.


The condition is sometimes referred to as pyruvate dehydrogenase complex (PDHC) deficiency because there is a "complex" of three enzymes normally used in the reaction; when any one or more of the enzymes needed for the above-described reaction are deficient, the condition results. 


Genetic Cause:

 mutations in the X-linked E1 alpha gene


Chances of each gender being affected:
Almost equal numbers of affected males and females have been identified However, there is a difference in the distribution of the type of mutations between both sexes.


Modes of inheritance of mutation:
X-linked dominant( Abnormal gene on the X chromosome-sex chromosome, dominates the other normal gene from another parent)

It may seem that the mode of inheritance is autosomal recessive mode of inheritance of the disease (Both parents are carriers of the mutation) since there is an almost equal chance of males or females being infected. This is because studies have shown that there is presence of  developmental lethality in males as the effect of mutation is more severe as compared to pattern of X-inactivation in females.



Mutations in the X-linked E1 alpha subunit gene:


missense/nonsense (found in all exons)
insertion/deletion mutations( found mostly in exon 10 and 11)
Mutations were never present in the somatic cells of the father



Sources
Non-scientific articles:
1.Frye, R. (2012, March 12). Medscape reference. Retrieved from http://emedicine.medscape.com/article/948360-overview
2.Genetic and rare diseases information center (gard). In (2011). National Institutes of Health. Retrieved from http://rarediseases.info.nih.gov/GARD/QnASelected.aspx?diseaseID=7513
Scientific article:
3.Lissens W. (2000). Retrieved from website: http://www.ncbi.nlm.nih.gov/pubmed/10679936