Galactosaemia

Synonyms: galactose-1-phosphate uridyltransferase deficiency, GALT deficiency, galactose diabetes

What is galactosaemia?

Classical galactosaemia is a rare inherited disorder of galactose metabolism. It is caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT) due to a mutation of the GALT gene on chromosome 9 at 9p13.¹This results in the accumulation of galactose metabolites. 80% of those affected present in the newborn period with life-threatening illness.²

Pathophysiology^{3 4}

There are over 300 genetic mutations responsible for galactosemia. Each affects one of four enzymes involved in galactose metabolism. Galactosemia can therefore be categorised into four forms (Type 1, 2, 3 and 4) according to which enzyme they affect.

GALT deficiency (Type 1) is the most common abnormality. The enzyme converts galactose-1-phosphate and uridine diphosphate (UDP) glucose to UDP galactose and glucose-1-phosphate.

It is thought that the accumulation of galactose metabolites causes the symptoms of this disease. However the exact mechanisms are unclear as symptoms develop in later life despite adherence to a galactose-restricted diet. Endogenous production of galactose as well as other reasons have been postulated as the cause.¹⁵

The disease varies in severity, with a Duarte variant widely considered comparatively benign. ⁶There is debate regarding treatment for those with Duarte variant as some literature states they do not develop clinical manifestations whilst others report developmental delay and physical complications compared to unaffected siblings.¹

How common is galactosaemia? (Epidemiology)

Galactosaemia (galactosemia in USA literature) is an autosomal recessive inherited condition.¹

Classical galactosaemia has a prevalence in western countries of between 1:16,000 and 1:60,000 live births.⁷

Symptoms of galactosaemia (presentation)^{1 6}

Almost 80% of those affected present in the neonatal period with often life-threatening illness. mechanisms for this are unknown. Neonatal symptoms include:

• Failure to thrive with feeding difficulty, vomiting and failure to gain weight.

• Lethargy and hypotonia.

• Jaundice and hepatomegaly with hepatocellular damage.

• Coagulation defects.

• Haemolytic anaemia.

• Metabolic acidosis.

• Sepsis (often with Escherichia coli).

• Cataracts.

• Renal tubule disease.

• Encephalopathy.

People with variants other than classical may present later in life. Symptoms which present later include:

• Developmental delay. This can affect speech, language, cognition and motor control.

• Adults may have short stature.

• Hypergonadotrophic hypogonadism is common and in women, premature ovarian failure. Those who conceive often have variant disease.

• Low bone-mineral density due to dietary deficiency whilst adhering to a galactose-restricted diet.

• Neurological complications. This may present with tremor, ataxia, dystonia, coordination or motor control difficulty.

Differential diagnosis

• Fructose-1-phosphate aldolase deficiency (fructose intolerance).

• Galactokinase deficiency.

• Hereditary haemochromatosis.

• Alpha-1-antitrypsin deficiency.

• Sepsis.

• Tyrosinaemia.

Diagnosing galactosaemia (investigations)^{8 514}

• The Galactosaemia Network (GalNet) recommends GALT enzyme activity in red blood cells and, or, GALT gene analysis.

• GALT gene analysis is only acceptable if it identifies a disease causing variant, as reported in online genetic databases.

• Where they are undertaken, newborn screening tests for galactosemia use total blood galactose and, or the GALT activity assay. These tests are prone to false positive and false negative results. Bacterial inhibition assay and urinary reducing substances have also shown false negatives for some variants.

Management of galactosaemia^{6 9}

In neonates presenting with acute life-threatening illness, treatment will be tailored to their presentation. Management of acute illness is not discussed here, other than immediately stopping galactose-containing feeds.

Once the diagnosis is suspected, feeds containing galactose must be stopped immediately and replaced with a soya-based formula. The majority of babies will recover; however a number will not survive.¹⁰

• GalNet recommends treating patients with red blood cell GALT enzyme activity less than 10% and, or, a pathological variant of both alleles of the GALT gene, including p.S135L with a galactose-restricted diet. They do not recommend dietary restriction for Duarte variant, though some centres do recommend this for the first year of life. Type 1 classical galactosemia is managed by life-long dietary galactose restriction. Other types are managed for varying periods of time.

• The current advice for a galactose-restricted diet eliminates sources of lactose and galactose from dairy products, but allows galactose from non-milk sources that have trace galactose content. Trace amounts of galactose are present in fruit and vegetables, and specific mature cheeses.

• Dietician input is advised. This can guide the galactose-restricted diet. Supplements such as calcium and vitamin D, are recommended where necessary to avoid deficiency.

• Developmental delay will benefit from special attention to education and schooling. The help of speech and language therapy is usually required. GalNet makes recommendations about neurological assessment, developmental assessment, ophthalmic assessment and follow up intervals.

• Hypergonadotrophic hypogonadism in affected females is common. The onset of puberty or menarche may be delayed. Concern should prompt screening. Medication to induce puberty is likely to require referral to an endocrinologist. In addition, primary ovarian insufficiency (premature ovarian failure) is experienced by 80% of females with classical type 1 galactosemia. Considerations should include counselling for subfertility and the consideration of HRT at the onset of secondary amenorrhoea.¹¹⁷

• If a woman with galactosaemia does become pregnant, the high level of galactose does not seem to have an adverse effect on the fetus. This is in contrast to the situation with phenylketonuria where the diet must be strictly observed in pregnancy.

Prognosis

Most affected patients experience neonatal manifestations (80%). Despite following an appropriate diet, 85% develop cognitive impairment and 26% develop low bone mineral density. 80% of affected females develop primary ovarian insufficiency. Detection by newborn screening and commencement of diet in the first week of life are associated with a more favourable outcome compared to later diagnosis.⁷

Early diagnosis seems important in the prevention of severe cataracts.¹²

Screening for galactosaemia

Prenatal screening is possible. Screening for galactosaemia in neonates occurs in some countries but is currently not recommended in the UK.¹³⁴