Galactokinase Deficiency

Overview

Plain-Language Overview

Galactokinase deficiency is a rare inherited disorder that affects how the body processes a sugar called galactose, which is found in milk and other dairy products. People with this condition lack enough of the enzyme galactokinase, which is needed to break down galactose properly. As a result, galactose builds up in the blood and can cause problems, especially in the eyes. The most common symptom is the early development of cataracts, which can affect vision. This condition usually does not cause severe liver or brain problems, making it milder than some other galactose metabolism disorders.

Clinical Definition

Galactokinase deficiency is an autosomal recessive inborn error of metabolism characterized by a deficiency of the enzyme galactokinase, which catalyzes the phosphorylation of galactose to galactose-1-phosphate in the Leloir pathway of galactose metabolism. This enzymatic defect leads to the accumulation of galactitol, a sugar alcohol derived from galactose, particularly in the lens of the eye, resulting in the formation of cataracts. Unlike classic galactosemia caused by galactose-1-phosphate uridyltransferase deficiency, galactokinase deficiency typically does not cause significant hepatomegaly, jaundice, or intellectual disability. The clinical presentation is often limited to early-onset cataracts in infancy or childhood. Diagnosis is confirmed by demonstrating reduced galactokinase activity in erythrocytes or fibroblasts and elevated galactose levels in blood and urine. Molecular genetic testing can identify mutations in the GALK1 gene. Management primarily involves dietary restriction of galactose to prevent cataract progression. The prognosis is generally favorable with early diagnosis and treatment.

Inciting Event

Introduction of galactose-containing milk or formula triggers symptom onset.

Latency Period

Symptoms typically develop within weeks after starting galactose-containing feeds.

Diagnostic Delay

Mild symptoms and absence of severe systemic toxicity often lead to delayed diagnosis.
Lack of routine newborn screening for galactokinase deficiency contributes to diagnostic delay.

Clinical Presentation

Signs & Symptoms

Early-onset bilateral cataracts are the hallmark clinical feature.
Mild galactosemia symptoms such as irritability may be present.

History of Present Illness

Parents may report bilateral cataracts or visual disturbances in an infant.
History of feeding with milk or formula containing galactose prior to symptom onset.

Past Medical History

No significant past medical history is typical before symptom onset.

Family History

Family history may reveal siblings with cataracts or known galactokinase deficiency.
Consanguinity or known carrier status in parents increases suspicion.

Physical Exam Findings

Presence of bilateral cataracts may be observed on eye examination.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of galactokinase deficiency is based on clinical suspicion in patients presenting with early-onset cataracts and confirmed by biochemical assays showing decreased galactokinase enzyme activity in erythrocytes or cultured fibroblasts. Elevated levels of galactose and galactitol in blood and urine support the diagnosis. Molecular genetic testing identifying pathogenic variants in the GALK1 gene provides definitive confirmation. Differential diagnosis includes other forms of galactosemia, which can be excluded by normal activity of galactose-1-phosphate uridyltransferase.

Pathophysiology

Key Mechanisms

Galactokinase deficiency results from a mutation in the GALK1 gene, leading to impaired phosphorylation of galactose to galactose-1-phosphate.
Accumulation of galactitol in the lens causes osmotic damage, leading to cataract formation.
Unlike classic galactosemia, toxic metabolites like galactose-1-phosphate do not accumulate significantly, resulting in a milder phenotype.

Involvement	Details
Organs	The eye is primarily affected, with cataracts developing due to galactitol accumulation in the lens.
Tissues	Lens tissue is affected by galactitol accumulation causing cataract formation in galactokinase deficiency.
Cells	Hepatocytes are involved in galactose metabolism and accumulate toxic metabolites in deficiency.
Chemical Mediators	Galactose-1-phosphate accumulates due to galactokinase deficiency, leading to cellular toxicity.

Treatment

Pharmacological Treatments

none
- Mechanism: none
- Side effects: none

Non-pharmacological Treatments

Strict dietary restriction of galactose and lactose to prevent accumulation of toxic metabolites.

Prevention

Pharmacological Prevention

None; no drug-based prevention is available for galactokinase deficiency.

Non-pharmacological Prevention

Strict dietary restriction of galactose and lactose to prevent cataract formation.

Outcome & Complications

Complications

Progressive visual impairment due to cataract formation if untreated.

Short-term Sequelae	Long-term Sequelae
Development of bilateral cataracts in infancy or early childhood.	Potential permanent vision loss if cataracts are not surgically treated.

Differential Diagnoses

Galactokinase Deficiency versus Classic Galactosemia (GALT Deficiency)

Galactokinase Deficiency	Classic Galactosemia (GALT Deficiency)
Isolated cataracts without liver dysfunction or sepsis.	Presence of hepatomegaly and jaundice in the neonatal period.
Elevated galactitol in lens leading to cataract formation.	Elevated galactose-1-phosphate levels in red blood cells.
Normal liver function tests and absence of systemic illness.	Risk of E. coli sepsis in affected infants.

Galactokinase Deficiency versus Galactose Epimerase Deficiency

Galactokinase Deficiency	Galactose Epimerase Deficiency
Mild phenotype with primarily isolated cataracts and no systemic involvement.	Severe systemic symptoms including liver failure and developmental delay.
Normal levels of galactose-1-phosphate in blood.	Elevated galactose-1-phosphate and galactose in blood.
Absence of hypoglycemia or coagulopathy.	Presence of hypoglycemia and coagulopathy.