What are the clinical features, diagnosis, and management of galactosemia?

Galactosemia: Clinical Features, Diagnosis, and Management

Clinical Features

Classic galactosemia (Type I) is a life-threatening disorder that, if untreated, causes failure to thrive, liver failure, sepsis, and death in the neonatal period. 1, 2

Acute Neonatal Presentation (Classic Galactosemia)

• Failure to thrive with poor feeding and vomiting within days of milk ingestion 1
• Hepatic dysfunction progressing to liver failure with jaundice and coagulopathy 1
• Sepsis susceptibility, particularly E. coli sepsis in the first week of life 1
• Lethargy and hypotonia as metabolic decompensation progresses 3

Long-Term Complications (Despite Dietary Treatment)

• Cognitive impairment and developmental delays affecting most patients 4
• Speech defects including verbal dyspraxia 5, 4
• Ovarian failure in females, leading to primary or premature ovarian insufficiency 5, 4
• Neurologic syndromes including ataxia and tremor 5

Type-Specific Features

• Galactokinase deficiency (Type II): Primarily causes infantile cataracts without systemic toxicity 1
• UDP-galactose-4'-epimerase deficiency (Type III): Variable presentation from benign to severe systemic disease 1
• Duarte variant galactosemia: Clinically benign with ~25% residual GALT activity; does not cause acute life-threatening complications 6

Diagnosis

Diagnosis is established by demonstrating severely reduced or absent enzyme activity in red blood cells, confirmed by DNA analysis of the affected gene. 1

Newborn Screening

• Universal screening is implemented in all U.S. states, identifying most cases before symptom onset 1, 2
• Screening methods include GALT enzyme activity measurement in dried blood spots and/or elevated total galactose 1
• Critical limitation: Screening may miss GALT deficiency in infants already on galactose-restricted formula 1

Confirmatory Testing Algorithm

1. RBC enzyme assay demonstrating severely reduced or absent activity:

   • GALT activity for classic galactosemia (Type I) 1
   • GALK activity for galactokinase deficiency (Type II) 1
   • GALE activity for epimerase deficiency (Type III) 1

2. Molecular genetic testing of GALT, GALK1, or GALE genes to identify pathogenic variants 1

3. For suspected Duarte variant: Test for the 4-bp GALT promoter deletion to distinguish D2 (pathogenic, ~50% activity reduction) from D1 (benign, normal activity) 1, 6

4. Metabolite measurement: Elevated galactose-1-phosphate (Gal-1-P) and galactose in blood/urine supports diagnosis 1

Common Pitfalls

• Do not rely solely on newborn screening results if clinical suspicion exists; infants with suggestive symptoms require immediate confirmatory testing regardless of screening results 3
• Blood transfusions can cause false-negative enzyme results by introducing donor RBCs with normal enzyme activity 1

Management

Immediate and lifelong dietary restriction of galactose is the standard of care and prevents acute mortality from liver failure and sepsis. 2

Acute Management (Neonatal Period)

• Eliminate all galactose sources immediately upon suspicion, before confirmatory results 2, 7
• Discontinue breastfeeding and lactose-containing formula 2, 4
• Initiate soy-based or elemental formula as galactose-free alternatives 4
• Supportive care for liver dysfunction, coagulopathy, and sepsis as needed 1

Long-Term Dietary Management

• Strict galactose restriction with goal of reducing intake to <10 mg/day 2
• Eliminate all foods containing:
  • Lactose (milk, dairy products) 2
  • Galactose-containing foods (certain legumes, organ meats) 7
  • Hidden sources in processed foods and medications 7

Monitoring Protocol

• RBC Gal-1-P levels every 3-6 months to assess dietary compliance, targeting 2-4 mg/dL 2
• Developmental assessments for early detection of cognitive and speech delays 4
• Ovarian function monitoring in females starting in adolescence 4
• Ophthalmologic examination particularly for galactokinase deficiency 1

Type-Specific Management Differences

• Duarte variant galactosemia does not require dietary galactose restriction, as it does not cause acute complications or long-term developmental issues 6
• Galactokinase deficiency requires galactose restriction primarily to prevent cataract formation 4
• Severe GALE deficiency requires galactose restriction similar to classic galactosemia 4

Critical Limitation of Current Treatment

Dietary restriction prevents acute mortality but fails to prevent long-term complications including cognitive impairment, speech defects, and ovarian failure in most patients with classic galactosemia 2, 5, 4. The mechanisms underlying these complications—whether from continuous low-level intoxication, critical metabolite depletion, or in utero damage—remain incompletely understood 5. Novel therapies including enzyme replacement, gene therapy, and bone marrow transplantation are under investigation but remain experimental 8.