Last updated date: 24-May-2023

    Originally Written in English




    All typical carbohydrate metabolism diseases are caused by a specific enzyme deficiency. Almost all of these enzyme deficiencies are inherited as autosomal recessive traits. These metabolic disorders may be divided into three categories based on how they affect glycogen, galactose, and fructose metabolism.

    A change in galactose metabolism caused by a lack of activity in one of three enzymes leads in an increase in blood galactose concentration (galactosemia). The most frequent and severe kind is classic galactosemia, which is characterized by a total lack of galactose-1-phosphate uridyl transferase (GALT). 

    Early signs and symptoms, such as liver dysfunction, susceptibility to infections, failure to thrive, and cataracts, can be avoided or reduced with early diagnosis and treatment, but individuals might still suffer from persistent and progressive neuropsychiatric deficits. The measurement of enzyme activity in red blood cells is required for diagnosis.

    Classic galactosemia affects around one in every 60,000 livebirths. However, the reported incidence of galactosemia varies widely, ranging from 1 in 30,000 to 40,000 in Europe to 1 in 1 million in Japan. In the United States, the estimated frequency is one in every 53,000 people.

    Eliminating lactose and galactose from the diet is the sole therapy for typical galactosemia (e.g. exclusion of dairy products containing lactose). Although a lactose-restricted diet is effective in treating acute difficulties, it is insufficient to avoid long-term consequences affecting the brain and female gonads. Long-term problems may include speech issues, learning impairments, neurological damage (e.g., tremors, etc.), and ovarian failure in certain people.


    Causes of Galactosemia

    Causes of Galactosemia

    Galactose is a sugar that is mostly present in human and bovine milk and milk products as part of the disaccharide lactose. Lactase, an intestine enzyme, hydrolyzes lactose to glucose and galactose. The galactose is subsequently transformed to glucose, which is used as an energy source. Some fruits and vegetables, such as tomatoes, brussels sprouts, bananas, and apples, contain free galactose. 

    Galactose metabolism is altered due to insufficient enzyme activity or poor liver function, resulting in high blood galactose concentrations and the disease known as galactosemia. Impaired galactose metabolism appears to change gene expression via epigenetic pathways, potentially contributing to cognitive and other issues.

    Galactosemia can be caused by deficits in three separate enzymes, each with its own phenotype:

    Galactose-1-phosphate uridyl transferase (GALT) deficiency: 

    GALT deficiency causes the most prevalent and severe type of galactosemia, which is caused by a lack of the enzyme that converts galactose-1-phosphate (galactose-1-P) to uridine diphosphate galactose.

    Classic galactosemia is characterized by a complete lack of GALT activity and is frequently referred to by the single word "galactosemia." Patients who are not treated often suffer failure to thrive, liver and renal dysfunction, and sepsis. Cataracts, aberrant neurodevelopment, and early ovarian failure can occur in both treated and untreated individuals. These complications' pathogenic mechanisms are unknown.

    There are various variations with partial GALT activity. The Duarte variation is the most frequent, in which individuals have one Duarte allele and one traditional allele, resulting in GALT activity that is 5 to 25% of normal. Patients who have two Duarte alleles have around 25% normal GALT activity. If left untreated, patients with GALT activity at 50% of normal tend to have little to no evidence of neonatal or long-term morbidity.

    Galactokinase (GALK) deficiency:

    GALK is the first enzyme in the galactose metabolic pathway, converting galactose to galactose-1-P. The only effect of GALK deficiency is the formation of cataracts. This localized defect's pathogenic processes are unknown.

    Uridine diphosphate (UDP) galactose 4-epimerase (GALE) deficiency:

    The abnormality in most people with GALE (or epimerase) deficiency is restricted to red blood cells (RBCs). The pathogenic processes causing this specific impairment remain unknown. Individuals with broad GALE deficiency in both RBCs and all other tissues often have normal growth and development, but those with classic galactosemia appear with symptoms comparable to classic galactosemia.


    Clinical features of variant types of Galactosemia

    Types of Galactosemia

    Classic galactosemia:

    The most frequent and severe kind is classic galactosemia, which is characterized by a total lack of galactose-1-phosphate uridyl transferase (GALT). Early detection and treatment may typically avoid or resolve early signs and symptoms such as liver dysfunction, susceptibility to infections, failure to thrive, and cataracts. Despite nutritional treatment, most adolescents and adults with this condition experience neuropsychiatric and ovarian issues.

