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Galactosaemia

This is part of Rare diseases.

Diagnosis: Galactosaemia

Synonyms: --


Publication date: 2013-12-30
Version: 1.1

ICD 10 code

E74.2

The disease

Galactosaemia is the name of a group of hereditary diseases associated with a deficiency of one of the enzymes required to convert the sugar galactose to glucose in the liver. Galactosaemia is the primary term used for this disease where there is a deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT), a condition often described as transferase deficiency. The other diseases in this group are extremely rare, and are not discussed in this material. When there is an absence of GALT, or only very low active levels, results may include damage to the liver, kidneys, central nervous system, the lenses of the eye and, in females, the ovaries.

In 1908, a child with galactosaemia was identified for the first time by the physician von Ruess, and the disease was subsequently described by Friedrich Goppert in 1917. In 1956, the Danish physician Herman Moritz Kalckar and his associates discovered that the condition was caused by a deficiency of the GALT enzyme.

Occurrence

In Sweden, galactosaemia as a result of GALT deficiency is more uncommon than in many other countries and occurs in approximately one child per 100,000 newborns, with as many girls as boys being affected. This means that in Sweden approximately one child every year is born with the condition. In total there are approximately 40 individuals with this form of galactosaemia in Sweden.

Cause

Galactosaemia is caused by a mutation in a gene, GALT, located on chromosome 9 (9p13), which controls the formation of (codes for) the GALT enzyme. Several hundred mutations in the GALT gene are known, some of which can cause very low levels of activity in, or an absence of, the enzyme.

The role of GALT is to facilitate and direct the second stage in the process by which enzymes break down the sugar galactose in the body.

Galactose is present in many foods, particularly in dairy products, but also in fruit, vegetables and offal. Lactose consists of equal proportions of galactose and glucose. The body itself can also produce galactose, which may be important for the occurrence of symptoms and the develoIpment of the disease.

If GALT activity is impaired or absent, galactose and galactose-1-phosphate, accumulate. High concentrations of galactose in the body result in the formation of galactitol, a type of alcohol which can lead to clouding of the lenses of the eye, and cause cataracts. It is as yet unclear why the brain is affected, or why liver and kidney functions may be affected so severely already in newborns, but there are several possible explanations. It is believed that the accumulation of galactose-1-phosphate, which even in moderate concentrations can interfere with the metabolism through inhibiting normal enzyme function, causes these acute symptoms and may contribute to damage to the nervous system. When GALT does not function, this leads to a deficiency in the substance which it normally produces, UDP galactose, which in turn plays an important role in the formation of certain hormones, receptors and structures in the nervous system. A UDP galacose deficiency and an accumulation of galactose-1-phosphate may also be the reason that certain sugars do not combine with proteins and lipids in the normal way, to form important structures in the brain and other parts of the body. Increased levels of galactose also appear to cause stress reactions in the cells of the body, which can seriously interfere with the cells' production of important substances, and even lead to cell death.

There are strong indications that foetal production of galactose is harmful, and that the accumulation of toxic products can result in damage to important structures, including those of the brain. This explains the fact that dietary treatment, even if started immediately after birth, in many cases cannot prevent injury to the brain.

Symptoms of galactosaemia may be caused by one or more of the processes described above. Another symptom may be damage to the ovaries, which sooner or later leads to sterility in the majority of women with the disease. Poor bone mineral content, which is also associated with the disease, may be caused by a number of factors, and there is a risk that people with the disease will have insufficient intake of calcium and vitamin D if the correct dietary regime is not followed.

As in many other diseases caused by genetic mutations, there are major variations in the nature and severity of symptoms among people with galactosaemia. This may be caused by different mutations in the GALT gene but there are also variations where the mutations are identical, while other genes can affect the degree of damage to the organs. The reasons for this are unknown, but both genetic and other factors may play a part.

