GALACTOSEMIA

Galactosemia, which means “galactose in the blood,” refers to a group of inherited disorders
that impair the body's ability to process and produce energy from a sugar called galactose. When
people with galactosemia injest foods or liquids containing galactose, undigested sugars build up
in the blood. Galactose is present in many foods, including all dairy products (milk and anything
made from milk), many baby formulas, and some fruits and vegetables.[1][2] The impaired ability
to process galactose can be due to the deficiency of any of 3 enzymes, caused by mutations in
different genes.[3] There are 3 main types of galactosemia which are distinguished based on their
genetic causes, signs and symptoms, and severity:[1][3][4][5][6]

 Classic galactosemia (type 1) - the most common and severe type, caused by mutations
in the GALT gene, and characterized by a complete deficiency of an enzyme called
galactose-1-phosphate uridyl transferase (GALT). Early signs and symptoms include
liver dysfunction, susceptibility to infections, failure to thrive, and cataracts. These can
usually be prevented or improved by early diagnosis and treatment, but other progressive
or long-term problems are common despite treatment. These include intellectual deficits,
movement disorders, and premature ovarian failure (in females).
 Galactokinase deficiency (type 2) - caused by mutations in the GALK1 gene and
characterized by a deficiency of the enzyme galactokinase 1. This type typically causes
only the development of cataracts, which may be prevented or resolved with treatment.
Rarely, this type causes pseudotumor cerebri (a condition which mimics the symptoms of
a large brain tumor when no brain tumor is present).
 Galactose epimerase deficiency (type 3) - caused by mutations in the GALE gene and
characterized by a deficiency of the enzyme UDP-galactose-4-epimerase. Symptoms and
severity of this type depend on whether the deficiency is confined to certain types of
blood cells or is present in all tissues. Some people with this type have no signs or
symptoms, while others have symptoms similar to those with classic galactosemia. Like
in classic galactosemia, many symptoms can be prevented or improved with treatment.

There is also a "variant" of classic galactosemia called Duarte variant galactosemia, in which a
person has mutations in the GALT gene but has only partial deficiency of the enzyme. Infants
with this form may have jaundice, which resolves when switched to a low-galactose formula.
Some studies have found that people with this form are at increased risk for mild
neurodevelopmental problems, but other studies have found there is no increased risk. The risk
may depend on the extent of the deficiency.[3][7]

Inheritance of all types of galactosemia is autosomal recessive.[1][3] The diagnosis may be

suspected based on symptoms or results of newborn screening tests, and can be confirmed by
measuring enzyme activity and genetic testing.[3] Depending on the type of galactosemia,
treatment may involve removing galactose from the diet (as soon as the disorder is suspected),
calcium supplementation, and individualized care for any additional symptoms.[6] The long-term
outlook for people with galactosemia varies depending on the type, symptoms present, and
commitment to the diet.[6]

Galactosemia
Introduction
During normal digestion of milk and dairy products, the body breaks down lactose, a
disaccharide into glucose and galactose. The metabolism of galactose produces fuel for cellular
metabolism through its conversion to glucose-1-phosphate in a series of reactions commonly
referred to as the Leloir pathway. Galactose plays an important role in the formation of
glycoproteins, glycolipids, and glycosaminoglycans.
Pathophysiology
An elevated blood galactose concentration is the result of altered metabolism of galactose
due to a genetic deficiency in enzyme activity or secondary hypergalactosemia due to liver
disease (congenital hepatitis, patent ductus venosus, congenital hepatic AVM). This review will
focus on galatactosemia caused by deficient enzyme activity. Galactosemia results from the
deficiency of one of three different enzymes, each with a distinct phenotype.

Enzyme
Disorder Symptoms Description
Deficiency
Galactose-1- Liver and renal dysfunction,
* Classic phospate uridyl cataracts, abnormal Most common and
Galactosemia transferase neurodevelopment, premature most severe form.
(GALT) ovarian failure
Galactokinase Galactokinase Bilateral cataracts, will resolve
Benign
Deficiency (GALK) with dietary therapy
Benign variant is
Generalized Uridine Similar to classic galactosemia
common, when the
UDPgalactose-4- diphosphate with additional findings of
defect is localized to
epimerase galactose 4- hypotonia, developmental
red blood cells- no
Deficiency epimerase (GALE) delay and neural deafness
treatment required

