Classic Galactosemia
Overview
Plain-Language Overview
Classic Galactosemia 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 an important enzyme needed to break down galactose properly. As a result, galactose builds up in the body and can cause serious health problems, especially in newborns. Symptoms often appear soon after birth and can include poor feeding, vomiting, jaundice, and liver problems. If untreated, it can lead to more severe complications such as intellectual disability, cataracts, and infections.
Clinical Definition
Classic Galactosemia is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). This enzyme deficiency impairs the conversion of galactose-1-phosphate to glucose-1-phosphate, leading to accumulation of toxic metabolites such as galactose-1-phosphate, galactitol, and galactonate. The disorder typically presents in the neonatal period with symptoms including feeding difficulties, failure to thrive, jaundice, hepatomegaly, and E. coli sepsis. Long-term complications include intellectual disability, speech defects, ovarian failure in females, and cataracts. Diagnosis is confirmed by measuring reduced GALT enzyme activity in red blood cells and identifying pathogenic mutations in the GALT gene. Newborn screening programs often detect elevated galactose or galactose-1-phosphate levels. Management requires lifelong dietary restriction of galactose and lactose to prevent acute and chronic complications.
Inciting Event
- Introduction of galactose-containing milk or formula shortly after birth initiates symptoms.
Latency Period
- Symptoms typically develop within the first few days to weeks of life after galactose exposure.
Diagnostic Delay
- Nonspecific early symptoms such as jaundice and feeding intolerance may be mistaken for other neonatal illnesses.
- Lack of routine newborn screening in some regions can delay diagnosis.
- Low clinical suspicion due to rarity of the disease may contribute to delayed recognition.
Clinical Presentation
Signs & Symptoms
- Jaundice and hepatomegaly in the neonatal period.
- Vomiting and poor feeding shortly after milk ingestion.
- Failure to thrive and lethargy.
- Development of cataracts within the first few weeks.
- Increased risk of sepsis, especially with Escherichia coli.
History of Present Illness
- Poor feeding and vomiting shortly after starting milk-based feeds.
- Development of jaundice, hepatomegaly, and lethargy within the first weeks of life.
- Onset of cataracts and failure to thrive if untreated.
Past Medical History
- No significant past medical history prior to birth as symptoms manifest postnatally.
- History of neonatal jaundice or sepsis-like illness may be present.
Family History
- Family history of consanguinity increases risk of autosomal recessive disorders like galactosemia.
- Siblings with similar neonatal illness or diagnosed galactosemia.
- Known carriers of GALT mutations in the family.
Physical Exam Findings
- Hepatomegaly due to liver dysfunction is commonly observed.
- Jaundice indicating hyperbilirubinemia may be present.
- Cataracts can be detected as lens opacities on eye examination.
- Poor feeding and failure to thrive are evident as growth retardation.
- Neurological examination may reveal hypotonia and developmental delay.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of classic Galactosemia is established by demonstrating markedly reduced or absent GALT enzyme activity in erythrocytes, elevated levels of galactose and galactose-1-phosphate in blood, and identification of pathogenic mutations in the GALT gene. Newborn screening typically reveals increased galactose or galactose-1-phosphate concentrations. Clinical presentation with neonatal jaundice, hepatomegaly, and sepsis supports the diagnosis. Confirmatory genetic testing and enzyme assays are essential to differentiate classic galactosemia from other galactose metabolism disorders.
Pathophysiology
Key Mechanisms
- Classic Galactosemia results from a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT), leading to accumulation of toxic metabolites.
- The buildup of galactose-1-phosphate causes cellular damage, particularly in the liver, brain, and kidneys.
- Impaired metabolism leads to hypoglycemia, hepatomegaly, and cataracts due to osmotic and toxic effects.
| Involvement | Details |
|---|---|
| Organs | Liver is a major organ affected, showing hepatomegaly, jaundice, and potential failure. |
| Eye involvement leads to cataract formation impairing vision. | |
| Brain involvement causes intellectual disability and motor dysfunction. | |
| Tissues | Liver tissue shows hepatomegaly and fibrosis from toxic metabolite accumulation. |
| Lens tissue develops cataracts due to galactitol-induced osmotic stress. | |
| Brain tissue may exhibit developmental abnormalities and white matter changes. | |
| Cells | Hepatocytes are primarily affected due to toxic metabolite accumulation causing liver dysfunction. |
| Lens epithelial cells are involved in cataract formation from galactitol accumulation. | |
| Neurons may be damaged leading to developmental delay and neurological symptoms. | |
| Chemical Mediators | Galactose-1-phosphate accumulates due to GALT deficiency causing cellular toxicity. |
| Galactitol accumulates in the lens leading to osmotic damage and cataracts. | |
| UDP-galactose deficiency disrupts glycoprotein and glycolipid synthesis affecting multiple tissues. |
Treatment
Pharmacological Treatments
none
- Mechanism: none
- Side effects: none
Non-pharmacological Treatments
- Strict dietary restriction of galactose and lactose to prevent toxic metabolite accumulation.
- Early initiation of a galactose-free formula in affected neonates to avoid acute symptoms.
- Regular monitoring of nutritional status and developmental milestones to manage complications.
Prevention
Pharmacological Prevention
- none
Non-pharmacological Prevention
- Early initiation of a galactose-restricted diet to prevent toxic metabolite accumulation.
- Avoidance of lactose-containing formulas and dairy products.
- Newborn screening programs to enable prompt diagnosis and dietary management.
Outcome & Complications
Complications
- Liver failure due to progressive hepatic damage.
- Cataract formation leading to visual impairment.
- Intellectual disability from chronic galactose toxicity.
- Increased susceptibility to sepsis.
- Premature ovarian insufficiency in females.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
|
Differential Diagnoses
Classic Galactosemia versus Galactokinase Deficiency
| Classic Galactosemia | Galactokinase Deficiency |
|---|---|
| Multisystem involvement including liver failure, sepsis, and coagulopathy | Isolated cataracts without liver dysfunction or severe systemic illness |
| Elevated galactose-1-phosphate due to GALT deficiency | Normal liver function tests and no coagulopathy |
| Neurologic symptoms such as developmental delay and hypotonia | Elevated galactitol but normal galactose-1-phosphate levels |
Classic Galactosemia versus Hereditary Fructose Intolerance
| Classic Galactosemia | Hereditary Fructose Intolerance |
|---|---|
| Symptoms triggered by galactose ingestion such as feeding intolerance and vomiting | Hypoglycemia after ingestion of fructose, sucrose, or sorbitol |
| Elevated galactose-1-phosphate in erythrocytes | Elevated serum fructose-1-phosphate levels |
| Early onset cataracts due to galactitol accumulation | Absence of cataracts in early infancy |
Classic Galactosemia versus Neonatal Sepsis
| Classic Galactosemia | Neonatal Sepsis |
|---|---|
| Elevated galactose-1-phosphate and reducing substances in urine | Positive blood cultures and systemic signs of infection |
| Symptoms triggered by milk feeding containing galactose | No specific metabolic abnormalities related to galactose metabolism |
| Liver dysfunction and cataracts not typical of isolated infection | Improvement with antibiotics without dietary changes |