Inborn errors of metabolism
Martin Andrew Crook in 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).
Archibald E. Garrod (1857–1936)
Krishna Dronamraju in A Century of Geneticists, 2018
When a third child with alkaptonuria was born to the parents of Thomas P., Garrod suspected that something more than mere chance was involved. When he learned that Thomas P.’s parents were blood relations—their mothers were sisters—he inquired into the backgrounds of other families with one or more children with alkaptonuria. In every instance, their parents were also first cousins. It was while walking home from the hospital one afternoon that Garrod conceived of the possibility that alkaptonuria might be a disease caused by heredity (genetics). Gregor Mendel’s work on the principles of heredity, newly discovered in England, offered a simple explanation. The mating of first cousins apparently created conditions under which a rare, recessive Mendelian factor (or gene) appeared in the offspring. Garrod’s classic paper on alkaptonuria was published in The Lancet in 1902.
Histopathology
Dimitris Rigopoulos, Alexander C. Katoulis in 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
Asiye Arıcı, Hatice Altun
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.
Related Knowledge Centers
- Cartilage
- Enzyme
- Mutation
- Ochronosis
- Oxide
- Osteoarthritis
- Gene
- Homogentisate 1,2-Dioxygenase
- Dominance
- Homogentisic Acid