Heredity

The inheritance pattern of galactosaemia is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

The severity of symptoms depends, among other things, on the levels of remaining enzyme activity. If enzyme activity is absent, the classic form of galactosaemia will manifest. If there is some enzyme activity left, symptoms are often milder. Children with the classic form of galactosaemia are often ill from birth. The first signs appear during the first days of life and are non-specific. The children may have slack muscles, have problems sucking and vomit frequently. Signs that liver function is affected include jaundice, an enlarged liver, low blood sugar (hypoglycaemia) and a tendency to bleed easily. Changes in muscle tone, clouding of the lens of the eye, and general sluggishness leading to unconsciousness are other possible symptoms. The child may sometimes also develop a serious general infection (sepsis).

Symptoms can appear in the foetal stage, and some children are born with cataracts.

If the disease is not treated, liver function deteriorates progressively, followed by kidney function. The course of the disease can be rapid and result in death. There are also milder forms with less acute, more diffuse, symptoms.

If a diagnosis can be made and correct treatment started in good time, acute symptoms may be relieved quite rapidly. However, the disease frequently leads to symptoms which gradually become more pronounced as the child is growing up, even if the correct treatment is given.

Learning difficulties and reduced cognitive function are common, as are tremors and various disabilities affecting speech and the voice. Movement is also affected in many people, with clumsiness, and gait and balance difficulties (ataxia) affecting some individuals. Depression and anxiety have been reported in some people with the disease, but it is not clear whether risks are higher than in the rest of the population. It has not been established that symptoms from the nervous system become worse with age. With advanced medical imaging technology it is possible to see abnormalities in the development of the white substance in the brain and a reduction in the sizes of both the cerebrum and the cerebellum. As mentioned above, it is as yet unknown why dietary treatment does not have sufficient effect on symptoms from the nervous system.

In girls and women with the disease the ovaries degenerate, leading to delayed or absent puberty, abnormal menstruation patterns and often to sterility at around the age of 20. Nevertheless, approximately 50 full-term pregnancies have been reported, some after specialized hormone treatment. The fertility of men with the disease is not significantly impaired.

People with galactosaemia may have reduced bone density with an increased risk of fractures. There is also an increased risk of caries.

Even when a full dietary regime is followed, there may still be many complications. The ovaries are often seriously affected, with abnormalities in over 90 per cent of women with the disease. Among complications affecting the nervous system, those affecting intellectual function are the most serious. The risk of clearly impaired cognitive function varies from study to study, the latest reports estimating the risk at a minimum of 25 per cent. However, it is important to point out that there is data which indicates that most people with the disease do not have any serious complications affecting the nervous system.

Foreign studies have shown that adults with galactosaemia run the risk of being socially isolated. They live alone to a far higher degree than their peers and are often unemployed.

Diagnosis

It can be difficult to make a diagnosis in the neonatal period as symptoms of other, more common, serious diseases are similar. The usual neonatal blood and urine tests taken when a newborn becomes ill do not show galactosaemia. High levels of galactose in the blood may also be found in some newborns with abnormalities which cause blood from the intestines to by-pass the liver.

For many years, galactosaemia has been one of the congenital diseases which is detected in the blood sample taken from newborns during the first days of life (the Swedish neonatal screening process, known as the "PKU-test"), sometimes before symptoms have appeared. The diagnosis is confirmed by an analysis of GALT in red blood cells, carried out in the laboratory at the Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Sweden.

A DNA analysis can also identify which mutation in the GALT gene caused the disease. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD), are available in families where the mutation is known.

Treatment/interventions

Responsibility for information, treatment and following up patients should be carried out by a medical centre specialising in inherited metabolic diseases, where specialised physicians and dieticians collaborate with geneticists, chemists, psychologists and counsellors. These centres also keep updated with research and development related to the disease. People with galactosaemia should visit such a centre at least once a year for a check up and information. It is also important to have regular contact with a local doctor who keeps in touch with specialists at the centre.

Galactosaemia is treated through dietary therapy. A galactose-free breast-milk substitute is critical for, and may save the life of, newborns showing acute symptoms of the disease, and it is natural to continue with a strict galactose-free diet when it is time to replace breast-milk substitute with other forms of nutrition. However, this is very difficult as small amounts of galactose are found in almost all food groups. It has been found that trying to eliminate very small amounts of galactose completely is counter-productive as it does not improve the results of the treatment. Currently, there is no scientifically-based information on how much galactose can be consumed regularly by people of different ages with the condition, without their running the risk of serious complications. It is therefore extremely important that strict dietary restrictions are complied with. According to current recommendations these restrictions are life-long.

