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Alkaptonuria
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
Homogentisic acid is a normal intermediate in the catabolism of the aromatic amino acids, phenylalanine and tyrosine (Figure 14.1). It accumulates because of a defective activity of homogentisic acid oxidase [7]. This enzyme, which in mammalian systems is found only in liver and kidney, has been shown to be defective in both tissues in alkaptonuria. It catalyzes the conversion of homogentisic acid to maleylacetoacetic acid, which is ultimately converted to fumaric and acetoacetic acids. The gene for homogentisic acid oxidase has been cloned and mapped to chromosome 3q21-23 [8, 9]. The gene contains 14 exons over 60 kb of genomic DNA [10]. The spectrum of mutations has recently been summarized to include a total of 91 variants in the HGD gene, 62 missense, 13 splice sites, 10 frameshift, and 5 nonsense [10–12]. Most reside in exons 3, 6, 8, and 13. In the country with the greatest frequency of the disease, two variants c.16-1G>A (INV11G>A) and p.G161R, were found in more than 50 percent of patients.
Archibald E. Garrod (1857–1936)
Published in Krishna Dronamraju, A Century of Geneticists, 2018
Garrod’s interest in joint disease led him to study the chemistry of pigments in urine. While working as a visiting physician at the Great Osmond Street Hospital for Sick Children, he examined a three-month-old boy, Thomas P., whose urine was stained a deep reddish-brown. Garrod’s diagnosis was alkaptonuria, which is caused by an abnormal build-up of homogentisic acid, or alkapton. In a normal person, the acid is broken down through a series of chemical reactions into carbon dioxide and water. But in rare cases, the metabolic process is interrupted and the acid is excreted in the urine, where it turns black on contact with the air. According to the germ theory of disease, which had transformed the study of medicine in Garrod’s time, alkaptonuria was thought to be a bacterial infection of the intestine. The disorder was almost always diagnosed in infancy, lasted throughout life, and was thought to be contagious. Garrod’s training in physical science, however, led him to investigate the disease as a series of chemical reactions. He reviewed 31 cases of alkaptonuria from his own practice and from the medical literature and presented his findings to the Royal Medical and Chirurgical (Surgical) Society of London in 1899. Alkaptonuria, he noted, although rare, tended to appear among children of healthy parents. It was not contagious and seemed to be a harmless error in metabolism.
Inborn errors of metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Alkaptonuria is an autosomal recessive disorder associated with a deficiency of homogentisic acid oxidase. Homogentisic acid accumulates in tissues and blood, and is passed in the urine. Oxidation and polymerization of homogentisic acid produce the pigment alkapton, in much the same way as polymerization of dihydroxyphenylalanine results in melanin. The deposition of alkapton in cartilages, with consequent darkening, is called ochronosis and results in visible darkening of the cartilages of the ears and often arthritis in later life. The conversion of homogentisic acid to alkapton is accelerated in alkaline conditions, and sometimes the most obvious abnormality in alkaptonuria is darkening of the urine as it becomes more alkaline on standing. Homogentisic acid, a reducing substance, reacts with Clinitest tablets (Fig. 27.4).
Pharmacogenetics and drug metabolism: historical perspective and appraisal
Published in Xenobiotica, 2020
Robert L. Smith, Stephen C. Mitchell
The work of Archibald Edward Garrod (1857–1936) helped to fuse a liason between the emerging sciences of genetics, chemical pathology and biochemistry (physiological chemistry). His interest in alkaptonuria, helped cement the understanding that inefficiencies in enzyme pathways could lead to clinical conditions. This seminal work rested upon the ability to see a darkening of the urine caused by the oxidation of homogentisic acid (melanic acid), an intermediate in the breakdown of tyrosine and phenylalanine that accumulates owing to underactivity of homogentisic dioxygenase (Garrod, 1902). This outward clinical sign of darkening urine had been observed centuries ago (Scribonius, 1584) as mentioned by Garrod himself. His findings on alkaptonuria together with albinism, cystinuria and pentosuria (sometimes known as Garrod’s tetrad) were given in a series of four lectures, the Croonian lectures, in 1908 (Garrod, 1908) later published in book form (Garrod, 1909) (Figure 1). The revised second edition of his book included the other hereditary ailments of congenital steatorrhea and congenital porphyrinuria (Garrod, 1923).
Successful treatment of attention-deficit/hyperactivity disorder accompanying to alkaptonuria with methylphenidate and risperidone
Published in Psychiatry and Clinical Psychopharmacology, 2019
Alkaptonuria (AKU) is a metabolic disorder resulting from deficiency of homogentisic acid (HGA) oxidase that converts HGA (an intermediate product in of tyrosine metabolism) to maleylacetoacetate. This rare disorder is inherited in an autosomal recessive manner with an estimated prevalence of 1:250,000–1,000,000 individuals; however, the prevalence is unknown in the Turkish population. Clinically, it may manifest with dark discolouration of urine, ochronosis at cartilage and connective tissues, arthritis at third of fourth decade of life, cardiac valve deficits, crystalluria and/or renal stone disease, spontaneous tendon rupture, and involvement of liver, small intestine, and colon. In a recent study, it was reported that HGA oxidase gene was expressed in human cerebral tissue and neuronal cells in AKU with multi-systemic organ involvement. However, the dark discolouration of the urine sample is almost the only marker for early diagnosis [1–6]. It is unknown whether amyloid or HGA accumulation in alkaptonuria has an apparent effect on brain development. Also, it has been found that the disease has no effect on life expectancy [7]. To the best of our knowledge, there is no study or case report about psychiatric comorbidities in patients with AKU, although comorbid psychiatric disorders such as mental retardation, attention-deficit/hyperactivity disorder (ADHD), impulse control disorder, or conduct disorder can be seen in some metabolic diseases such as mucopolysaccharidosis (MPS), Wilson’s disease, or phenylketonuria (PKU) [8–10]. Here, we presented a paediatric AKU patient with comorbid ADHD, ODD/CD, and borderline intellectual functioning that was successfully treated with extended-release methylphenidate (OROS-MPH) and risperidone.