Galactosemia

Baby Detect > Metabology > Galactosemia

GALT, GALK1, GALE and GALM genes

Also known as: Galactose-1-Phosphate Uridylyltranserase Deficiency, GALT Deficiency, GALK Deficiency, GALE Deficiency and GALM Deficiency.

OMIM#230400 https://omim.org/entry/230400

OMIM#230200 https://omim.org/entry/230200

OMIM#230350 https://omim.org/entry/230350

OMIM#2618881 https://omim.org/entry/618881

1. The Disease:

The term “galactosemia” refers to disorders of galactose metabolism including (a) classic galactosemia, (b) clinical variant galactosemia and (c) biochemical variant galactosemia (Duarte variant galactosemia). All three forms are inherited in an autosomal recessive pattern – a mutation must be present in the copies inherited from both the mother and the father – for the disease to manifest itself. When left untreated, some forms of galactosemia lead to liver failure, which can result in death.

A. GALT Gene:

a. Classic galactosemia: Resulting from two pathogenic variants in the GALT gene. This form typically results in life-threatening complications for untreated infants including feeding problems, failure to thrive, liver failure and E. coli sepsis. If a lactose-restricted diet is initiated during the first days of life, the neonatal symptoms usually disappear and the complications of liver failure, sepsis, and neonatal death are prevented. However, despite early treatment, children remain at increased risk for developmental and speech delays, as well as cataracts. Nearly all females with classic galactosemia present premature ovarian insufficiency (POI).

b. Biochemical variant galactosemia (Duarte galactosemia): Resulting from a combination of a pathogenic variant in the heterozygous state and a Duarte GALT allelic variant (D2) in either the heterozygous or homozygous state. Infants with this form on breast milk or lactose formula are generally, but not always, asymptomatic. Abnormalities such as jaundice, may be seen in some infants, but resolve quickly when switched to a galactose-free formula. Many healthcare professionals believe that Duarte galactosemia does not result in clinical disease, regardless of dietary intervention; however, this can still be considered polemic. POI has not been reported for females with Duarte galactosemia.

B. GALK1, GALE and GALM Genes:

a. Clinical variant galactosemia: Resulting from two pathogenic mutations in one of these 3 genes. The GALE form can also result in life-threatening complications for untreated infants including feeding problems, failure to thrive and hepatocellular damage (i.e., cirrhosis and bleeding). GALK1 and GALM forms seem to be restricted to the eyes, manifesting as cataract. No cognitive impairment in the GALK1 form, more date is needed for GALM forms. These individuals may be missed on traditional newborn screening (NBS) as the level of galactose may not be as markedly increased as that seen in the classic form. If a lactose-restricted diet is initiated during the first days of life, the severe acute neonatal complications are usually prevented. Females with adequate early treatment do not appear to be at risk for long-term complications including POI.

2. The Symptoms:

Newborns with any form of galactosemia are asymptomatic at birth. The onset of symptoms can appear as early as the first week of life, especially in the classic and clinical variant forms. The lack of early signs or symptoms does not exclude the diagnosis.

A. The most common early symptoms include somnolence, hyporexia, hypoactivity and irritability (“hidden signs” of hypoglycemia).

B. Later symptoms include prolonged jaundice, cholestasis and bleeding events. If left untreated, progression to liver failure and seizures (recurrent hypoglycemia) may occur.

C. Less frequent findings include feeding difficulties, diarrhea, hepatomegaly, E.coli infections and sepsis. Clinical variant forms can be asymptomatic and have cataracts as first sign later in life (first decade).

3. Actions to take in case of early diagnosis:

  1. Infants with a positive genetic test should IMMEDIATELY collect biochemical tests (item B) and then start a lactose-free formula (e.g.,a soy formula). Early treatment, through initiation of a galactose-free diet, is essential in preventing complications.
  2. Infants with a positive genetic test should have confirmatory biochemical testing in serum or plasma.
    1. For patients with classic galactosemia, erythrocyte galactose-1-phosphate concentration is > 10 mg/dL, and erythrocyte GALT enzyme activity is ≤10% of control activity.
    2. For patients with clinical variant galactosemia, erythrocyte galactose-1-phosphate concentration is > 10 mg/dL and erythrocyte GALK1, GALE or GALM enzyme activity is ≤10% of control activity.
    3. For Duarte galactosemia, no biochemical confirmation is needed.
    4. If erythrocyte enzyme techniques are not available, biochemical newborn screening for galactosemia (filter paper techniques) can help.
  3. For patients with classic and clinical variant galactosemia, the following treatments are recommended:
    1. Lifelong lactose and galactose-free diet:
      • Avoidance of milk and dairy products, casein or whey-containing foods and certain medications containing lactose and galactose.
      • Lactose-free infant formula with strict avoidance of breast milk.
      • Management becomes less important after infancy/early childhood.
      • Of note, it appears that only patients with < 15% of GALT/GALK1/GALE/GALM activity will be symptomatic at any given time without treatment.
    2. Calcium supplementation to prevent decreased bone mineralization, sometimes combined with vitamin D and vitamin K supplementation.
    3. Monitoring health:
      • Developmental assessment at one year of age by a psychologist or pediatrician is recommended.
      • Cataract surgery may be necessary in the first year of life.
      • Childhood apraxia and dysarthria require expert speech therapy.

4. For patients with Duarte variant galactosemia, the following treatments are recommended:

  • Immediate suspension of galactose-free diet with clinical follow-up for 1 year, or continuation of diet until 1 year of age with subsequent suspension.
  • Discharge of child at 1-2 years of age is recommended.
  • As available data about the neurodevelopmental outcomes of children with Duarte galactosemia are conflicting, further research is necessary to determine the long-term outcome and whether the dietary intake of galactose in the first year of life is influential.

4. For more information

Orphanet: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11265&Disease_Disease_Search_diseaseGroup=galactosemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Classic-galactosemia&title=Classic%20galactosemia&search=Disease_Search_Simple

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