Galactosemia

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Classic galactosemia
Duarte galactosemia
Galactokinase (GALK) deficiency disease
Galactose-1-phosphate uridyl-transferase deficiency disease
UDP-galactose-4-epimerase (GALE) deficiency disease

ICD-10 Coding

E74.21, Galactosemia

Disorder Category

Galactosemia

Screening

Abnormal Finding

Deficiency of galactose-1-phosphate uridylyltransferase (GALT)

Tested By

Semiquantitative, fluorometric GALT enzyme assay
Results may be compromised by excess heat exposure to the sample resulting in a false positive or transfusion prior to specimen collection resulting in a false negative.

Description

Galactose is found in many foods and is produced when lactase splits lactose into glucose and galactose. Four enzymes are involved in the metabolism of galactose into uridine diphosphate (UDP)-glucose and, ultimately, to carbon dioxide. Mutations of each of these genes can result in galactosemia, though the conditions themselves are quite different:
  • Galactose-1-phosphate uridyl-transferase (GALT) deficiency results in classic galactosemia, where affected patients have <1% enzyme activity (often due to homozygousity of the Q188R variant). In clinical variant galactosemia, there is 1-10% residual GALT activity. This is more common in patients of African descent and can present similarly to classic galactosemia. In Duarte variant galactosemia (aka biochemical variant galactosemia), patients have residual GALT activity of 10-25%, but this is considered by most not to have clinical significance.
  • Galactokinase 1 (GALK1) deficiency also causes elevated blood galactose levels (directly measured by a minority of programs), but GALT enzyme activity is normal. Therefore, galactokinase deficiency is not typically identified by most screening programs. The presentation is also different, with early-onset cataracts and, in rare cases, pseudotumor cerebri.
  • UDP-galactose-4-epimerase (GALE) deficiency is most commonly a benign biochemical phenotype in which the enzyme is only deficient in red blood cells. However, a very rare and severe form has been reported in which the enzyme is deficient in most tissues, resulting in symptoms similar to classic galactosemia. These individuals have normal GALT enzyme activity and, therefore, will also be missed by most newborn screening programs.
  • Galactose mutarotase (GALM) deficiency is a particularly rare cause of elevated blood galactose levels in which cataracts and elevated liver transaminases have been reported in the few described in the medical literature.
Though a seemingly simple metabolic pathway, the underlying pathophysiology is complex and insufficiently understood. Galactose-1-phosphate appears to be the primary toxic metabolite in classic galactosemia, thereby causing alterations in other pathways. Galactitol also plays a role by which accumulation is responsible for cataracts and pseudotumor cerebri.

Clinical Characteristics

For classic galactosemia, symptoms develop shortly after ingestion of milk or other lactose-containing nutrition. In most cases, this will occur before there are newborn screening results.
With treatment, good health may be expected. However, even with early and adequate treatment, many with classic galactosemia will still experience speech defects, poor intellectual function, neurologic deficits (predominantly extrapyramidal findings with ataxia), and in females, premature ovarian insufficiency. Additionally, fertility in males and females is compromised, though some women with hormonal stimulation may be able to conceive.

Without treatment, there is a significant risk for life-threatening complications.

Initial signs/symptoms of galactosemia may include:
  • Poor feeding
  • Vomiting
  • Diarrhea
  • Jaundice
  • Bleeding diasthesis
  • Lethargy
  • Hepatomegaly
  • Failure to thrive
  • Increased risk of sepsis with gram-negative organisms
If not treated promptly (first 10 days of life), patients may experience:
  • Progressive liver failure
  • Severe brain damage

Incidence

Classic galactosemia occurs in about 1 in 30,000 live births; Duarte variant occurs in about 1 in 16,000. [Therrell: 2015]

Inheritance

Autosomal recessive - Genetic testing is possible for at-risk family members if both disease-causing mutations of an affected family member have been identified.

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for related symptoms.
  • Provide same-day emergency treatment and referral to Biochemical Genetics (Metabolics) (see OH providers [1]) for any symptoms of poor feeding, lethargy, jaundice, bleeding, bulging fontanel, and vomiting. Severity may be screened rapidly with liver function tests (LFTs), prothrombin time with international normalized ratio (PT/INR), and urine reducing substance assay
  • Discontinue all breastmilk and lactose-containing formula feeds. Start soy formula (e.g., Prosobee or Isomil) feeds immediately.
  • Patients with a positive screening test (GALT activity level < 2.0 U/gHb) or who are symptomatic should be on a lactose/galactose-free diet until the GALT enzyme activity level and galactosemia DNA panel results.
  • Patients with a positive screening test with a GALT activity level >2.0 U/gHb do not need preemptive dietary changes.

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see OH providers [1]).
  • Follow-up testing will involve galactose-1-phosphate uridyltransferase activity and GALT gene sequencing. In classic galactosemia, GALT activity is absent or barely detectable and Gal-1-P is markedly elevated. Clinical variant galactosemia tends to have less remarkable elevations of Gal-1-P or, in some cases, may even be in the normal range, but GALT activity will still be significantly reduced to ~1%. With biochemical variant (e.g., Duarte) or carrier status, the GALT activity is moderately reduced to approximately 25% or greater compared to controls and Gal-1-P range from normal to elevated. Normal GALT activity is consistent with a false positive or may be a sign of a different primary or secondary type of hypergalactosemia (e.g., Galactokinase deficiency, GALE deficiency, or GALM deficiency).

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see OH providers [1]).
  • Refer the family to Genetic Testing and Counseling (see OH providers [6]).
  • If the galactose-1-phosphate uridyltransferase and/or the GALT gene sequencing are consistent with classical galactosemia (GG genotype with low activity level), dietary restriction of galactose should continue. Duarte galactosemia patients do not require dietary restrictions. In Duarte galactosemia, the galactose-1-phosphate level may be elevated in the first year of life, but no deficits occur.
  • Educate the family regarding the signs, symptoms, and need for urgent care when the infant becomes ill.
  • Assist in implementing and maintaining rigid dietary exclusion of lactose and galactose.
  • Monitor for developmental delays, speech delay, and, in females, ovarian failure.
  • Assist in the developmental management of the patient, particularly with developmental and educational interventions when needed.

Resources

Information & Support

Related Content
Galactosemia
Assessment and management information for the primary care clinician caring for the child with galactosemia.

Galactosemia
Answers to questions families often have about caring for their child with galactosemia.

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Galactosemia (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

For Parents and Patients

Galactosemia (MedlinePlus)
Information for families includes a description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Galactosemia Foundation
Provides information about galactosemia and facilitates networking among families, clinicians, and researchers.

Tools

ACT Sheet for Classical Galactosemia (ACMG)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

ACT Sheet for Primary or Secondary Hypergalactosemia (ACMG)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Services for Patients & Families in Ohio (OH)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

PubMed search for galactosemia and neonatal screening, last 5 years.

Freer DE, Ficicioglu C, Finegold D.
Newborn screening for galactosemia: a review of 5 years of data and audit of a revised reporting approach.
Clin Chem. 2010;56(3):437-44. PubMed abstract

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2022
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J.
Current status of newborn screening worldwide: 2015.
Semin Perinatol. 2015;39(3):171-87. PubMed abstract