Galactosaemia

Classic galactosaemia is an autosomal recessive disorder of galactose metabolism caused by deficiency of galactose-1-phosphate uridyltransferase (GALT, 9p13), with accumulation of galactose, galactose-1-phosphate and galactitol. Incidence is about 1 in 30,000 to 60,000. The common variants are Q188R (Europeans) and S135L (African Americans; milder with partial enzyme activity). Other types: galactokinase deficiency (GALK1; cataract only) and UDP-galactose-4-epimerase deficiency (GALE).

• Neonatal presentation within days of starting breast or lactose containing milk: poor feeding, vomiting, diarrhoea, jaundice (conjugated and unconjugated), hepatomegaly, hypoglycaemia, hepatic failure and coagulopathy, cataracts (oil drop), lethargy, seizures, and Escherichia coli sepsis (up to 30 to 50% of untreated neonates; neonatal sepsis due to gram negative bacteria is characteristic), and death without treatment
• Long term complications despite treatment: speech and language delay (verbal dyspraxia), learning difficulties, cognitive impairment, tremor and ataxia, premature ovarian insufficiency (80 to 90% of females; ovarian failure and infertility), osteopenia, and growth failure; cataracts can recur
• S135L variants: mild or no symptoms

1. Newborn screening: total galactose and galactose-1-phosphate and GALT enzyme activity on dried blood spot (note that results can be falsely normal after non-lactose feeding, and in blood transfusion).
2. Confirmatory: erythrocyte GALT enzyme activity (absent in classic; not valid after transfusion until 3 months), erythrocyte galactose-1-phosphate (elevated), and GALT genotyping. Urinary reducing substances positive with negative glucose oxidase (screening, unreliable).
3. Evaluate liver function, coagulation, glucose, blood culture, and slit lamp examination.
4. Cascade testing of siblings and prenatal diagnosis.

• Immediate cessation of lactose and galactose: switch to a soy based, elemental or lactose free formula (galactose free; casein hydrolysate formulae with lactose are not suitable) as soon as suspected, even before confirmation.
• Treat sepsis (broad spectrum antibiotics, for example cefotaxime 50 mg/kg every 8 hours with gentamicin 4 to 5 mg/kg daily), hypoglycaemia (dextrose 2 mL/kg of 10%), and coagulopathy (vitamin K 1 mg IV, fresh frozen plasma 10 to 15 mL/kg), and manage acute liver failure.
• Lifelong galactose restricted diet: avoid milk and dairy products, lactose containing foods, organ meats, some legumes, and medications with lactose excipients; mature cheeses, which have low galactose, may be tolerated in some patients. Calcium (1,000 to 1,200 mg/day), vitamin D (800 to 1,000 IU) and vitamin K2 supplementation.
• Monitor: erythrocyte Gal-1-P (target below 3.5 mg/dL, though does not correlate with outcomes), growth, development and speech (early speech therapy; verbal dyspraxia), ophthalmology yearly, bone density, and endocrine function.
• Girls: monitor puberty from age 10; replace sex steroids for primary ovarian insufficiency (transdermal oestradiol 25 to 100 micrograms/day with cyclical progestin), and discuss fertility preservation options (oocyte or embryo cryopreservation) with early referral.
• Cognitive and behavioural therapy, with psychological support.
• Genetic counselling: 25% recurrence risk; prenatal diagnosis and maternal galactose restriction in subsequent pregnancies (to limit prenatal damage).