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Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene.

Unidad de Patología Molecular, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain.
Journal of Medical Genetics (Impact Factor: 5.7). 08/2002; 39(7):E40. DOI: 10.1136/jmg.39.7.e40
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    ABSTRACT: Objectifs. – Confirmer le diagnostic de rhumatisme alcaptonurique par le dosage de l'acide homogentisique urinaire chez les 14 sujets examinés. Tenter d'établir une corrélation génotype–phénotype chez les cinq patients ayant bénéficié d'une étude moléculaire du gène de l'homogentisate 1,2-dioxygénase. Méthodes. – Nous rapportons 14 observations d'alcaptonurie (dix hommes et quatre femmes) dans 11 familles algériennes. La consanguinité est connue dans seulement trois familles (F = 1/16). Les mutations du gène de l'homogentisate 1,2-dioxygénase ont été identifiées par séquençage de l'ADN génomique. Résultats. – Le diagnostic d'alcaptonurie a toujours été confirmé par le dosage de l'acide homogentisique urinaire. Quatre mutations du gène de l'homogentisate 1,2-dioxygénase ont été mises en évidence : une mutation faux-sens, serine189isoleucine à l'état homozygote chez deux sœurs s'accompagnant d'un phénotype peu sévère ; une mutation au niveau du site d'excision–épissage de l'intron 1 (IVS1–1G>A) à l'état homozygote chez un homme associée à un phénotype sévère (décès à l'âge de 61 ans d'une insuffisance rénale) ; une mutation silencieuse, alanine470alanine à l'état hétérozygote chez un homme avec un phénotype peu sévère ; une délétion de G en position c.819 conduisant à un décalage du cadre de lecture après Gly217 (Gly217fs) puis à un codon stop en c.850. Cette mutation nouvelle est présente à l'état hétérozygote chez une femme de phénotype peu sévère. Conclusions. – Les deux mutations à l'état homozygote s'accompagnant respectivement d'un phénotype peu sévère et sévère, aucune corrélation génotype–phénotype n'a pu être établie.
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    ABSTRACT: Alkaptonuria (AKU) is an ultra-rare metabolic disorder of the catabolic pathway of tyrosine and phenylalanine that has been poorly characterized at molecular level. As a genetic disease, AKU is present at birth, but its most severe manifestations are delayed due to the deposition of a dark-brown pigment (ochronosis) in connective tissues. The reasons for such a delayed manifestation have not been clarified yet, though several lines of evidence suggest that the metabolite accumulated in AKU sufferers (homogentisic acid) is prone to auto-oxidation and induction of oxidative stress. The clarification of the pathophysiological molecular mechanisms of AKU would allow a better understanding of the disease, help find a cure for AKU and provide a model for more common rheumatic diseases. With this aim, we have shown how proteomics and redox proteomics might successfully overcome the difficulties of studying a rare disease such as AKU and the limitations of the hitherto adopted approaches.
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    ABSTRACT: Ochronosis / Alkaptonuria is a tyrosine metabolism disorder where accumulation of homogentisic acid, in eye, skin, cartilage and several other connective tissues leads to a black pigmentation of the affected tissues. It is autosomal-recessive inherited in men with a frequency of 1-9/1,000,000. While it is clear that pigment deposits lead to joint destruction, renal stone formation and cardiac valvulopathy respectively, the significance of ocular findings is still unclear. We therefore aim to evaluate the frequency and clinical significance of ocular findings in ochronosis and discuss possible therapeutic options. Systematic review of literature via Medline and Web of Science. Only case reports in English, German, French, Spanish or Italian documenting detailed ophthalmologic examination were included. Our search revealed 36 case reports including 40 patients. Average age at the onset of ocular signs was 40.6 years. The most frequent sign was symmetric brown sclera pigmentation present in 82.5 percent of the patients. "Oil-drops", brown pigment spots in the limbus are generally considered pathognomonic but were a little less frequent (75 percent). Vermiform pigment deposits at the level of the conjunctiva or increased conjunctival vessel diameter is also frequent. We found an increased incidence of central vein occlusion and elevated intraocular pressure going along with chamber angle hyperpigmentation. Another condition observed twice is rapid progressive astigmatism attributable to corneoscleral pigment accumulation. Our observations suggest that ocular findings are of double relevance. First, characteristic ocular findings can anticipate the time of diagnosis and second, ocular findings may complicate to various conditions putting sight at risk. Opthalmologists and general physicians should be aware of both. Therapeutic options include protein restriction, administration of high dose vitamin C or nitisonone. Evidence for all of them is limited.
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