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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
Alkaptonuria is inherited as an autosomal recessive trait [36]. Consanguinity was originally noted by Garrod [1], and subsequently by others [37]. Heterozygote detection should be possible by assay of the enzyme in the biopsied liver, but this has not been done. Cloning of the gene for homogentisic acid oxidase in man [7, 8] has permitted molecular studies in patients with alkaptonuria and their families.
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.
Histopathology
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Inherited ochronosis (alkaptonuria) is caused by a defect in the enzyme homogentisic acid oxygenase, which inhibits the metabolism of homogentisic acid. Intermediates of homogentisic acid bind to collagen fibers of skin and cartilage. The skin shows gray or black macules and patches on the face, neck, and distal extremities. Bluish discoloration of the sclerae and of the cartilage of the ears, and sometimes of the nose, may also be present. Histopathologically, the fibers are orange, and in the skin they may fill the entire dermis (Figure 23.19).3,46
Inflammatory rheumatic diseases in patients with ochronotic arthropathy
Published in Modern Rheumatology, 2021
Tuba Yuce Inel, Pelin Teke Kisa, Ali Balci, Sadettin Uslu, Zumrut Arslan, Burcu Ozturk Hismi, Ulku Ucar, Nur Arslan, Fatos Onen, Ismail Sari
Alkaptonuria (AKU) is an autosomal recessive metabolic disease caused by mutations in the homogentisate 1, 2-dioxygenase (HGD) gene. The prevalence of AKU is rare, which is estimated at 1 in 250000 to 1000000 individuals [1]. The defect in the HGD enzyme leads to the accumulation of homogentisic acid (HGA) and its products in the connective tissues (ochronosis) [2]. Patients with ochronosis tend to be asymptomatic in early adulthood and become symptomatic during the second and third decades of life [2,3]. The involvement of the musculoskeletal (MSK) system, which is known as ochronotic arthropathy (OcA), mainly affects weight-bearing peripheral joints such as the knee and hip, spine, and soft tissues. Premature osteoarthritis, osteopenia, and fractures, rupture of the tendons, muscles, or ligaments due to the altered tissues could be seen in the course of the OcA [4,5].
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.