Galactosemia

1. DEFINITION AND ETIOLOGY

• Definition: Inborn error of carbohydrate metabolism characterized by the inability to convert galactose to glucose due to enzymatic deficiency.
• Enzyme Defects:
  • Type 1 (Classic): Galactose-1-phosphate uridyl transferase (GALT) deficiency. Most common and severe form.
  • Type 2: Galactokinase (GALK) deficiency (primarily cataracts).
  • Type 3: Uridine diphosphate galactose-4-epimerase (GALE) deficiency.
• Genetics:
  • Inheritance: Autosomal Recessive.
  • Gene: GALT gene on chromosome 9p13.
  • Variants:
    • p.Gln188Arg (Q188R): Most common severe variant in Whites; associated with premature ovarian insufficiency.
    • p.Ser135Leu (S135L): Common in Blacks; milder phenotype.
    • Duarte Variant (D2): Partial deficiency (approx. 25% activity); typically asymptomatic and may not require treatment.

2. PATHOPHYSIOLOGY

• Metabolic Block: Inability to metabolize galactose-1-phosphate (Gal-1-P).
• Toxicity:
  • Accumulation of Gal-1-P results in cellular toxicity to the liver, kidney, and brain.
  • Alternative pathway reduction of galactose to Galactitol causes osmotic damage (cataracts, cerebral edema).
  • Endogenous production of galactose can cause prenatal injury.

3. CLINICAL FEATURES

• Presentation: Onset typically in the second half of the first week of life after initiation of breast milk or cow's milk (lactose) feeding.
• Acute Neonatal Symptoms:
  • Hepatic: Jaundice (often conjugated), hepatomegaly, hepatic failure, coagulopathy, ascites.
  • Gastrointestinal: Vomiting, feeding intolerance, poor weight gain.
  • Neurologic: Lethargy, irritability, seizures, cerebral edema (pseudotumor cerebri with bulging fontanelle).
  • Ophthalmologic: Nuclear cataracts ("oil drop" appearance) detectable within days to weeks.
• Infection Risk: High susceptibility to E. coli neonatal sepsis; onset often precedes the metabolic diagnosis.
• Renal: Renal Fanconi syndrome (aminoaciduria, phosphaturia, acidosis) due to tubular toxicity.

4. INVESTIGATIONS

• Screening Tests:
  • Newborn Screening (NBS): Measures total galactose and/or GALT enzyme activity.
  • Urine Reducing Substances: Positive Clinitest (detects galactose) with Negative Clinistix (specific for glucose). Note: False negatives possible if infant is not feeding or vomiting.
• Confirmatory Tests:
  • RBC GALT Enzyme Activity (Gold Standard): Absent or markedly reduced activity. Caution: Avoid testing after blood transfusion (false negative).
  • Metabolites: Elevated Erythrocyte Galactose-1-Phosphate (Gal-1-P) (>10 mg/dL) and urinary galactitol.
• Molecular Genetics: Sequencing of GALT gene to identify specific mutations (e.g., Q188R).
• Supportive Labs:
  • Liver Function Tests: Elevated conjugated bilirubin, transaminases, prolonged PT/aPTT.
  • Renal: Generalized aminoaciduria, albuminuria.

5. MANAGEMENT

• Acute Management:
  • Immediate cessation of all galactose-containing feeds (breast milk, cow’s milk formulas) on clinical suspicion, even before confirmation.
  • Initiate Soy-based formula or elemental formula (galactose-free).
  • Treat complications: Sepsis (antibiotics covering E. coli), Vitamin K for coagulopathy, phototherapy for jaundice.
• Long-Term Dietary Management:
  • Lifelong elimination of dietary galactose and lactose.
  • Contraindicated: Milk, dairy products, whey, casein hydrolysates (if not galactose-free), organ meats.
  • Allowed: Soy protein, fruits, vegetables, unprocessed meats.
  • Supplementation: Calcium and Vitamin D to prevent decreased bone mineral density.

6. COMPLICATIONS AND LONG-TERM OUTCOME

Despite strict dietary compliance, endogenous galactose production leads to chronic complications:

• Ovarian: Premature Ovarian Insufficiency (POI) in >80-90% of females. Primary or secondary amenorrhea, hypergonadotropic hypogonadism.
• Neurologic/Cognitive:
  • Speech defects (childhood apraxia of speech).
  • Learning disabilities, cognitive impairment (IQ often lower than siblings).
  • Tremors, ataxia.
• Skeletal: Decreased bone mineral density (osteopenia/osteoporosis).

7. PROGNOSIS

• Acute survival is excellent with early diagnosis and diet.
• Reversal of acute symptoms (hepatomegaly, cataracts) is typical.
• Poor prognosis for long-term reproductive function (females) and optimal neurocognitive outcomes despite treatment.