AUTHOR INFORMATION

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Authored by Karl S Roth, MD, Chair, Professor, 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 Association for the Advancement of Science, 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

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, 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; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, August 1 2005, VOLUME 6, Number 8

INTRODUCTION

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Background: As with all hexose sugars, metabolism of ingested galactose requires an initial phosphorylation of the molecule using ATP. Unlike the metabolism of glucose, which ordinarily depends upon the activity of hexokinase with a wide substrate-specificity to carry out this reaction, galactose is phosphorylated exclusively by activity of the substrate-specific galactokinase.

In 1965, researchers discovered the first patient deficient in galactokinase. This patient 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 patient differed from the initial characterization of classical galactosemia in many important respects, having neither hepatosplenomegaly nor any signs of mental retardation. When it became apparent that the patient did not accumulate galactose-1-phosphate, despite the accumulated galactose, the lack of the enzyme mediating 1-phosphorylation of galactose was deduced as the patient's underlying defect.

Pathophysiology: Appreciation of the distinct differences between the enzyme deficiencies and their clinical manifestations are 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 the only symptom usually seen in an infant with kinase deficiency. In transferase-deficient galactosemia, galactose-1-phosphate accumulates, while in kinase deficiency, galactose-1-phosphate cannot be produced. Galactose-1-phosphate is assumed to be the substance causing the devastating manifestations seen in classical galactosemia. Note that this assumption lacks definitive proof, despite the intrinsic and compelling logic.

By contrast, the mechanism that produces galactose-related cataracts is understood fairly well. The lens 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 diffuses very slowly. While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most observers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation. The evidence favors this view because patients with galactokinase deficiency cannot produce galactose-1-phosphate, yet they still form cataracts.

While patients deficient in galactokinase accumulate galactitol in the liver at rates comparable to those patients with transferase-deficient galactosemia, only the latter show evidence of hepatic damage. Hence, much remains to be learned about the pathophysiologic implications of galactose metabolic impairment.

Frequency:

• In the US: Because most newborn screening programs are designed to identify transferase deficiency, accumulated galactose in submitted blood samples are missed. Accordingly, the data are insufficient to provide an accurate assessment of prevalence, although the estimated range is 1 case per 50,000-100,000 live births.

• Internationally: The prevalence among certain Eastern European populations, in particular the Romani ("Gypsy") populace, is estimated to be approximately 1:10,000. The Romani people generally possess a mutation known as P28T, considered the founder mutation.

Mortality/Morbidity: In addition to the regular occurrence of cataracts in an untreated individual, pseudotumor cerebri has been very rarely reported. Both remit with effective therapy.

• The literature indicates no risk of mortality.

• Morbidity is limited to cataract formation, although very rare cases of pseudotumor cerebri have been reported.

• Mental retardation and hepatic damage are not associated with galactokinase deficiency.

Sex: As an autosomal recessive condition, the disorder is distributed equally between genders.

Age: Because galactokinase deficiency is a genetic disease, it is present from conception and may be revealed at birth by the presence of congenital cataracts.

CLINICAL

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History:

• Hepatosplenomegaly at birth (reported in a single case) is not a general feature in the affected neonate.

• Failure to develop a social smile or to follow objects may be initial signs of visual deficit due to cataracts.



• GI symptoms associated with ingestion of galactose are conspicuously absent.



• Growth parameters are unaffected.



• Expect absence of a relevant family history.



• If the infant fortuitously has been fed soy formula for other reasons, the development of cataracts and a consequent diagnosis of galactokinase deficiency may be the result. However, later introduction of milk products into the diet 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 may be reached late or not at all. These include tracking, reaching, and social smiling.

Causes: Galactokinase deficiency is an autosomal recessive genetic disorder mapped to gene locus 17q24. At least 20 mutations are known to exist, of which the P28T mutation is considered the founder mutation.

DIFFERENTIALS

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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

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Lab Studies:

• Clinitest


• • Most hospitals have a Clinitest, the simplest laboratory test available for detection of reducing sugars in the urine.
  
  
  
  • Always correlate a positive Clinitest result with a test specific for glucose, such as Clinistix. Alternatively, galactose can be identified directly by paper or gas chromatography. If galactose is found, galactose-1-phosphate concentration should also be measured, in order to conclusively exclude transferase-deficient galactosemia.
  
  
  
  • Definitive biochemical diagnosis is based upon 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.

TREATMENT

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Medical Care:

• Treatment can be performed 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.



• Since soy formulas are generally poor calcium sources, ensure dietary supplementation of calcium intake.



