Molecular Aspects Of Variegate Porphyria In South Africa And Their Biochemical And Clinical Conseqltences

ABSTRACT

Variegate porphyria (VP) is the clinical disorder associated with. a deficiency of the haemsynthesising

enzyme protoporphyrinogen oxidase of the commonest

monogenic inherited disorders in South Africa. The chmcal effects mclu~e p~otocutaneous

sensitivity and the development of potentially life-threatening ~cute porp?ync cnses. . .

Section 1 of this dissertation examines the molecular basIS for VP m South Africa. It IS

shown to be a genetically heterogeneous disorder. The identification of 10 discrete mut.atio~s

is reported and their characteristic features described. One mutation, the R59W mu:atton, IS

highly prevalent and represents the original founder mutation imported from Holland m 1688.

Section 2 examines the value of routine porphyrin analyses of urine, stool and plasma in

the diagnosis of VP as correlated with the presence or absence of a PPO mutation on DNA

analysis. Biochemical testing is shown to be imprecise and subject to individual variation in

interpretation. All children and 30% of adults carrying a PPO mutation fail to express

abnormal biochemistry. Using the statistical techniques of discriminant analysis and

classification tree analysis, it is shown that an elevation of stool coproporphyrin and

pentacarboxylic porphyrin are the most important biochemical predictors of VP. The

predictive value of qualitative porphyrin analyses is assessed and plasma fluorescence

scanning is demonstrated to represent the most sensitive biochemical test for VP.

Section 3 examines the clinical expression of VP. In a study of a single kindred carrying

the R59W mutation, it is shown that approximately 60% of adults are clinically silent, skin

disease is present in 40% and that the probability of an acute attack is now low. The mutations

present in 4 subjects with compound heterozygous VP are described and their biochemical

features and clinical course described. A 10-year personal experience with the management of

more than 100 episodes of the acute porphyric crisis in Groote Schuur Hospital is reviewed.

Unusual presentations and complications are discussed, and the outcome of treatment

reported.

The significance of these findings and their implications for the care of patients with VP

and for further research are briefly discussed in Section 4. The bibliography and appendices

follow.