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Alkaptonuria and Ochronosis – Experience from Slovakia Alkaptonúria a Ochronóza – Skúsenosti Zo Slovenska

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Alkaptonuria and Ochronosis – Experience from Slovakia Alkaptonúria a Ochronóza – Skúsenosti Zo Slovenska Acta Fac. Pharm. Univ. Comen. LXI, 2014 (1), p. 29–35 ISSN 1338-6786 (online) and ISSN 0301-2298 (print version) DOI 10.2478/afpuc-2014-0001 ACTA FACULTATIS PHARMACEUTICAE UNIVERSITATIS COMENIANAE ALKAPTONURIA AND OCHRONOSIS – EXPERIENCE FROM SLOVAKIA ALKAPTONÚRIA A OCHRONÓZA – SKÚSENOSTI ZO SLOVENSKA Original research article Rovenský, J.1, Urbánek, T.1, Imrich, R.2 1National Institute of Rheumatic Diseases, Piešťany, Slovak Republic 1Národný ústav reumatických chorôb, Piešťany, Slovenská republika 2Center for Molecular Medicine, Institute of Experimental Endocrinology, / 2Centrum molekulárnej medicíny, Ústav experimentálnej endokrino- Slovak Academy of Sciences, Bratislava, Slovak Republic lógie, Slovenská akadémia vied, Bratislava, Slovenská republika Received February 14, 2014, accepted April 2, 2014 Abstract Alkaptonuria is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive con- dition that is caused due to a defect in the enzyme homogentisate 1,2-dioxygenase, which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide accumulate in the blood and are excreted in urine in large amounts. The polymer of homogentisic acid called alkapton impregnates bradotrophic tissues. Slovak Alakptonúria je zriedkavé hereditárne ochorenie, ktoré je spôsobené poruchou metabolizmu fenylalanínu a tyrozínu. Je to auto- abstract zomálne recesívne ochorenie spôsobené defektom enzýmu 1,2-dioxygenázy, ktorá sa podieľa na degradácii tyrozínu. Výsledkom je, že kyselina homogentisová a jej oxid sa akumulujú v krvi a sú vylučované močom. Polymér kyseliny homogentisovej, ktorý sa nazýva alkaptón, impregnuje bradytropné tkanivá. Keywords alkaptonuria; ochronosis; homogentisic acid in urine Kľúčové slová: alkaptonúria; ochronóza; kyselina homogentisová v moči DEFINITION Alkaptonuria is an inherited disorder of metabolism of aro- alkaptonuria is an inherited metabolic disease and that defi- matic amino acids phenylalanine and tyrosine that is caused ciency of the enzyme that metabolises homogentisic acid is a due to the lack of activity of the enzyme homogentisate result of a defective gene. This concept was later proved cor- 1,2-dioxygenase (HGD). The homogentisic acid is not me- rect. His article about alkaptonuria was published in Lancet in tabolised – it accumulates in the body and is excreted into 1902 (Garrod, 1902). At that time it was a bold statement when urine. The polymer – the ochronotic pigment – impregnates one considers how little was known about enzymes, human bradytrophic tissues. genetics and intermediary metabolism. His knowledge was later summarised in his book Inborn Errors of Metabolism (Gar- CLINICAL SIGNS rod, 1909). In 1958, the study by La Du et al. provided a bio- chemical evidence of the defect in alkaptonuria (La Du et al., Alkaptonuria is characterised by: 1958). They demonstrated the absence of homogentisic acid • homogentisic acid accumulation in the body metabolising enzyme activity in liver homogenates from a • presence of homogentisic acid in urine patient with alkaptonuria. He found that the defect is related • visible, functionally benign symptoms of eyes and ears to one enzyme – 1,2-dioxygenase of the homogentisic acid. • debilitating changes in the locomotor system. He suggested that the people affected do not synthesise the enzyme. The gene responsible for alkaptonuria was identified HISTORY in 1993 by Pollak et al. and it was localised to chromosome 3q2 (Pollak et al., 1993). In alkaptonuria, the homogentisic Scientists found alkaptonuria in the Egyptian mummy acid is not broken down due to the lack of enzyme activity Harwa dated to around 1500 BC. The name alkaptonuria that metabolises the homogentisic acid; it accumulates in was first used in 1859 in a patient whose urine contained the body and is excreted in the urine. The homogentisic acid a reducing compound (alkapton) later identified as the ho- builds an oxidised polymer in the body, which is stored in the mogentisic acid. In 1902, Garrod postulated a hypothesis that form of blue-black deposits in tissues (ochronosis). * [email protected] 29 © Acta Facultatis Pharmaceuticae Universitatis Comenianae Acta Fac. Pharm. Univ. Comen. LXI, 2014 (1), p. 29–35 ALKAPTONURIA AND OCHRONOSIS – EXPERIENCE FROM SLOVAKIA AETIOLOGY AND PATHOGENESIS as the countries where the highest incidence of alkaptonuria (1 in 19 000 inhabitants) was found. The world prevalence is Phenylalanine and tyrosine are the simplest aromatic amino one case in 250 000–1 000 000 inhabitants. Increased preva- acids derived from alanine. Phenylalanine is an essential ami- lence in Slovakia is explained