    Galactosemia is included in newborn screening (NBS) programs in all states in the United States and numerous other nations. However, afflicted newborns may develop symptoms before the screening findings are available (about 10 to 14 days following sample collection). As a result, doctors must examine the diagnosis in newborns who exhibit the following signs and symptoms.

    • Early manifestations:

    Classic galactosemia often manifests in the first few days after birth and the beginning of galactose-containing feedings (ie, breast milk or cow's milk-based formula), frequently before the findings of NBS are known. The use of galactose-limited or galactose-free formulae (such as the soy protein-based Enfamil ProSobee, which has been shown to be safe in galactosemia newborns) may disguise the initial presentation.

    Specific indications and symptoms appear with varying frequency. The following are the most prevalent findings:

    1. Jaundice.
    2. Vomiting 
    3. Hepatomegaly 
    4. Failure to thrive 
    5. Poor feeding 
    6. Lethargy 
    7. Diarrhea 
    8. Sepsis 

    The most prevalent pathogen among newborns with sepsis is Escherichia coli sepsis. Coagulopathy, ascites, and seizures are less common observations.

    Infants generally seem jaundiced on physical examination, with hepatomegaly, lethargy, and hypotonia. Edema and ascites, a full fontanelle, encephalopathy, and severe bruising or bleeding are all possibilities.

    Cataracts can be present from birth, however they usually emerge after two weeks due to galactitol accumulation in the lens. Untreated classic galactosemia and galactokinase deficiency usually cause clouding of the embryonic nucleus in the central lens, which then spreads to the cortex. Children who are not detected early may acquire a nuclear cataract as they grow.


    • Late manifestations:

    Monitoring for and management of the later problems that develop in patients with galactosemia, including neurodevelopmental impairment, cataracts, growth delay, and premature ovarian failure, are discussed in detail separately. 

    Laboratory findings of classic galactosemia include the following:

    1. Abnormal carbohydrate metabolism – Increased plasma galactose and red blood cell (RBC) galactose-1-P concentration, increased blood and urine galactitol levels.
    2. Liver dysfunction – Conjugated and/or unconjugated hyperbilirubinemia, abnormal liver function tests (elevated transaminases), coagulopathy, increased levels of plasma amino acids (especially phenylalanine, tyrosine, and methionine).
    3. Renal tubular dysfunction – Metabolic acidosis, galactosuria (which may be indicated by the presence of reducing substances in the urine), glycosuria, aminoaciduria, albuminuria.
    4. Hemolytic anemia.


    Galactokinase (GALK) deficiency:

    Lenticular cataracts, similar to those observed in classic galactosemia, are a constant phenotypic characteristic of GALK deficiency. Cataracts are frequently bilateral and can be treated with dietary modifications.

    Pseudotumor cerebri is an uncommon manifestation of GALK deficiency. Increased cerebrospinal fluid (CSF) oncotic pressure caused by increased CSF galactitol content is suggested to be the mechanism. Clinical manifestations of conventional galactosemia, such as liver, kidney, and brain damage, are usually absent in GALK deficiency. The sole aberrant biochemical test result is hypergalactosemia. On standard laboratory testing, there are no other noteworthy laboratory results for GALK deficiency.

    Uridine diphosphate galactose 4-epimerase (GALE) deficiency:

    GALE deficiency was once assumed to be limited to erythrocytes. Affected patients are often asymptomatic, despite having increased galactose-1-P levels in their erythrocytes. This enzyme's generalized deficit is seldom documented.

    Five children from two families with widespread epimerase deficiency showed dysmorphic facial traits, sensorineural hearing, poor growth, and global developmental delay but no ovarian failure, according to one study. Another study of ten individuals discovered a range of GALE activity ranging from 15 to 64 percent of control values, suggesting that the metabolic abnormality is a continuum of mild (red cell) to severe (both red cells and lymphoblasts) impairment of galactose metabolism in vitro.


    How Galactosemia can be diagnosed? 

