Galactosaemia

In affected infants, classic galactosaemia presents within days of feeding with breast milk or lactose-containing formula, manifesting as feeding difficulty, failure to thrive, hypoglycaemia, hepatocellular damage with jaundice, bleeding diathesis, and increased susceptibility to E. coli sepsis. Even with prompt initiation of a galactose-restricted diet, chronic diet-independent complications develop in a substantial proportion of individuals from age one to two years onwards. These include bilateral cataracts, speech and language impairment, poor growth, cognitive impairment, and extrapyramidal or cerebellar neurological deficits, including ataxia. In females, hypergonadotropic hypogonadism and premature ovarian insufficiency are common.

Individuals with clinical variant galactosaemia present with overlapping but generally milder features; untreated neonates may nevertheless develop feeding problems, failure to thrive, hepatocellular damage including cirrhosis, and bleeding, while long-term sequelae may include early cataracts, mild intellectual disability with ataxia, and growth restriction.

In many countries, classic galactosaemia is included in newborn screening programmes, enabling early diagnosis and prompt initiation of dietary treatment.

Worldwide newborn screening programmes report a prevalence of approximately 1/48,000.

Galactosaemia is caused by biallelic germline pathogenic variants in GALT (9p13.3), which encodes the enzyme galactose-1-phosphate uridylyltransferase. Loss of GALT activity causes accumulation of galactose-1-phosphate, galactose and galactitol, driving osmotic lens injury that manifests as cataracts, prenatal toxicity to the developing central nervous system, and the chronic diet-independent complications that persist despite galactose restriction.

Galactosaemia is inherited in an autosomal recessive manner. Each child of two heterozygous carriers has a 25% risk of being affected, a 50% risk of being a heterozygous carrier, and a 25% risk of inheriting neither variant. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is established by demonstrating elevated erythrocyte galactose-1-phosphate concentration combined with reduced or absent erythrocyte GALT enzyme activity and confirmed by identification of biallelic pathogenic variants in GALT.

Main differential diagnoses include:

• Epimerase deficiency galactosaemia: liver disease and elevated erythrocyte galactose-1-phosphate with normal GALT activity; GALE
• Galactokinase deficiency: cataracts with elevated plasma galactose but no erythrocyte galactose-1-phosphate accumulation; GALK1
• : liver disease and renal tubular dysfunction presenting after introduction of fructose-containing foods; ALDOB

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for informed genetic counselling of affected individuals and their families.
• Identification of the underlying pathogenic variants enables specific and individualised surveillance for the recognised long-term complications of the condition and is a prerequisite for targeted medical care, with management decisions taken by the treating physicians in consultation with the affected individual.
• Knowledge of the familial pathogenic variants enables targeted carrier testing of at-risk relatives within the family.

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