Galactokinase (GALK) deficiency, also called type II galactosemia, is one of four known congenital metabolic disorders of galactose metabolism. It follows an autosomal recessive inheritance pattern and is caused by mutations in the GALK1 gene (17q25.1). More than 30 pathogenic mutations have been identified to date1). The two most frequent mutations are the founder mutation c.82C>A (p.Pro28Thr) and the Osaka mutation c.593C>T (p.Ala198Val)1).
It is the mildest form of galactosemia, with no systemic symptoms; cataracts are the only manifestation.
The overall incidence of galactosemia in Japan is estimated at 1 in 900,000 to 1,000,000 people. Worldwide, the incidence of GALK deficiency varies from 1:150,000 to 1:1,000,0001). In the Roma population, a founder mutation (p.Pro28Thr) results in a higher frequency of 1:40,0001). In the United States, the estimated incidence is 1 in 100,000 newborns.
Classic galactosemia (type I, GALT deficiency) is a severe form involving liver damage, sepsis, and central nervous system disorders. In contrast, GALK deficiency has no systemic symptoms, and cataract is the only manifestation. In blood tests, type I shows elevated galactose-1-P, whereas GALK deficiency shows normal galactose-1-P levels1).
In infancy, dramatic symptoms are scarce, and recognition may be delayed. If cataracts are overlooked, they may be noticed through the following symptoms.
Heterozygous carriers also have an increased risk of juvenile cataract (onset before age 40).
Systemic symptoms are generally absent, but the following have been rarely reported.
Mutations in the GALK1 gene cause deficiency of galactokinase, impairing the Leloir pathway, the main route of galactose metabolism. Unmetabolized galactose is diverted to an alternative pathway (aldose reductase pathway), producing galactitol, which has osmotic properties 1).
Because aldose reductase is abundant in the anterior lens, elevated blood galactose levels lead to excessive accumulation of galactitol in the lens. This causes swelling of lens fibers, cell lysis, and protein denaturation, resulting in cataract formation 1).
Early detection through newborn mass screening is ideal. Once a diagnosis of galactosemia is made, lactose intake restriction should be initiated. However, not all countries’ screening programs include GALK deficiency, and detection may be delayed1).
The following are measured as confirmatory tests:
Definitive diagnosis is possible by GALK1 gene analysis 1). In one case, a compound heterozygote of a known pathogenic mutation c.919_921delATG (p.Met307del) and a novel missense mutation c.500C>A (p.Ala167Asp) was identified 1).
In infants presenting with bilateral congenital cataracts, the following conditions should be differentiated:
The diseases included in newborn screening vary by country and region. If galactose metabolism disorders are not included in the screening, diagnosis may be delayed1). If bilateral congenital cataracts are found without a family history, galactose metabolism disorders should be strongly suspected and tested.
This is the most important treatment for achieving a good outcome.
Even with strict dietary compliance, galactitol levels may exceed normal values1). In type II, long-term observation for cataract onset and progression is necessary.
Dietary Therapy
Indications: Early detection cases. Ideally within 2–3 weeks after birth.
Method: Strict galactose-restricted diet plus calcium supplementation. Use soy-based formula for infants.
Effect: Cataracts may become reversible. Continued management beyond infancy is required.
Cataract Surgery
Indications: When significant cataract affecting visual function has progressed.
Method: Lens extraction. The decision to insert an intraocular lens depends on the case.
Postoperative management: In one case, bilateral surgery was performed at 11 months of age, and normal neurodevelopment was confirmed 2 years after surgery1).
If dietary therapy is started within 2 to 3 weeks after birth, cataracts may regress. However, if detection is delayed or cataracts have progressed, surgery may be necessary. Dietary therapy must be continued beyond infancy to avoid the risk of cataract recurrence or other complications1).
Galactose is primarily metabolized via the Leloir pathway. This pathway proceeds in the order: galactose → (GALK) → galactose-1-phosphate → (GALT) → UDP-galactose → (GALE) → UDP-glucose1).
When GALK deficiency impairs the first step of the Leloir pathway, galactose is diverted to the alternative aldose reductase pathway. In this pathway, galactose produces galactitol 1).
Galactitol has osmotic properties, and when it accumulates in lens fibers, it forms cataracts through the following process 1).
In a normal lens, 70–80% of energy metabolism is provided by anaerobic glycolysis, 10% by the pentose phosphate pathway, and 10% by the sorbitol pathway. In the lens, aldose reductase activity is higher than hexokinase activity, but hexokinase has a higher affinity for glucose. Under hypergalactosemia, hexokinase becomes saturated, and substrate influx into the aldose reductase pathway increases. This mechanism is common with diabetic cataract.
The ophthalmic features of the three types of galactosemia are compared below.
| Type | Deficient enzyme | Main symptoms other than cataract |
|---|---|---|
| Type I (GALT deficiency) | GALT | Liver damage, sepsis, central nervous system disorders |
| Type II (GALK deficiency) | GALK | None (cataract only) |
| Type III (GALE deficiency) | GALE | Mild to severe range |
More than 30 pathogenic mutations in the GALK1 gene have been reported to date, but identification of novel mutations continues.
Cordeiro et al. (2021) identified a compound heterozygote of the known pathogenic mutation c.919_921delATG (p.Met307del) and a novel missense mutation c.500C>A (p.Ala167Asp) in a 12-month-old girl of Moldovan origin living in Portugal1). The latter is a predicted pathogenic variant, showing a different genetic background from the founder mutation common in the Roma population.
The inclusion of GALK deficiency in newborn mass screening is being considered in various countries1). Currently, not all national screening programs include galactose metabolism disorders, leading to delays in diagnosis. Expanding screening is expected to promote early detection and treatment, preventing cataracts.