Modern dietary guidelines continue to eliminate all dairy and other food products with high levels of lactose and galactose. However, hard, mature cheeses which are completely, or nearly, galactose-free and fruit and vegetables which at best contain very small amounts of galactose, are allowed. It is particularly important to be aware that foodstuffs which are labelled lactose-free are not automatically galactose-free. For this reason it is important always to read the list of contents carefully and ask a dietician for advice if one is uncertain. It is important that advice on nutrition is given by a dietician who has special expertise in the disease.

Pregnant women who are carriers of the disease should not limit their galactose intake, whether or not the expected child has the disease.

During the neonatal period the child's diet will alleviate or eliminate symptoms. After this period, children with galactosaemia require regular check-ups. The family should also have contact with a dietician who can provide advice. It is important to ensure that the diet contains all nutrients. As the child cannot drink milk, calcium, and sometimes vitamin D and K supplements should be given. The goal is that the child should grow normally. Regular check ups are also important to detect abnormalities in motor or intellectual development at an early stage. In order to provide the right support and treatment, a neuropsychological examination may be essential.

Girls with galactosaemia often require hormone treatment during puberty because their ovaries do not function normally and they require careful monitoring by an endocrinologist from the age of 11 or 12. Although fertility is reduced, pregnancy is not out of the question. Experience indicates that it is very important to contact a Fertility Centre as soon as the question of having children arises, in order to receive help where necessary.

Cataracts are repaired surgically. Children who do not have cataracts as newborns do not require opthalmologists to monitor for this condition as they develop.

Children and young people who develop neurological complications need to establish contact with a habilitation team. This team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. Habilitation focuses on existing needs, may vary over time and take place in collaboration with individuals close to the child.

As galactosaemia is so rare, schools and school healthcare services often lack the requisite knowledge of the child's special needs. Good communication between the school and members of the team responsible for the child's treatment has often been shown to be essential if the child is to receive the correct support.

Continuous social and psychological support is important to counteract the loneliness and isolation which some adults with the disease experience. For some individuals, there may be a need for a continued, individually-designed, habilitation programme.

Practical advice

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National and regional resources in Sweden

Teams with specialist expertise in galactosaemia work at:

The Queen Silvia Children's Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Astrid Lindgren Children's Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00. Also, CMMS Laboratory, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Uppsala University Children's Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.

The Children's Hospital at Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

Resource personnel

Specialist Physician Katrin Adrian, Centre for Congenital Metabolic Diseases, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: katrin.adrian@gu.se.

Associate Professor Olov Ekwall, Centre for Congenital Metabolic Diseases, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: olov.ekwall@vgregion.se.

Senior Physician Maria Halldin, Uppsala University Children's Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: maria.halldin@kbh.uu.se.

Senior Physician Anna Nordenström, Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, email: anna.nordenstrom@ki.se.

Senior Physician Domniki Papadopoulou, Children's Hospital, Skåne University Hospital/Lund, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00, email: domniki.papadopoulou@skane.se.

Specialist Physician Annika Reims, Centre for Congenital Metabolic Diseases, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: annika.reims@vgregion.se.

Senior Physician Rolf Zetterström, Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, email: rolf.zetterstrom@ki.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

Currently, there is no Swedish association, but there is galactosaemia association in Norway, www.galaktosemi.no.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, fax: +46 8 546 404 94, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se.
Rare Diseases Sweden is a federation of rare disease organizations, serving the interests of people with rare disorders.

There is also a European association, the European Galactosaemia Society (EGS), which monitors research and organizes meetings, www.galactosaemia.com.