Classic galactosemia (Incidence- 1/60,000) refers to the complete deficiency of the GALT
enzyme, inherited in an autosomal recessive pattern with over 150 mutations currently
identified. Prenatal diagnosis can be made with a GALT assay in fibroblasts cultured from
amniotic fluid or a chorionic villus biopsy and may be undertaken if high index of suspicion or
positive family history is present. Mutation analysis is usually not useful for prognosis or therapy
because the phenotype does not necessarily correlate with genotype. Additionally, because of
the high number of identified mutations, negative results of genetic panels do not exclude the
possibility of disease. There are numerous variants where GALT activity is impaired, but not
absent, resulting in mild or absent symptoms (such as the Duarte variant).

Signs/Symptoms
Symptoms appear early in the neonate as the average newborn normally receives up to 20%
caloric intake as lactose. Without the GALT enzyme, the infant is unable to metabolize
galactose-1-phosphate, and the resulting accumulation leads to injury in the kidney, liver, and
brain. The injury can begin prenatally in the affected fetus via transplacental delivery of
galactose or by endogenous production of galactose in the fetus.

Presenting Symptoms include: Jaundice (74%), Vomiting (47%), Hepatomegaly (43%), Failure
to thrive (29%), Lethargy (16%), Sepsis (10%), particularly due to E.coli, is the principle
cause of early mortality (exam favorite!)

A mutation common in Hispanic/African American individuals is associated with a milder

presentation and these children can present later in childhood.

Physical Exam: hepatomegaly, hypotonia, edema, ascites, full fontanelle, encephalopathy, and
excessive bruising or bleeding.

Lab Findings
 1. Liver dysfunction- conjugated/unconjugated hyperbilirubinemia, abnormal LFTs,
coagulopathy, increased plasma aa (phenylalanine, tyrosine, methionine)
2. Renal tubular dysfunction- metabolic acidosis, galactosuria and glycosuria, albuminuria
3. Abnormal carbohydrate metabolism- increased plasma galactose and RBC galactose-1-P
concentration, increased blood and urine galactitol levels
4. Hemolytic anemia

Diagnosis
Most states include galactosemia in their newborn screen. However, many babies who test
positive on the newborn screen do not have classical galactosemia, so it is important to consider
the secondary causes of hypergalactosemia.

An infant with a positive newborn screen should be changed immediately to a soy-based infant
formula and evaluated for signs of sepsis and hepatic failure. The screen should also be
repeated. If the second screen is positive, the gold standard for diagnosis is a quantitative assay
of erythrocyte GALT which measures the level of enzyme activity.

1. Fluorimetric assay- Can give a false negative if within three months of blood transfusion.
This assay does not detect galactokinase or epimerase deficiency. Can also cause a false
positive if G6PD deficient.
2. GALT electrophoresis- Helps to distinguish between classic galactosemia and the
“Duarte variant”, where some enzyme activity is present.
3. Bacterial inhibition assay- Detects elevated blood galactose. Can result in false negatives
with poor feeding, soy intake, or antibiotic use. Galactose can also be mildly elevated in
normal newborns (6-10 mg/dl).

If the RBC GALT assay is normal, evaluate for GALK and GALE abnormalities.

Conversely, affected infants may become symptomatic before screening results are available.
Testing the urine for reducing substances (such as galactose) is a quick test which can be done in
the pediatrician's office to gauge the level of suspiscion for galactosemia, however this test
should be interpreted carefully as it can result in false positives and negatives.

Prognosis
With proper dietary management, most patients with classic galactosemia are healthy and
intellectually normal during childhood, but frequently develop symptoms during adolescence and
adulthood. It is not clear why dietary restriction of galactose fails to prevent long-term
complications, current theories include the impact of endogenous production of galactose,
accumulation of galactose-1-phosphate or abnormal galactosylation.

1. Neurodevelopment- Problems with speech and language function; dietary compliance

and RBC galactose-1-P levels do not appear to affect IQ (averages from 70-90). Focal
findings such as tremor, ataxia, and dysmetria
2. Ovarian failure- Premature ovarian failure (81%), increased LH/FSH consistent with
hypergonadotrophic hypogonadism
3. Cataracts- Sublenticular cataracts (30%), detected after two weeks of age, the result of
galactitol deposition in the lens
4. Notably, some reports have described age-related decreases in IQ

Management
If a neonate presents in crisis and classical galactosemia is suspected or confirmed, restriction
of dietary galactose should be always be started immediately. Additionally, Vitamen K
supplementation, FFP administration, initiation of antibiotics with good gram negative coverage
and implementation of phototherapy should be considered.

