Galactosaemia

Synonyms: Galactose-1-Phosphate Uridyltransferase Deficiency, GALT deficiency, GALT, galactose diabetes

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 period. The cardinal features are hepatomegaly, cataracts and mental handicap. It is caused by mutation in the galactose-1-phosphate uridyltransferase (GALT) gene on chromosome 9 at 9p13.

The disease can be variable in terms of severity with a Duarte variant that is comparatively benign. Those who are homozygous for the Duarte variant still have enzyme levels that are about 50% of normal.¹ There are many variants of the disease but most affect one of three enzymes.

• GALT deficiency is the commonest abnormality. The enzyme converts galactose-1-phosphate and 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.
• Uridine diphosphate (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 produces the characteristic features of the disease.

Galactosaemia (galactosemia in United States literature) is an autosomal recessive inherited condition.² The incidence of classical galactosaemia in white Americans is around 1 in 47,000.³ The incidence seems to be rather lower in people of African and Asian descent. In Ireland the incidence has been estimated as 1 in 30,000 but as high as 1 in 480 in the travellers community.⁴ In the UK the incidence is 1 in 70,000. There is an equal sex incidence.

This may be rather variable and not all features listed below will be found. It almost invariably presents in the neonatal period.

• 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 develops.
• There are often associated coagulation defects.
• Sepsis (often with E. 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.
• In adults there is often short stature and there may be ataxia and 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.

• Fructose-1-phosphate aldolase deficiency (fructose intolerance)
• Galactokinase deficiency
• Hereditary haemochromatosis
• Alpha-1-antitrypsin deficiency
• Sepsis
• Tyrosinaemia

• 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 6 months until the age of 3 and annually thereafter.
• The Beutler test involves a fluorescent spot test for galactose-1-phosphate uridyl transferase 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.

• As soon as the diagnosis is made, milk should be discontinued to remove the lactose load. This will have some immediate benefit but will not halt all aspects of the disease. 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 and endorsed 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.⁵
• The aetiology of short stature is not understood and there is no known treatment.
• The help of an endocrinologist may be required with hypergonadotrophic hypogonadism. Fertility is unlikely. With premature ovarian failure the use of HRT to prevent osteoporosis should be considered and androgen deficiency may well merit attention in men but the risk of hypogonadism in men with the condition is much less than in affected women.
• There are no drugs that are known to benefit this condition.
• Puberty in girls may be induced by supervised gradual introduction of ethinyl oestradiol before moving to a low dose combined oral contraceptive such as Loestrin.
• Sepsis and liver disease is 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 but 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.

Unrecognised and untreated, galactosaemia can be a rapidly fatal disorder. There is a risk of neonatal death from E. coli sepsis but the life expectancy in those who reach adult life has not been investigated. Fatty infiltration and inflammatory changes can progress to cirrhosis. With long term control even cataracts may reverse. There is much that remains unknown about how this metabolic abnormality affects those who suffer from it and why dietary restriction is only partially effective⁶ and outcome does not appear to be related to stage of diagnosis and compliance with diet.⁷ It is possible that endogenous production of galactose is a problem.⁸

A paper from Germany, published in 1993, examined the outcome for 134 patients with galactosaemia born between 1955 and 1989.⁹

• Of the 134, 20 had already died.
• Clinical, psychometric and laboratory testing was performed on 83 with just medical history in 31. Of the 83 tested patients, there were 78 homozygotes and 5 compound heterozygotes.
• In 48 out of 78 classical galactosaemia patients, galactose avoidance had been started before the 15th day, in 19 between days 15 and 56 and in 11 patients after the 56th day.
• Puberty was delayed in just 1 of 18 males but 6 of 11 females.
• There were 6 patients with ataxia, 11 with intention tremor and 10 with microcephaly.
• Speech abnormalities were found in 43 of 66 patients over 3 years old and disturbance of visual perception with or without arithmetical deficits in 29.
• Intelligence declined with age. A developmental quotient (DQ) or intelligence quotient (IQ) less than 85 was found in 4 out of 34 patients less than 6 years of age (12%), in 10 out of 18 between 7 and 12 years (56%) and in 20 out of 24 older than 12 years (83%).
• Metabolite patterns such as RBC galactose-1-phosphate and UDP-galactose, plasma and urinary galactitol, did not correlate with DQ or IQ. Dietary compliance was good in almost all patients.
• The 5 compound heterozygotes had normal mental and growth development and all laboratory parameters were in the normal range.

Prenatal screening is possible.¹⁰ Many, but not all states in the USA have a neonatal screening programme for galactosaemia as do Austria and the Republic of Ireland but a systematic review from December 1997, published in the National Screening Library for the UK concluded that There is no evidence to support a newborn screening programme for galactosaemia in the UK and any current newborn screening for galactosaemia should be discontinued.¹¹ Even with screening there is usually evidence of clinical disease before the results are back.

The first description of galactosaemia is attributed to Thalhammer in 1908 but the first detailed description of galactosemia was given by Goppert in 1917. The patient had a large liver, jaundice, failure to thrive, and urinary loss of albumen and sugar. After exclusion of galactose from the diet, there was reversion to normal. He was mentally retarded with a developmental quotient of 14 months at 36 months of age. He tolerated sucrose, maltose, glucose, and fructose but after lactose or galactose there was dose-dependent galactosuria. His oldest brother had suffered from jaundice and hepatomegaly a few days after birth and had had a life-threatening haemorrhage after ritual circumcision. He died after 6 weeks. Autopsy showed a huge liver tumour, and the cause of his death was attributed to nephritis. His third sib, born somewhat prematurely, became icteric, and died after 4 weeks. Goppert concluded that the patient was suffering from a familial liver disorder and that in such cases lactose must be replaced by another sugar such as sucrose or maltose.

Another early description of galactosaemia was given by Mason and Turner in 1935. The Duarte variant was first described by Beutler in 1965 and the following year he described a simple blood spot screening test for the disease. Duarte is in California. Harley et al in 1974 found low levels of galactose-1-phosphate uridylyltransferase and galactokinase in mothers of children with otherwise unexplained infantile cataract. This was presumably a heterozygous state. They suggested that a lactose load in combination with the low enzyme level leads to cataract. The UK galactosaemia register was started in 1993.