• Many lactose-free foods are known to contain free galactose; counsel from a skilled nutritionist can help a patient avoid these items.



• Under kosher dietary law, all foods labeled kosher must also be identified as meat, dairy, or neither. Thus, shopping for kosher meats and the parve food category (meaning neither meat nor dairy) can save a great deal of shopping effort.

Activity: No restriction is necessary.

MEDICATION

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

FOLLOW-UP

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Further Outpatient Care:

• Follow up with affected individuals on a regular and frequent schedule to assess dietary intake and to perform eye examinations.

In/Out Patient Meds:

• Medication is unnecessary.

Complications:

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

Prognosis:

• 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 needed 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

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Medical/Legal Pitfalls:

• Failure to recognize the disorder as a treatable cause of congenital cataracts



• Failure to maintain close follow-up to prevent cataract formation



• Failure to monitor calcium intake to prevent osteomalacia and osteoporosis while on a soy formula

TEST QUESTIONS

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CME Question 1: Which of the following is not a complication of galactokinase deficiency?

A: Mental retardation
B: Hepatosplenomegaly
C: Cirrhosis of the liver
D: Failure to thrive
E: All of the above

The correct answer is E: The prognosis for galactokinase deficiency is excellent. Cataracts are the only complication.

CME Question 2: Which of the following statements is false?

A: Galactose can be eliminated safely from the human diet.
B: Patients on soy formula require calcium supplementation.
C: Development is compromised in infants with galactokinase deficiency.
D: Cataracts are the sole clinical manifestation of galactokinase deficiency.
E: None of the above

The correct answer is C: Growth parameters are unaffected. Whereas vomiting, failure to thrive, jaundice, hepatomegaly, and cataracts are characteristic of the onset of transferase-deficient galactosemia, cataract development is the only symptom usually seen in an infant with kinase deficiency.

Pearl Question 1 (T/F): Galactitol is the substance that accumulates in the lens and initiates cataract formation in patients with galactokinase deficiency.

The correct answer is True: Galactitol, the sugar alcohol formed by reduction of galactose by aldose reductase, accumulates in the lens and initiates cataract formation.

Pearl Question 2 (T/F): Many organs are affected by galactokinase deficiency and provide important clues about transferase galactosemia.

The correct answer is False: Accumulation of galactose has important consequences for the eye alone. On the other hand, 1-phosphorylated galactose has toxic implications for a variety of different cell types.

Pearl Question 3 (T/F): Galactose is phosphorylated by glucokinase when galactokinase is deficient.

The correct answer is False: Glucose is a substrate for both the primary phosphorylating enzyme, hexokinase, and the less important and more specific glucokinase. Galactose is not acted upon by hexokinase and, therefore, can undergo only the galactokinase reaction.

Pearl Question 4 (T/F): Awareness of kosher dietary laws can help anyone avoid products containing lactose.

The correct answer is True: As a consequence of kosher dietary law, all foods labeled kosher must also be identified as meat, dairy, or neither. Thus, shopping for kosher meats and foods labeled parve (meaning neither meat nor dairy) can save a great deal of shopping effort.

BIBLIOGRAPHY

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• Berry GT: The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr 1995; 154(7 Suppl 2): S53-64[Medline].
• Beutler E, Matsumoto F, Kuhl W: Galactokinase deficiency as a cause of cataracts. N Engl J Med 1973 Jun 7; 288(23): 1203-6[Medline].
• Bosch AM, Bakker HD, van Gennip AH, et al: Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis 2002 Dec; 25(8): 629-34[Medline].
• Gitzelmann R: Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res 1967; 1: 14-23.
• 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.
• Kerr MM, Logan RW, Cant JS: Galactokinase deficiency in a newborn infant. Arch Dis Child 1971 Dec; 46(250): 864-6[Medline].
• Levy NS, Krill AE, Beutler E: Galactokinase deficiency and cataracts. Am J Ophthalmol 1972 Jul; 74(1): 41-8[Medline].
• Pickering WR, Howell RR: Galactokinase deficiency: clinical and biochemical findings in a new kindred. J Pediatr 1972 Jul; 81(1): 50-5[Medline].
• 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.
• Sangiuolo F, Magnani M, Stambolian D: Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat 2004; 23: 396.
• Thalhammer O, Gitzelmann R, Pantlitschko M: Hypergalactosemia and galactosuria due to galactokinase deficiency in a newborn. Pediatrics 1968 Sep; 42(3): 441-5[Medline].

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