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Classical galactosaemia
This condition is caused by a deficiency in the GALT enzyme, leading to a build-up of harmful substances. If untreated, it can cause severe health problems in infants, including liver damage, cataracts, and developmental issues.
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Overview
Classical galactosaemia is an inherited metabolic condition, meaning it is passed down through families. It affects the body's ability to break down a specific type of sugar called galactose, which is found in lactose (milk sugar). In individuals with classical galactosaemia, an essential enzyme called galactose-1-phosphate uridylyltransferase (GALT) is deficient or absent. This enzyme is crucial for converting galactose into a form the body can use for energy [PMID:33005183].
Without a properly functioning GALT enzyme, galactose and its toxic by-products accumulate in the body. This build-up can damage various organs and systems, especially if the condition is not identified and managed early. Classical galactosaemia is typically detected through newborn screening programmes in the UK, which is vital for preventing severe complications.
The exact prevalence of classical galactosaemia is estimated to be between 1 in 30,000 and 1 in 60,000 live births in the UK. This makes it a rare condition, but one with significant health implications if left untreated.
Symptoms & clinical features
Symptoms of classical galactosaemia typically appear within the first few days or weeks of life after an infant starts consuming milk (breast milk or formula). The initial signs can be non-specific, making early diagnosis challenging without newborn screening.
Common early symptoms include poor feeding, vomiting, lethargy (lack of energy), and jaundice (yellowing of the skin and eyes) due to liver involvement [PMID:33005183]. Infants may also experience diarrhoea and fail to gain weight or grow as expected, a condition known as 'failure to thrive'.
If the condition remains undiagnosed and untreated, more severe symptoms can develop. These may include enlarged liver and spleen, fluid accumulation in the abdomen (ascites), bleeding disorders, and increased susceptibility to serious bacterial infections, particularly E. coli sepsis [PMID:33005183]. Eye problems, such as cataracts, can also emerge within the first few weeks or months.
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Affected organs
Classical galactosaemia primarily affects several key organ systems due to the toxic build-up of galactose and its metabolites. The liver is often one of the first organs to show signs of damage, leading to jaundice, enlargement (hepatomegaly), and impaired liver function. If untreated, this can progress to severe liver disease and potentially liver failure.
The brain can also be affected, leading to developmental delays and intellectual disabilities if early intervention is not provided. The eyes are vulnerable, with cataracts developing due to the accumulation of galactitol, a by-product of galactose metabolism. The kidneys can also be impacted, potentially affecting their normal function. Additionally, the immune system may be compromised, increasing the risk of severe infections.
Risks & severity
The severity of classical galactosaemia varies depending on how quickly it is diagnosed and treated. Without treatment, the condition can be life-threatening in the newborn period due to liver failure, severe infections, and brain damage. With early diagnosis through newborn screening and strict adherence to a galactose-free diet, many of the acute, life-threatening complications can be prevented.
Despite early and consistent dietary management, individuals with classical galactosaemia may still face long-term health challenges. These can include speech and language difficulties, developmental delays, movement problems (ataxia), and a reduced bone mineral density [PMID:33005183]. Females with classical galactosaemia are also at a significantly increased risk of premature ovarian insufficiency, which can lead to infertility [PMID:33005183]. Regular monitoring and multidisciplinary care are essential throughout life to manage these potential long-term risks.
Genetic causes
Classical galactosaemia is caused by pathogenic changes in the *GALT* gene. This gene provides instructions for making an enzyme called galactose-1-phosphate uridylyltransferase. This enzyme is vital for the second step in the process of breaking down galactose, converting it into glucose, a sugar the body can easily use for energy.
Pathogenic variants in *GALT* lead to a deficiency or complete absence of the functional GALT enzyme. This means the body cannot effectively metabolise galactose. Consequently, galactose and its toxic by-products, such as galactose-1-phosphate and galactitol, accumulate in the blood and tissues, causing cellular damage and the clinical symptoms associated with the condition.
Several different types of changes in the *GALT* gene have been identified that can cause classical galactosaemia. The specific variant can sometimes influence the residual enzyme activity, although even individuals with some residual activity typically require strict dietary management to prevent severe complications.
- GALT galactose-1-phosphate uridylyltransferaseThe *GALT* gene provides instructions for an enzyme crucial for the body's metabolism of galactose, a sugar found in dairy products and many foods.
Inheritance pattern
Classical galactosaemia has an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the *GALT* gene - one from each parent - to develop the condition.
If a person inherits only one altered copy of the *GALT* gene and one normal copy, they are considered a 'carrier'. Carriers typically do not show any symptoms of classical galactosaemia because their single working copy of the gene produces enough functional GALT enzyme. However, if two carriers have children together, there is a 25% chance with each pregnancy that their child will inherit two altered copies of the gene and therefore be affected by classical galactosaemia. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two normal copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
In the UK, classical galactosaemia is primarily diagnosed through the NHS Newborn Blood Spot Screening Programme. This screening test, usually performed when a baby is about 5 days old, checks for several rare but serious conditions, including galactosaemia. A small blood sample is taken from the baby's heel and analysed.
