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Oculocutaneous tyrosinemia/tyrosine aminotransferase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Analysis of the organic acids of the urine reveals large amounts of p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. The excretion of large amounts of p-hydroxyphenylpyruvic acid and p-hydroxyphenyllactic acid in the urine seems at first to be inconsistent with the site of the metabolic block. It is explained (Figure 21.8) by the widespread distribution of the other transaminase, mitochondrial tyrosine aminotransferase (aspartate aminotransferase, EC 2.6.1.1), in tissues other than liver, which lack the hydroxylase that catalyzes the conversion of p-hydroxyphenylpyruvic acid to homogentisic acid [58]. Accumulated tyrosine found in the blood is converted to p-hydroxyphenylpyruvic acid in tissues such as muscle. This compound is readily reduced to p-hydroxyphenyllactic acid [59]. Both p-hydroxyl compounds are then transported in the blood to the kidney, where they are effectively cleared and excreted in the urine [60].
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The major biochemical defect manifesting in tyrosinemia patients is the elevated blood tyrosine level and excessive urinary elimination of tyrosine and tyrosyl compounds. The clinical features include enlargement of the liver and spleen, nodular cirrhosis of the liver, and multiple renal tubular reabsorption defects. Slight mental retardation is seen in some cases, but mental deficiency is not a constant symptom in tyrosinemia. This inborn error is probably also derived from the lack of p-hydroxyphenylpyruvic acid oxidase.
The potential of nitisinone for the treatment of alkaptonuria
Published in Expert Opinion on Orphan Drugs, 2019
Anti-oxidant therapies, such as ascorbic acid (ASC) more commonly known as Vitamin-C, have been suggested as potentially inhibitors of the polymerization of HGA, showing effectiveness in reducing the conversation of HGA to its quinone intermediate on the way to ochronotic pigment, it did not reduce the amount of HGA excreted in the urine [24]. A greater understanding of the tyrosine degradation pathway also highlights that ASC is a co-factor for 4-hydroxyphenylpyruvate dioxygenase, which causes increased HGA production by ensuring the conversion of 4-hydroxyphenylpyruvic acid to HGA, this may actually increase the amount of HGA formed and therefore the amount of HGA available to undergo the polymerization process to pigmentation. Evidence of the use of ascorbic acid in the pediatric population demonstrated a concerning increase in the urinary concentration(s) of HGA which may facilitate pigmentation in earlier age groups [25]. This increase in HGA levels may also contribute to the formation of renal oxalate stones. This is concerning, as AKU patients are already at high risk for developing renal calculi and prostatic calculi in males [26–28]. The mechanism of calculi formation in AKU patients is unclear, it is documented that the development of calculi forms in a similar manner to that in the general population. However, the literature reports that there is an increase in the prevalence of any type of stones; renal, prostatic or even submandibular in the AKU population [29,30]. Formation of oxalate stones, requires an interaction between the renal system epithelia and the crystal. Usually, the crystals formed within the system are discharged in the urine, small crystals that become attached to the epithelial lining are thought to be digested by macrophages or lysosomes. Factors that initiate the formation of stones include reduced urinary volume or alterations in urinary pH or a combination of these factors [31]. Given that AKU patients are excreting gram quantities of HGA daily in their urine [32], this will cause perturbations in their urinary pH and may be a factor in the increased formations of stones in renal, or any other excretory, or secretory system in these patients. The association of ochronotic pigment and calcium crystals has previously been documented both in calculi, but also in other calcified pathological areas of the body suggesting an overlap in the process [33]. It is not ultimately clear exactly how HGA or calculi interact and further work is needed in this area to decrease the disease burden in AKU patients [34]. It has been shown that liver transplantation is a successful means to eradicate HGA from the body, due to the presence of the HGD enzyme in the donor liver hepatocytes [35]. This halted the progression of the disease, but is unlikely to have reversed the presence of any ochronosis that already existed in the tissues.