Courses, exchanges of experience for personnel

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Research and development

The disease has been recognized for many years and there is successful treatment available which saves the lives of newborn children. However, the challenge remains, as it is still not possible to save many people from developing chronic symptoms, which manifest later in life. Despite the fact that the abnormalities in genetic material have been localised and functional impairments recognized, there is still insufficient knowledge of how the disabilities associated with the disease arise. Galactosaemia is one of the most common metabolic diseases in several large countries, and there is much interest in research which will provide a basis for establishing new methods of treatment. Active research is under way into this disease in many centres.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, "Mer hos oss" in the column on the right-hand side.

Information on galactosaemia (2003, 2011) is available at the Centre for Rare Disorders, Oslo University Hospital HF, Rikshospitalet, 4950 Nydalen, NO-0424 Oslo, Norway. Tel: +47 947 23 07 53 40, email: sjeldnediagnoser@ous-hf.no, www.sjeldnediagnoser.no.

Literature

Batey LA, Welt CK, Rohr F, Wessel A, Anastasoaie V, Feldman HA et al. Skeletal health in adult patients with classic galactosemia. Osteoporos Int 2013; 24: 501-509.

Berry GT. Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia? J Inherit Metab Dis 2011; 34: 345-355.

Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HSA, Wijburg FA, Last BF. Living with classical galactosemia: Health-related quality of life consequences. Pediatrics 2004; 113: 423-428.

Coss KP, Doran PP, Owoeye C, Codd MB, Hamid N, Mayne PD et al. Classical galactosaemia in Ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis 2013; 36: 21-27.

Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E. Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 2011; 34: 357-366.

Fridovich-Keil JL. Galactosemia: The good, the bad, and the unknown. J Cell Physiol 2006; 209: 701-705.

Hoffmann B, Dragano N, Schweitzer-Krantz S. Living situation, occupation and health-related quality of life in adult patients with classic galactosemia. J Inherit Metab Dis.2012; 35: 1051-1058.

Hoffmann B, Wendel U, Schweitzer-Krantz S. Cross-sectional analysis of speech and cognitive performance in 32 patients with classic galactosemia. J Inherit Metab Dis 2011; 34: 421-427.

Hughes J, Ryan S, Lambert D, Geoghegan O, Clark A, Rogers Y et al. Outcomes of siblings with classical galactosemia. J Pediatr 2009; 154: 721-726.

Jumbo-Lucioni PP, Garber K, Kiel J, Baric I, Berry GT, Bosch A et al. Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. J Inherit Metab Dis 2012; 35: 1037-1049.

Potter NL, Lazarus JAC, Johnson JM, Steiner RD, Shriberg LD. Correlates of language impairment in children with galactosemia. J Inherit Metab Dis 2008; 31: 524-532.

Ridel KR, Leslie ND, Gilbert DL. An updated review of long-term neurological effects of galactosemia. Pediatr Neurol 2005; 33: 153-161.

Rubio-Gozalbo ME, Gubbels CS, Bakker JA, Menheere PPCA, Wodzig WKWH, Land JA. Gonadal function in male and female patients with classical galactosemia. Hum Reprod Update 2010; 16: 177-188.

Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-Krantz S, Wendel U. Longitudinal assessment of intellectual achievement in patients with classical galactosemia. Pediatrics 2010; 125: e374-381.

Schweitzer S, Shin Y, Jacobs C, Brodehl J. Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 1993; 152: 36-43.

Segal S. Galactosaemia today: the enigma and the challenge. J Inherit Metab Dis 1998; 21: 455-471.

Tang M, Odejinmi SI, Vankayalapati H, Wierenga KJ, Lai K. Innovative therapy for classic galactosemia - tale of two HTS. Mol Genet Metab 2012; 105: 44-55.

Waggoner DD, Buist NRM, Donell GN. Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inher Metabl Dis 1990; 13: 802-818.

Waisbren SE, Potter NL, Gordon CM, Green RC, Greenstein P, Gubbels CS et al. The adult galactosemic phenotype. J Inherit Metab Dis 2012; 35: 279-286.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: galactosemia

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews)
Search: Galactosemia

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Ola Hjalmarson, The Queen Silvia Children's Hospital, Gothenburg, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2013-12-30
Version: 1.1
Publication date of the Swedish version: 2013-06-03

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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