Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

ICD-10 Coding

Disorder Category

Abnormal Finding

Tested By

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.

Clinical Characteristics

Incidence

Inheritance

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 NM 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 NM providers [3]).
• 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 NM providers [2]).
• Refer the family to Genetic Testing and Counseling (see NM 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.