What is galactokinase deficiency?

Risk Factors

Galactokinase deficiency is an autosomal recessive disease. It manifests if the patient’s parents each carry one copy of the mutated GALK1 gene, even if they do not show signs and symptoms. Both sexes are equally affected. The familial risk factor is increased in consanguineous marriages. The incidence of galactokinase deficiency has been found to be higher (approximately 1 per 10,000) in Roma populations of eastern Europe with endogamous traditions. In the United States, the estimated incidence is 1 per 50,000–100,000 live births.

Etiology and Genetics

Galactokinase deficiency is associated with mutations in the GALK1 gene, located on the long (q) arm of chromosome 17, from base pair 71,265,612 to 71,272,874. The gene contains eight exons and spans approximately 7.3 kilobases (kb) of genomic DNA. It encodes the enzyme galactokinase (EC 2.7.1.6), which phosphorylates galactose to galactose-1-phosphate. Phosphorylation is the first of three enzymatic steps in galactose metabolism. Galactose-1-phosphate uridyltransferase (EC 2.7.7.10; GALT) and UDP-galactose-4-epimerase (EC 5.1.3.2; GALE) are responsible in this order for the next two metabolic steps. Inborn metabolic errors linked to impaired activity of each enzyme lead to galactosemia. Galactosemia linked to galactokinase deficiency results in the least severe symptoms compared to classic galactosemia linked to GALT deficiency (with life-threatening signs and symptoms) and galactosemia linked to GALE deficiency (the rarest kind, which causes damages to tissues and organs).

More than twenty-three different mutations within the GALK1 gene have been identified in galactokinase deficiency. Most of these are missense (a codon for one amino acid is substituted by the codon for a different amino acid) or deletion (part of a chromosome or sequence of DNA is missing) mutations that cause changes in the stability and activity of the enzyme. Private mutations, found only in the kindred of patients, are not uncommon in galactokinase deficiency. A founder mutation was identified in Roma patients as the P28T mutation, in which proline at position 28 is substituted by threonine.

Symptoms

The most consistent symptoms of galactokinase deficiency include congenital cataracts in infants and presenile cataracts in adults. The disease also results in galactosemia and galactosuria. Pseudotumor cerebri (idiopathic intracranial hypertension) is rare but consistently reported in galactokinase-deficient patients. Both cataract and pseudotumor cerebri can be ascribed to accumulation of galactitol, a product of an alternative route of galactose utilization, which results in osmotic swelling; both resolve with therapy. A variety of clinical abnormalities have also been reported, but a causal relationship with galactokinase deficiency could not be determined.

Screening and Diagnosis

Galactokinase deficiency is rare, and the diagnosis is not immediately apparent. Unlike classic galactosemia, galactokinase deficiency does not present with severe manifestations; thus, most cases are diagnosed after the development of lens opacity in the infant. Because the disease is rare, genetic screening is not usually done. The diagnosis is established by demonstrating deficient activity of the galactokinase enzyme in erythrocytes.

Treatment and Therapy

The only treatment for galactokinase deficiency is to restrict galactose (and sugars containing galactose units, such as lactose) in the diet. This is usually effective in reversing symptoms.

Prevention and Outcomes

The development of early cataracts in homozygous affected infants is fully preventable through early diagnosis and treatment with a galactose-restricted diet. Ideally, screening programs in genetically at-risk populations would allow prevention of galactokinase deficiency. In reality, such programs are not usually available, and the disease is not identified until cataract and blindness develop.

According to some studies, depending on milk consumption later in life, heterozygous carriers of galactokinase deficiency may be prone to presenile cataracts at twenty to fifty years of age. The general outcome for patients with galactokinase deficiency is positive, and with dietary precautions the patients lead a normal life.

Bibliography

Bayarchimeg, Mashbat, et al. "Galactokinase Deficiency in a Patient with Congenital Hyperinsulinism." JIMD Reports. Ed. Verena Peters. Vol. 5. Heidelberg: Springer, 2012. 7–11. Print.

Berry, Gerard T. "Classic Galactosemia and Clinical Variant Galactosemia." GeneReviews. Ed. Roberta A. Pagon et al. Seattle: U of Washington, Seattle, 1993–2014. NCBI Bookshelf. Natl. Center for Biotechnology Information, 3 Apr. 2014. Web. 23 July 2014.

Bosch, A. M., et al. “Clinical Features of Galactokinase Deficiency: A Review of the Literature.” Journal of Inherited Metabolic Diseases 25.8 (2002): 629–34. Print.

Kalaydjieva, Luba, et al. “A Founder Mutation in the GK1 Gene Is Responsible for Galactokinase Deficiency in Roma (Gypsies).” American Journal of Human Genetics 65.5 (1999): 1299–1307. Print.

Novelli, Giuseppe, and Juergen K. V. Reichardt. “Molecular Basis of Disorders of Human Galactose Metabolism: Past, Present, and Future.” Molecular Genetics and Metabolism 71.1–2 (2000): 62–65. Print.

Segal, Stanton, and Gerard T. Berry. “Disorders of Galactose Metabolism.” The Metabolic and Molecular Bases of Inherited Disease. Ed. C. R. Scriver et al. 7th ed. Vol. 1. New York: McGraw, 1995. 967–1000. Print.

Singh, Ramandeep, et al. "Galactokinase Deficiency Induced Cataracts in Indian Infants: Identification of 4 Novel Mutations in GALK Gene." Current Eye Research 37.10 (2012): 949–54. Print.