Galactosaemia

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

Classical galactosaemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, with a clinical picture that can be resolved by a galactose-restricted diet¹ .

Although it is a rare inherited disease, it is among the most common carbohydrate metabolism disorders. It can be a life-threatening illness during the newborn period² . The cardinal features are hepatomegaly, cataracts and mental handicap. It is caused by mutation in the GALT gene on chromosome 9 at 9p13³ .

Pathophysiology²

The disease can be variable in terms of severity with a Duarte variant that is comparatively benign⁴ . Those who are homozygous for the Duarte variant still have enzyme levels that are about 50% of normal. There are many variants of the disease but most affect one of three enzymes.

• GALT deficiency is the most common abnormality. The enzyme converts galactose-1-phosphate and uridine diphosphate (UDP) glucose to UDP galactose and glucose-1-phosphate. Patients with GALT deficiency have abnormal galactose tolerance.

• Galactokinase converts galactose to galactose-1-phosphate and deficiency is rather more uncommon.

• UDP galactose-4-epimerase epimerises UDP galactose to UDP glucose and deficiency is also less common.

Hypergalactosaemia is associated with these enzyme deficiencies and it is the toxic effects of this that produce the characteristic features of the disease.

Epidemiology

Galactosaemia (galactosemia in USA literature) is an autosomal recessive inherited condition³ .

Classical galactosaemia has a prevalence in western countries of between 1:16,000 and 1:60,000 live births⁵ .

Presentation^{3 4}

This may be rather variable and not all features listed below will be found. It almost invariably presents in the neonatal period. Variant disease can present later in life.

• There is often feeding difficulty, with vomiting and failure to gain weight, with poor growth in the first few weeks of life.

• Lethargy and hypotonia occur.

• Jaundice and hepatomegaly develop.

• There are often associated coagulation defects.

• Sepsis (often with Escherichia coli) can be fatal.

• Cataracts may be apparent even in the early days of life.

• Ascites may even be apparent in early life.

• The fontanelle is full.

• Developmental delay may affect speech, language and general learning.

• Adults may have short stature, ataxia and/or tremor.

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

Galactosaemia should be considered when a term infant gets an E. coli sepsis and when a neonate develops cataracts. It should also be considered with neonatal jaundice and haemorrhage.

Differential diagnosis

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

• Galactokinase deficiency.

• Hereditary haemochromatosis.
  

• Alpha-1-antitrypsin deficiency.

• Sepsis.

• Tyrosinaemia.

Investigations⁶

• If the child is having milk, and hence lactose that will be split to glucose and galactose, there will be galactose in the urine. This is a reducing sugar and so gives a positive test with Fehling's or Benedict's reagent but a negative test with glucose oxidase test strips. Galactose may appear in the urine of any patient with liver disease and in galactosaemia it can swiftly disappear.

• LFTs should be performed. Hyperbilirubinaemia is often unconjugated at first but becomes conjugated later. Fatty infiltration and inflammatory changes may occur in the liver early on. Portal hypertension and pseudoacinar formation develop later. Cirrhosis in the final stage is indistinguishable from other causes.

• There is albuminuria and, later, a generalised aminoaciduria. Eliminating lactose from the diet removes the albuminuria. Amino acids are raised in the blood and raised phenylalanine may give a false positive test for phenylketonuria.

• There is a metabolic acidosis.

• Haemolytic anaemia may occur.

• If there is doubt about cataracts, slit-lamp examination by an ophthalmologist may be required. It should be performed as a routine screening test every six months until the age of 3 years and annually thereafter.

• Beutler's test involves a fluorescent spot test for GALT activity. It is now widely used for the diagnosis of galactosaemia but will give false positives with glucose-6-phosphate dehydrogenase deficiency.

• A quantitative erythrocyte analysis for GALT is required.

• A GALT isoelectric-focusing electrophoresis test helps distinguish variant forms such as the Duarte defect. GALT genotyping may provide a specific molecular diagnosis if available. About 60% of British patients with galactosaemia are homozygous for the Q188R mutation.

Management^{4 7}

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 survive⁸ .

• If an infant is to be fed without milk, the advice of a dietician should be sought. A certain amount of galactose is present even in fruit and vegetables and so total elimination is very difficult. As the patient matures, the ability to tolerate lactose improves but milk should be restricted throughout life.

• Milk substitutes can be prescribed on an FP10 prescription and endorsed Advisory Committee on Borderline Substances (ACBS).

• Antibiotics, intravenous fluids and vitamin K are often required.

• Referral should be made to a clinical geneticist to confirm the diagnosis and give counselling to the parents.

• Developmental delay will benefit from special attention to education and schooling. The help of speech and language therapy may be required as the problems of speech appear to be greater than would be expected merely from the reduced intelligence.

• The aetiology of short stature is not understood and there is no known treatment.

• Primary ovarian insufficiency is the most common long-term complication experienced by females with classical galactosaemia, presenting with hypergonadotrophic hypo-oestrogenic infertility affecting at least 80% of females despite newborn screening and lifelong galactose dietary restriction⁹ .

• The help of an endocrinologist may be required with hypergonadotrophic hypogonadism. With premature ovarian failure the use of HRT to prevent osteoporosis should be considered and androgen deficiency may well merit attention in men; however, the risk of hypogonadism in men with the condition is much less than in affected women.

• Puberty in girls may be induced by supervised gradual introduction of ethinylestradiol before moving to a low-dose combined oral contraceptive.

• Sepsis and liver disease are treated as in any other situation. It is important to make the diagnosis early to implement lactose avoidance to reduce long-term problems before such conditions as cirrhosis and cataracts develop; however, most patients will still develop at least one major complication.

• 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 brain impairments, 80% primary ovarian insufficiency and 26% diminished bone mineral density. Detection by newborn screening and commencement of diet in the first week of life are associated with a more favourable outcome⁵ .

Early diagnosis seems important in the prevention of severe cataracts¹⁰ .

Screening

Prenatal screening is possible. Screening for galactosaemia in neonates is currently not recommended in the UK¹¹ .