'n Moontlike defek in melanienbiosintese by 'n pasiënt met die simptome van hipopigmentering en die verdonkering van liggaamsvloeistowwe

Abstract

A possible defect in melanin biosynthesis in a patient with the symptoms of hypopigmentation and the darkening of body fluids Many congenital metabolic defects present certain characteristic clinical and biochemical features in affected persons. Investigation of the clinical and biochemical characteristics of a person with a possible metabolic defect is an important aid in the diagnosis of a metabolic disease. In this study certain symptoms, indicating a defect in melanin biosynthesis, of a patient were investigated. The patient presents both the symptoms of hypopigmentation and the sporadic darkening of body fluids. Both these symptoms might be caused by a defect in melanin biosynthesis. In this study these two symptoms were investigated to determine whether they could be associated with a defect in melanin biosynthesis. The hypopigmentation and other clinical features of the patient resemble the clinical characteristics of Chediak Higashi syndrome, a type of oculocutaneous albinism. The first main goal of this investigation was to determine if the patient had Chediak Higashi syndrome. Chediak Higashi syndrome is caused by mutations in a single gene called the Lyst gene. Mutations in this gene leads, among other defects, to abnormalities in the synthesis and development of melanosomes, the organelles in which melanin is produced. Chediak Higashi syndrome is characterised by the pigment cells in affected persons containing giant melanosomes. The hair root pigment cells and keratinocytes of the patient were investigated by transmission electronmicroscopy. By this ultrastructural investigation it was determined that the patient is unlikely to have Chediak Higashi syndrome, because no giant melanosomes could be observed in the hair root pigment cells or keratinocytes of the patient. An atypical presentation of Chediak Higashi syndrome cannot however be ruled out and it is possible that

the patient has an atypical mutation in the Lyst gene. A definitive answer may be obtained by mutation analysis of the Lyst gene in the patient. Any condition or treatment which leads to an increase in the levels of melanin related metabolites in urine or saliva can cause the darkening of these body fluids by the polymerization of melanin precursors to the pigment melanin. The second main goal of this study was to determine whether raised levels of melanin related metabolites are responsible for the sporadic darkening of urine, saliva and perspiration of the patient. The melanin related metabolites 5-S-cysteinyldopa (SSSD), 6-hydroxy-5-methoxy-indole-2-carboxylic acid (6H5Ml2K), 3,4-dihydroxyphenylalanine (L-DOPA), 0-methyldopa (OMD), dopamine (DA) and tyrosine were quantified in the urine by electrospray mass spectrometry. The following organic acid products of the catabolism of L-DOPA, DA and OMO were quantified in urine by gaschromatography-mass spectrometry: homovanillic acid (HVA), dihydroxyphenylacetate (DOPAC), 3-methoxy-4- hydroxyphenyllactate (VLA) and 4-hydroxy-3-methoxymandelic acid (VMA). Two alternative metabolites of tyrosine, the beginning substrate of the melanin biosynthetic pathway, were also quantified in urine by gaschromatography-mass spectrometry. Quantification of all these metabolites were performed in urine collected during periods of body fluid darkening, periods that darkening didn't take place and periods during which the dose of L-DOPA medication of the patient was reduced. This made it possible to determine whether body fluid darkening could be associated with the urinary levels of certain compounds and to determine the influence of medication on the results of quantification. From the investigation it was evident that there is a distinct association between the darkening of body fluids and the urinary concentration of OMD and to a lesser extent the urinary concentration of L-DOPA. No association between the darkening of body fluids and the other compounds which were quantified could be found. OMD is the main metabolite of the Sinemet medication taken by the

patient. From this investigation it was evident that the darkening of body fluids is related to raised levels of melanin related metabolites in the body fluids. The raised levels of melanin related metabolites in the body fluids of the patient were however related to the medication taken by the patient rather than to a defect in the melanin biosynthetic pathway.