    Galactosemia Diagnosis

    In many countries throughout the world, babies are routinely screened for galactosemia through newborn screening (NBS). This enables a diagnosis to be established when the individual is still a newborn. Galactosemia often manifests as lethargy, vomiting, diarrhea, failure to thrive, and jaundice in infants. None of these symptoms are unique to galactosemia, which frequently leads to diagnostic delays. If the baby's family has a history of galactosemia, doctors can test him or her before birth by obtaining a sample of fluid from surrounding the fetus (amniocentesis) or from the placenta (chorionic villus sampling or CVS). Galactosemia is often discovered by newborn screening, which, if accessible, may identify the majority of afflicted infants.

    A galactosemia test is a blood or urine test that looks for three enzymes that are required to convert galactose sugar present in milk and milk products into glucose, a sugar that the human body needs for energy. Galactosemia is caused by a lack of one of these enzymes. This results in elevated amounts of galactose in the blood or urine.

    Affected children might suffer major, lasting consequences or possibly die within days of being born. It is critical that babies get checked for metabolic abnormalities as soon as possible. Galactosemia can even be identified with NBS before any galactose-containing formula or breast milk is consumed.

    Because detection of the condition using NBS does not need protein or lactose consumption, it should be recognized on the first specimen unless the newborn has been transfused. Prior to transfusion, a specimen should be collected. If the sample analysis is delayed or subjected to high temperatures, the enzyme is vulnerable to harm.

    The routine NBS is effective in detecting galactosemia. To screen newborns with galactosemia, two screening tests are used: The Beutler's test and the Hill test. The Beutler's test detects galactosemia by measuring the infant's enzyme level. As a result, intake of formula or breast milk has no effect on the results of this section of the NBS, and the NBS is accurate for diagnosing galactosemia prior to galactose ingestion.


    Is Galactosemia curable?

    Galactosemia Treatment

    The main goal of long-term treatment of galactosemia is to minimize dietary galactose intake. Galactose should be excluded from the diet as soon as galactosemia is suspected.

    Other initial care should be provided as needed to treat jaundice, sepsis, and abnormalities of the liver, kidneys, and central nervous system. Supportive therapy typically includes intravenous hydration, antibiotics, and treatment of coagulopathy, although problems usually resolve quickly after dietary treatment is begun.

    Nutritional therapy:

    Galactose restriction: Infants with suspected galactosemia require immediate dietary management. The elimination of milk and dairy products from the diet reduces dietary galactose. A dietitian with competence in dietary therapy for inborn metabolic defects should give dietary management guidance.

    Human milk or formula based on bovine milk is terminated in babies, and a soy-based formula is provided instead. Alsoy, Isomil, Nursoy, and ProSobee are soy-based baby formulae that are suitable for galactosemia. Lactose-free newborn formulae should not be used since they have not been shown safe for galactosemia patients.

    Ingredients containing lactose and galactose should be avoided after meals are introduced. Other kinds of lactose-containing milk (e.g., nonfat dry milk, whey, or casein) should be avoided in addition to milk, butter, cream, and cheese. Lactate, lactic acid, and lactalbumin, on the other hand, do not contain lactose and are thus safe to consume. Fruits, legumes, and some hard cheeses are negligible sources of galactose when compared to endogenous production, and should be avoided in most situations.


    Calcium supplements: Adequate calcium is provided by soy formula in infancy as long as appropriate volumes are taken. However, as the amount of food increases and formula volume declines after approximately one year of age, calcium supplements should be given. A nutritionist familiar with galactosemia should evaluate the patient's diet for calcium content and supplementation should be provided as needed to ensure that the dietary intake of the individual with galactosemia is meeting the recommended dietary allowance (RDA) for calcium. 



    Galactosemia patients should be observed for the rest of their lives. Outpatient follow-up should be done every three months until one year, every four months until two years, every six months until 14 years, and thereafter yearly, according to the UK Galactosaemia Steering Group. These suggestions should be customized to the specific patient. To measure pubertal growth, girls may need to be visited more regularly.

    Additional examinations are conducted in addition to laboratory testing to monitor the difficulties that may emerge in children with galactosemia. Neurodevelopmental impairment, cataracts, growth retardation, and premature ovarian failure should all be diagnosed as soon as possible so that relevant therapies can be implemented.

