eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Galactokinase Deficiency

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Updated: Sep 2, 2009

Introduction

Background

As 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.¹

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.

Pathophysiology

UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.

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.

Frequency

United States

Because 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.

International

The 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

The literature indicates no risk of mortality. Morbidity is limited to cataract formation in untreated individuals, although rare cases of pseudotumor cerebri have been reported. Both resolve with effective therapy. Mental retardation and hepatic damage are not associated with galactokinase deficiency.

Sex

As an autosomal recessive condition, the disorder is distributed equally between sexes.

Age

Because galactokinase deficiency is a genetic disease, it is present from conception and may be discovered at birth through the presence of congenital cataracts.

Clinical

History

• Hepatosplenomegaly at birth (reported in a single case) is not common in neonates with galactokinase deficiency.
• Failure to develop a social smile or to follow objects may represent initial signs of a visual deficit due to cataracts.
• GI symptoms associated with the ingestion of galactose are conspicuously absent.
• Growth parameters are unaffected.
• Family history is not relevant.
• Soy formula (given to the infant for other reasons) may curtail the development of cataracts and delay the consequent diagnosis of galactokinase deficiency. However, milk products introduced into the diet later will result in cataract formation.

Physical

• Cataracts may be apparent upon gross inspection of the eye.
• Opacities may be visualized during attempts at funduscopic examination.
• Vision-based developmental landmarks, such as tracking, reaching, and social smiling, may be reached late or not at all.

Causes

• Galactokinase deficiency is an autosomal recessive genetic disorder mapped to band 17q24.
• At least 20 mutations are known, of which the P28T mutation is considered the founder mutation.
• Many genetic variations of GALK1 have been identified in the patients with galactokinase deficiency.²

Differential Diagnoses

Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
Hypoparathyroidism
Oculocerebrorenal Dystrophy (Lowe Syndrome)
Osteogenesis Imperfecta
Wilson Disease

Other Problems to Be Considered

Fabry disease
Myotonic dystrophy
Steroid administration

Workup

Laboratory Studies

• Clinitest
  • Most hospitals use Clinitest in the diagnosis of galactokinase deficiency, the simplest laboratory test available to detect reducing sugars (eg, glucose, lactose, or fructose, which reduce copper salts in Clinitest tablets) in the urine.
  • Always correlate a positive Clinitest result with a test specific for glucose, such as Clinistix. Alternatively, galactose may be identified directly with paper or gas chromatography. If galactose is found, galactose-1-phosphate concentration should also be measured to conclusively exclude transferase-deficient galactosemia.
  • Definitive biochemical diagnosis is based on assessment of red cell galactokinase activity.

Imaging Studies

• No imaging studies are required.

Other Tests

• Once a definitive diagnosis is established, no further testing is needed.

Procedures

• No diagnostic procedures are required.

Histologic Findings

• No histologic findings are associated with galactokinase deficiency. Cataracts bear no distinguishing features that identify their etiology.

Treatment

Medical Care

• Treatment may be provided on an outpatient basis.
• Cataracts that do not regress or disappear with therapy may require hospitalization for surgical removal.

Surgical Care

• Cataracts may require surgical removal.

Consultations

• Biochemical geneticist
• Nutritionist
• Ophthalmologist

Diet

• Diet is the foundation of therapy. Elimination of lactose and galactose sources suffices for definitive therapy.
• Because soy formulas are typically poor calcium sources, ensure adequate calcium intake through dietary supplements.
• Many lactose-free foods are known to contain free galactose; counsel from a skilled nutritionist may help a patient avoid these items.
• Under kosher dietary law, all foods labeled kosher must also be identified as meat, dairy, or pareve (neither meat nor dairy). Thus, shopping for foods from the kosher meat and pareve food categories exclusively can simplify purchasing food.

Activity

• No restriction is necessary.

Medication

Drug therapy is not a component of the standard of care for this disease. See Treatment.

Follow-up

Further Outpatient Care

• Evaluate patients with galactokinase deficiency on a regular and frequent schedule to assess dietary intake and to perform eye examinations.

Inpatient & Outpatient Medications

• Medication is unnecessary.

Complications

• Dietary indiscretions resulting in small, frequent doses of galactose encourage initial or recurrent cataract formation.

Prognosis

• The prognosis is excellent. The disorder has no implications for any organ other than the lens. Problems can be eliminated with proper care.

Patient Education

• Affected individuals must learn to master the dietary restrictions required to eliminate galactose ingestion.
• Patients should undergo an annual slit-lamp examination to detect cataract formation.
• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Cataracts.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize the disorder as a treatable cause of congenital cataracts
• Failure to observe patients regularly and frequently to prevent cataract formation
• Failure to monitor calcium intake to prevent osteomalacia and osteoporosis while the patient is on a soy formula

Multimedia

Media file 1: UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.

References

1. Cuthbert C, Klapper H, Elsas L. Diagnosis of inherited disorders of galactose metabolism. Curr Protoc Hum Genet. Jan 2008;Chapter 17:Unit 17.5. [Medline].

2. Park HD, Kim YK, Park KU, Kim JQ, Song YH, Song J. A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype. BMC Med Genet. Mar 24 2009;10:29. [Medline].

3. Berry GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr. 1995;154(7 Suppl 2):S53-64. [Medline].

4. Beutler E, Matsumoto F, Kuhl W, Krill A, Levy N, Sparkes R, et al. Galactokinase deficiency as a cause of cataracts. N Engl J Med. Jun 7 1973;288(23):1203-6. [Medline].

5. Bosch AM, Bakker HD, van Gennip AH, van Kempen JV, Wanders RJ, Wijburg FA. Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis. Dec 2002;25(8):629-34. [Medline].

6. Gitzelmann R. Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res. 1967;1:14-23.

7. Hunter M, Heyer E, Austerlitz F. The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma(Gypsy) patients across Europe. Pediatr Res. 2002;51:602-606.

8. Kerr MM, Logan RW, Cant JS, Hutchison JH. Galactokinase deficiency in a newborn infant. Arch Dis Child. Dec 1971;46(250):864-6. [Medline].

9. Levy NS, Krill AE, Beutler E. Galactokinase deficiency and cataracts. Am J Ophthalmol. Jul 1972;74(1):41-8. [Medline].

10. Pickering WR, Howell RR. Galactokinase deficiency: clinical and biochemical findings in a new kindred. J Pediatr. Jul 1972;81(1):50-5. [Medline].

11. Reich S, Hennerman J, Vetter B. An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening. Pediatr Res. 2002;51:598-601.

12. Sangiuolo F, Magnani M, Stambolian D. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat. 2004;23:396.

13. Thalhammer O, Gitzelmann R, Pantlitschko M. Hypergalactosemia and galactosuria due to galactokinase deficiency in a newborn. Pediatrics. Sep 1968;42(3):441-5. [Medline].

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

Contributor Information and Disclosures

Author

Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth, MD 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
Disclosure: MDS Pharma Salary Employment

Medical Editor

Michael Fasullo, PhD, Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College
Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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