You are in: eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases Galactokinase DeficiencyArticle Last Updated: Sep 10, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine Karl S Roth is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center Author and Editor Disclosure Synonyms and related keywords: galactosemia II, GALK deficiency, cataracts, galactosuria, hexose sugar, galactose, glucose, hexokinase, galactosemia, galactose-1-phosphate uridyltransferase galactosemias, hexokinase, galactokinase deficiency, transferase-deficient galactosemia, galactose-related cataracts INTRODUCTIONSection 2 of 10
  BackgroundAs with all hexose sugars, metabolism of ingested galactose requires an initial phosphorylation of the molecule using adenosine triphosphate (ATP). Unlike the metabolism of glucose, which ordinarily depends on the activity of hexokinase with a wide substrate-specificity to carry out this reaction, substrate-specific galactokinase activity exclusively phosphorylates galactose. In 1965, galactokinase deficiency was first identified in a patient who presented with cataracts and galactosuria that developed upon drinking milk. The concurrence of cataracts and galactosuria in a single individual suggested the possibility of a new type of galactosemia. This presentation differed from that of classic galactosemia in many important aspects; neither hepatosplenomegaly nor signs of mental retardation were present. When the researchers realized that the patient did not accumulate galactose-1-phosphate despite the accumulated galactose, the patient's underlying defect was deduced as the lack of the enzyme mediating 1-phosphorylation of galactose. PathophysiologyAn appreciation of the differences between the enzyme deficiencies and their clinical manifestations is key to understanding the pathophysiology of galactokinase and galactose-1-phosphate uridyltransferase galactosemias. Whereas vomiting, failure to thrive, jaundice, hepatomegaly, and cataracts are characteristic of the onset of transferase-deficient galactosemia, cataract development is usually the only symptom observed in an infant with kinase deficiency. In people with transferase-deficient galactosemia, galactose-1-phosphate accumulates; in those with kinase deficiency, galactose-1-phosphate cannot be produced. Galactose-1-phosphate is assumed to be the substance that causes the devastating manifestations seen in people with classic galactosemia. Note that this assumption lacks definitive proof despite the intrinsic and compelling logic. In contrast, the mechanism that produces galactose-related cataracts is understood fairly well. The lens of the eye contains the aldose reductase enzyme. When presented with accumulated galactose, this enzyme reduces the aldehydic end group and produces galactitol, the analogous sugar alcohol. This compound exerts osmotic pressure within the lens because it slowly diffuses. While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most researchers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation. The evidence favors this view because patients with galactokinase deficiency who cannot produce galactose-1-phosphate still form cataracts. While patients who are deficient in galactokinase accumulate galactitol in the liver at rates comparable to those with transferase-deficient galactosemia, only the latter display evidence of hepatic damage. Hence, much remains to be learned about the pathophysiologic implications of galactose metabolic impairment. FrequencyUnited StatesBecause most newborn screening programs are designed to identify transferase deficiency, accumulated galactose in submitted blood samples is missed. Accordingly, the data are insufficient to provide an accurate assessment of prevalence, although the estimated range is 1 per 50,000-100,000 live births. InternationalThe prevalence among certain Eastern European populations, in particular the Romani (Gypsy) population, is estimated to be approximately 1 per 10,000. The Romani people generally possess a mutation known as P28T, considered the founder mutation. Mortality/Morbidity
SexAs an autosomal recessive condition, the disorder is distributed equally between sexes. AgeBecause galactokinase deficiency is a genetic disease, it is present from conception and may be discovered at birth through the presence of congenital cataracts. CLINICALSection 3 of 10
History
Physical
CausesGalactokinase deficiency is an autosomal recessive genetic disorder mapped to band 17q24. At least 20 mutations are known to exist, of which the P28T mutation is considered the founder mutation. DIFFERENTIALSSection 4 of 10
Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia) Hypoparathyroidism Oculocerebrorenal Dystrophy (Lowe Syndrome) Osteogenesis Imperfecta Wilson Disease
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