    Biochemical status: The content of galactose-1-phosphate in red blood cells (RBC) is measured on an irregular basis to detect major departures from the restricted diet. Frequent assessment is not required since levels only reflect galactose intake in the preceding 24 hours, have a significant intraindividual variability, and do not correspond with long-term outcomes. Furthermore, due to endogenous galactose synthesis, levels are raised in certain individuals who adhere to the lactose-free diet, as detailed further below.

    Because collecting urine is difficult in young children, obtaining blood samples is typically more practical. Furthermore, urine galactitol readings may be difficult to obtain. Because of methodological discrepancies, normal values for galactose-1-phosphate and galactitol vary between laboratories.

    testing RBC galactose-1-phosphate is suggested every three months in children younger than one year of age and then every six months from one to three years of age. After age three years, we obtain either RBC galactose-1-phosphate or urinary galactitol levels every six months until age 14 years, then annually.


    Endogenous galactose synthesis: Because of endogenous galactose synthesis, blood and urine concentrations of galactose and its metabolites remain high in typical galactosemia, even with food limitation. Endogenous galactose production rate (0.53 to 1.05 mg/kg per hour) was varied in galactosemic adults (homozygous for the Q188R allele) and in a range close to that of normal adults, according to one research.

    The rate of endogenous galactose production is negatively related to age. Because the rate of endogenous synthesis surpasses the quantity of galactose in a nondairy diet, increased galactose levels are more likely to be the result of endogenous production than noncompliance with dietary limitations. The varying production rate may potentially contribute to phenotypic heterogeneity, even in patients with comparable genotypes.


    Developmental status: Neurodevelopment should be evaluated on a regular basis. After the age of two years, it should include an annual review of speech and cognitive function. Referrals are provided when needed for speech therapy and for the examination of neurologic symptoms.


    Cataract detection: At the time of diagnosis, an ophthalmologic examination to identify cataracts should be undertaken. Eye exams are conducted every six months until the child reaches the age of three, after which they are done yearly. If cataracts are found, more regular assessments are required.


    Ovarian function: Most females with classic galactosemia have primary ovarian insufficiency. At the age of ten, the amounts of follicle stimulating hormone, luteinizing hormone, and estradiol are examined in girls. If gonadotrophin levels are high but estradiol levels are low, the patient should be sent to a pediatric endocrinologist for estradiol treatment.




    Galactosemia is a condition that alters how the body processes a simple sugar called galactose. Many foods include a trace of galactose. It is essentially a component of a bigger sugar known as lactose, which is found in all dairy products and many infant formulae. The signs and symptoms of galactosemia are caused by an inability to utilise galactose to create energy.

    Galactosemia can be classified into different categories, according to researchers. These diseases are caused by mutations in a specific gene and impact distinct enzymes involved in the breakdown of galactose.

    The most prevalent and severe form of galactosemia is type I, often known as classic galactosemia. If newborns with classic galactosemia are not quickly treated with a low-galactose diet, life-threatening problems arise within a few days after birth. Feeding difficulties, a lack of energy (lethargy), a failure to gain weight and grow as predicted (failure to thrive), yellowing of the skin and whites of the eyes (jaundice), liver damage, and abnormal bleeding are common in affected newborns.

    Overwhelming bacterial infections (sepsis) and shock are other serious complications of this disorder. Children who are affected are also more likely to have delayed development, clouding of the lens of the eye (cataract), speech issues, and intellectual incapacity. Females with classic galactosemia may experience reproductive difficulties as a result of an early loss of ovarian function (premature ovarian insufficiency).

    Galactosemia types II (galactokinase deficit) and III (galactose epimerase deficiency) induce distinct patterns of signs and symptoms. Galactosemia type II is associated with less medical complications than the classic form. Affected newborns get cataracts but have little long-term consequences. Galactosemia type III symptoms range from moderate to severe and might include cataracts, delayed growth and development, intellectual disabilities, liver disease, and renal problems.

    Eliminating lactose and galactose from the diet is the sole therapy for typical galactosemia (e.g. exclusion of dairy products containing lactose).

    Although a lactose-restricted diet is effective in treating acute difficulties, it is insufficient to avoid long-term consequences affecting the brain and female gonads.