If the newborn screen indicates a high likelihood of galactosaemia, further diagnostic tests are performed to confirm the diagnosis. These typically include measuring GALT enzyme activity in red blood cells and performing genetic testing to identify pathogenic variants in the *GALT* gene. Genetic testing can precisely confirm the diagnosis and identify the specific genetic changes, which can be important for family planning and genetic counselling. These tests are usually organised by a specialist metabolic team, often following referral from a GP or paediatrician. Genetic testing for galactosaemia falls under NHS R-code R115.
Management & lifestyle
The cornerstone of managing classical galactosaemia is a strict, lifelong galactose-restricted diet. This means eliminating all sources of lactose and galactose, primarily milk, dairy products, and certain processed foods, from the diet. For infants, this involves using special lactose-free formulas. Dietary management should be initiated as soon as the diagnosis is suspected, ideally within the first few days of life, to prevent acute and severe complications.
Ongoing management involves regular monitoring by a specialist metabolic team, which typically includes a metabolic consultant, dietitian, and genetic counsellor. This team monitors growth, nutritional status, and organ function, such as liver and eye health. Regular blood tests are used to check levels of galactose metabolites and ensure dietary adherence. Individuals may also receive calcium and vitamin D supplementation to support bone health, as dairy products are a significant source of these nutrients.
Even with strict dietary control, some long-term complications, such as developmental and speech difficulties, and premature ovarian insufficiency in females, may still occur. Therefore, ongoing developmental assessments and specialist referrals are often part of the comprehensive care plan. Genetic counselling is also recommended for affected individuals and their families to understand the inheritance pattern and implications for future pregnancies.
UK care pathway
In the UK, the care pathway for classical galactosaemia begins with the NHS Newborn Blood Spot Screening Programme, which aims for early detection. If a positive screen is identified, infants are promptly referred to specialist metabolic centres within the NHS. These centres provide multidisciplinary care, including specialist metabolic paediatricians, dietitians, and genetic counsellors.
Genetic testing for classical galactosaemia is available through the NHS Genomic Medicine Service (GMS) as part of the rare disease genomic testing directory, under R-code R115. This testing confirms the diagnosis and identifies the specific genetic changes in the *GALT* gene. Genetic counsellors play a crucial role in providing information and support to families regarding the genetic aspects of the condition, inheritance patterns, and reproductive options.
Frequently asked questions
What is the main treatment for classical galactosaemia?
The main treatment for classical galactosaemia is a strict, lifelong diet free of galactose. This means avoiding all milk, dairy products, and other foods containing lactose or galactose. For infants, this involves using special lactose-free formulas.
Can classical galactosaemia be cured?
Classical galactosaemia cannot be cured, as it is a genetic condition. However, it can be effectively managed with a strict galactose-free diet, which helps prevent many of the severe acute complications and reduces the risk of long-term health problems.
How is classical galactosaemia inherited?
Classical galactosaemia is inherited in an autosomal recessive pattern. This means a child must inherit two altered copies of the *GALT* gene, one from each parent, to develop the condition. Parents who carry one altered copy are usually unaffected.
What are the long-term effects of classical galactosaemia?
Even with early and strict dietary management, individuals with classical galactosaemia may experience long-term effects such as developmental delays, speech difficulties, reduced bone density, and premature ovarian insufficiency in females.
Is classical galactosaemia detected at birth in the UK?
Yes, classical galactosaemia is one of the conditions screened for in all newborns in the UK as part of the NHS Newborn Blood Spot Screening Programme. Early detection is crucial for starting treatment promptly.
References
- Bosch AM. Classical galactosaemia revisited. Journal of inherited metabolic disease. 2006. PMID: 16838075
- Sardharwalla IB, Wraith JE. Galactosaemia. Nutrition and health. 1987. PMID: 3328119
- Lak R, Yazdizadeh B, Davari M. Newborn screening for galactosaemia. The Cochrane database of systematic reviews. 2020. PMID: 32567677
- Lak R, Yazdizadeh B, Davari M. Newborn screening for galactosaemia. The Cochrane database of systematic reviews. 2017. PMID: 29274129
- Maratha A, Stockmann H, Coss KP. Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis. European journal of human genetics : EJHG. 2016. PMID: 26733289
- Mayatepek E, Hoffmann B, Meissner T. Inborn errors of carbohydrate metabolism. Best practice & research. Clinical gastroenterology. 2010. PMID: 20955963
- Maratha A, Colhoun HO, Knerr I. Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review. JIMD reports. 2017. PMID: 27502837
- Neville S, O'Sullivan S, Sweeney B. Friedreich Ataxia in Classical Galactosaemia. JIMD reports. 2016. PMID: 26219880