by the fact that patients come no acid that cannot be synthesised by our body. This is not from mountainous areas where the population evolved as true for tyrosine. The body can synthesise tyrosine, but only genetic isolates with frequent marriages of parents related to if there is sufficient amount of phenylalanine – a precursor of each other. However, it should be noted that the active way of tyrosine and the enzyme involved in the conversion of phe- looking for patients, which has been a tradition in Slovakia for nylalanine to tyrosine. Phenylalanine and tyrosine are closely more than 50 years and dates back to the first case described related; phenylalanine is converted to tyrosine in the liver and by Siťaj, also contributed to the sample size. to phenylpyruvate in the kidneys. Aromatic amino acids have Siťaj, Červeňanský and Urbánek described ochronosis, its a common intermediary metabolism. The conversion of phe- development in patients with alkaptonuria and the de- nylalanine to tyrosine and further metabolism are controlled tailed clinical picture as well as manifestations in the joints by a complex enzymatic system. The failure to convert phe- (Siťaj, 1947; Siťaj and Lagier, 1973; Urbánek and Siťaj, 1955; nylalanine to tyrosine is known as phenylketonuria – one of Červeňanský et al., 1959). They published the results in a the most common recessive inborn diseases (approximately monograph titled Alkaptonuria and ochronosis (1956), which 1 affected in 10 000 newborns). Phenylketonuria is caused was the first in the world literature (Siťaj et al., 1956). Their by the lack of the enzyme phenylalanine hydroxylase, which pioneering work is still being cited. Sršeň et al. from the re- converts phenylalanine to tyrosine or its cofactor tetra- search laboratory of clinical genetics in Martin followed up hydrobiopterrine. Alkaptonuria arises as a result of the lack of on their epidemiological studies and continued in the ge- another enzyme – 1,2-dioxygenase of the homogentisic acid netic analysis of patients with alkaptonuria in Slovakia (Sršeň (homogentisate 1,2-dioxygenase; HGD). This enzyme is a part and Neuwirth, 1974; Sršen, 1984; Sršeň et al., 1996; Sršeň et al., of the degradation pathway of aromatic amino acids pheny- 2002). Institutions participating in the molecular characterisa- lalanine and tyrosine. Homogentisate excreted in the urine tion of mutations in the Slovak population include: Institute is then oxidised by oxygen in the air to brownish-black pig- of Molecular Physiology and Genetics SAS, Bratislava and ment – alkapton. Other symptoms later in life include ochro- Faculty of Natural Sciences of Comenius University in Brati- nosis – pigmentation of the connective tissue (cartilage). The slava (Zaťková et al., 2000a; Zaťková et al., 2000b; Zaťková et mechanism of ochronosis is the oxidation of homogentisate al., 2000c). Most of the observed families came from sites in polyphenoloxidase resulting in the production of benzochi- Slovakia studied by Siťaj et al. (Siťaj, 1947; Siťaj et al., 1956; non acetate, which polymerises and binds to macromolecules Siťaj and Lagier, 1973). Later work was continued by Rovenský of the connective tissue. Exogenous ochronosis results from and coworkers (Rovenský and Urbánek, 2000; Rovenský and prolonged treatment of ulcers with carbol and some other Urbánek, 2003) and the genetic aspects by Bošák in coopera- chemicals. Endogenous ochronosis is due to alkaptonuria. tion with laboratories in Bratislava (Bošák, 2010; Zaťková et al., 2000a; Zaťková et al., 2000b). EPIDEMIOLOGY AND GENETIC ASPECTS In 1958, La Du with co-workers found that the biochemical essence of alkaptonuria is the lack of biological activity of the The observation of alkaptonuria inheritance described by enzyme HGD in the liver, thus confirming the original assump- Garrod was studied closely by Hogben et al. (1932) who con- tion of Garrod that it is a metabolic disorder (La Du, 1958). firmed that alkaptonuria is inherited in an autosomal reces- HGD is an enzyme that is involved in the catabolism of phe- sive manner. They found that about half of the affected indi- nylalanine and tyrosine. It has a molecular weight of 50 kDa viduals came from kin marriages. and consists of 445 amino acids. It is specific for homogentisic The list of scientists who significantly contributed to the acid and does not oxidase related substances such as gen- knowledge of the clinical manifestations of alkaptonuria and tisic acid and phenylacetic acid. The gene that encodes the ochronosis includes Siťaj, Červeňanský, Urbánek, Hüttl and HGD enzyme was cloned in 1996, thereby opening the era others (Siťaj, 1947; Siťaj et al., 1956; Siťaj and Lagier, 1973; of molecular genetics of alkaptonuria (Granadino et al., 1997). Urbánek and Siťaj, 1955; Červeňanský et al., 1959; Hüttl et al., We now know that the HGD gene
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