Galactosemia

Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Serious neurologic complications such as speech and motor deficits (e.g., ataxia) may occur. Diagnosis is made through blood testing, which detects an absence or low level of the enzymes necessary to process galactose. Treatment is avoidance of lactose and galactose in the diet.

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Overview

Definition

Galactosemia is an autosomal recessive, inborn error of carbohydrate metabolism resulting in the inability of the body to metabolize galactose into glucose.

Classification

  • Type I (classic):
    • Most common and severe form
    • Deficiency of galactose-1-phosphate uridyltransferase
    • Presents days after birth with lethargy, failure to thrive (FTT), jaundice, and other features of liver injury
  • Type II:
    • Deficiency of galactose kinase
    • Mild variety (limited or no symptoms)
  • Type III:
    • Deficiency in galactose-6-phosphate epimerase
    • Presentation varies from mild to severe disease; may include cataracts, delayed development, and kidney disease

Etiology

Galactosemia is an inherited disorder caused by a genetic mutation, which leads to enzyme deficiency.

  • Type I: GALT gene (chromosome 9p13) encodes for galactose-1-phosphate uridylyltransferase, converting galactose-1-phosphate to UDP-galactose
  • Type II: GALK1 gene (chromosome 17q24) encodes for galactokinase, converting galactose to galactose-1-phosphate
  • Type III: GALE gene (chromosome 1p36–p35) encodes for UDP-galactose-4-epimerase, converting UDP-galactose to UDP-glucose

The condition is autosomal recessive: Each child has a 25% chance of inheriting the disease if both parents are affected.

Epidemiology

  • Type I galactosemia prevalence: 1 per 30,000–60,000 live births
  • Type II and type III galactosemia prevalence: fewer than 1 per 100,000 live births
  • Prevalence varies: 
    • Geographically:
      • 1 per 30,000 in Europe
      • 1 per 1,000,000 in Japan
    • By ethnicity:
      • Most prevalent in the Irish Traveller population (prevalence: 1 per 480)
Galactose (Haworth projection)

A structure of the monosaccharide galactose (Haworth projection):
Patients with galactosemia are unable to degrade galactose. Glucose and galactose have the same chemical formula but differ in the location of the 1 hydroxyl group.

Image: “Beta-D-Galactopyranose” by NEUROtiker. License: Public Domain

Clinical Presentation

Symptoms may appear days to weeks after birth.

  • Constitutional:
    • Declining weight or failure to gain weight
    • FTT
    • Lethargy
  • GI:
    • Anorexia
    • Nausea and vomiting
    • Diarrhea
    • Hepatomegaly and splenomegaly
    • Ascites
  • Renal: kidney failure
  • Neurologic:
    • Convulsions
    • Irritability
    • Developmental delay
    • Hypotonia
    • Sensorineural hearing loss
  • Ocular: cataracts
Baby with galactosemia

A baby with galactosemia:
As noted in the image, galactosemia has numerous clinical signs and symptoms. Neurologic, renal, hepatic, and ocular side effects may occur. The symptoms appear early and are often apparent within the 1st month of life.

Image by Lecturio.

Diagnosis

Screening

  • The newborn screening test is common in many regions.
  • Amniocentesis or chorionic villus sampling is advised for families with a history of galactosemia.

Galactosemia test

The test should be performed on all infants who exhibit symptoms.

  • Blood or urine test: checks for the enzymes necessary to process galactose
  • Galactose-1-phosphate elevated in RBCs
  • Low GALT enzyme activity = positive test

Management and Complications

Management

  • Lifelong avoidance of lactose and galactose:
    • Soy formula
    • Lactose-free formula
    • Avoid milk products
  • Calcium supplements
  • Speech therapy for patients with language deficits
  • Hormonal therapy for patients with delayed puberty
  • Consider genetic counseling

Complications

  • Premature ovarian failure
  • Permanent neurologic deficits (e.g., speech deficits)
  • Decreased bone density with increased risk of fracture

Differential Diagnosis

  • Lactose intolerance: a condition caused by an inability to process lactose. Symptoms occur after lactose ingestion. Patients present with GI complaints such as abdominal pain, diarrhea, flatus, and nausea. Diagnosis is based upon clinical history. Treatment involves removing lactose from the diet. Lactase supplementation can be offered to patients who continue to consume lactose products. Unlike lactose intolerance, no supplement is available for patients with galactosemia. Galactosemia may result in severe neurologic and renal impairment, however, the clinical presentation is milder in lactose intolerance.
  • Biliary atresia: a condition caused by fibrosis and obliteration of the bile ducts. Biliary atresia is a rare condition and slightly more common in women. Within the 1st 2 months of life, children present with progressive jaundice, white stools, cola-colored urine, and hepatosplenomegaly. Liver biopsy is required for definitive diagnosis and the definitive treatment modality is surgery. Unlike galactosemia, presentation with neurologic deficits is uncommon in children. 
  • Hemochromatosis: an autosomal-recessive disorder causing severe iron overload. The condition is caused by gene mutations, which lead to low production of hepcidin and resultant increased iron absorption. The classic triad of symptoms includes cirrhosis, diabetes, and increased skin pigmentation. Patients are diagnosed through a combination of iron studies, genetic testing (showing known genetic mutations), and biopsy (when the initial approach is nondiagnostic). Patients require phlebotomy, iron chelation, and dietary restriction for management. Unlike galactosemia, hemochromatosis usually presents later in life (5th or 6th decade). Juvenile hemochromatosis is uncommon but can present in the 2nd decade of life.

References

  1. Sutton, V.R. (2021). Galactosemia: Clinical features and diagnosis. UpToDate. Retrieved April 15, 2021, from https://www.uptodate.com/contents/galactosemia-clinical-features-and-diagnosis
  2. Powell, K.K., et al. (2009). Long-term speech and language developmental issues among children with Duarte Galactosemia. Genetics in Medicine. 11(12), 874–9. https://pubmed.ncbi.nlm.nih.gov/19904210
  3. Coelho, A.I., Rubio-Gozalbo, M.E., Vicente, J.B., Rivera, I. (2017). Sweet and sour: an update on classic galactosemia. Journal of Inherited Metabolic Disease. 40(3), 325–42. https://pubmed.ncbi.nlm.nih.gov/28281081/

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