The treatment for galactosemia is to minimize dietary galactose by excluding milk and dairy
products. Soy formulas can be used but remember, some lactose free formulas do contain
galactose. Parents should also be reminded to ask pharmacists about galactose content in
medications. Fruits and legumes are insignificant sources of galactose and do not need to be
restricted. After 1 year, calcium should be supplemented. Blood and urine concentrations of
galactose remain elevated in classic galactosemia, with dietary restriction, due to endogenous
galactose production.

Some physicians have raised the idea that lactose/galactose restriction can be relaxed in
adulthood since endogenous galactose production slows with age, others even suggest continued
galactose restriction is harmful, however both of these claims are controversial.

Follow-Up
While traditionally, the follow-up care of patients affected by galactosemia was centered around
the monitoring of biochemical markers, the inability to treat long-term effects based on those
markers has caused a shift in focus towards the early detection and treatment of functional
deficits using a multi-disciplinary approach.

1. Every 6 month testing of RBC galactose-1-P (every 3 months up to 3 years)

2. Annual evaluation of speech and cognitive function after age two
3. Eye exams every six months up to 3 years and then annually for cataract detection
4. Yearly dietary assessment
5. FSH, LH, estradiol measurement in girls at age 10

Future Treatment
Due to the theorized role of galactose-1-phosphate in long-term complications seen in classical
galactosemia, several galactokinase (GALK) inhibitors have been identified and are currently in
animal trials. Researchers are hopeful that GALK inhibition could prevent build-up of galactose-
1-phostphate and thus decrease disease burden.

Galactosemia is a rare genetic disorder that affects how your body metabolizes galactose.
Galactose is a simple sugar found in milk, cheese, yogurt, and other dairy products. When it’s
combined with glucose, it makes lactose.

Galactosemia means having too much galactose in the blood. The buildup of galactose can lead
to serious complications and health problems.

Symptoms
Symptoms of galactosemia usually develop several days or weeks after birth. The most common
symptoms include:

 loss of appetite
 vomiting
 jaundice, which is yellowing of the skin and other parts of the body
 liver enlargement
 liver damage
  fluid building up in the abdomen and swelling
 abnormal bleeding
 diarrhea
 irritability
 fatigue or lethargy
 weight loss
 weakness
 higher risk of infection

Babies who have galactosemia have problems eating and tend to lose weight. This is also known
as failure to thrive. Learn more about what failure to thrive means for your child.

Complications
Multiple complications can appear if galactosemia isn’t diagnosed and treated right away. The
buildup of galactose in the blood can be dangerous. Without diagnosis and intervention,
galactosemia can be life-threatening in newborns.

Common complications of galactosemia include:

 liver damage or liver failure

 serious bacterial infections
 sepsis, which is a life-threatening problem caused by infections
 shock
 delayed development
 behavioral problems
 cataracts
 tremors
 speech problems and delays
 learning disabilities
 fine motor difficulties
 low bone mineral density
 reproductive problems
 premature ovarian insufficiency

Premature ovarian insufficiency is only seen in women. The ovaries stop functioning at an early
age and affect fertility. This usually occurs before the age of 40. Some of the symptoms of
premature ovarian insufficiency are similar to menopause.

What causes galactosemia?

Galactosemia is caused by mutations in genes and a deficiency of enzymes. That causes the
sugar galactose to build up in the blood. It’s an inherited disorder, and parents can pass it down
to their biological children. The parents are considered carriers of this disease.

Galactosemia is a recessive genetic disorder, so two copies of the defective gene have to be
inherited for the disease to appear. This usually means a person inherits one defective gene from
each parent.

Incidence
Type 1 galactosemia occurs in 1 out of every 30,000 to 60,000 babies. Type 2 galactosemia is
less common than type 1 and occurs in 1 out of every 100,000 babies. Type 3 and Duarte variant
galactosemia are very rare.

Galactosemia is more common among those who have Irish ancestry and among people of
African descent living in the Americas.
Diagnosis
Galactosemia is usually diagnosed though tests that are done as part of newborn screening
programs. A blood test will detect high levels of galactose and low levels of enzyme activity.
The blood is usually taken by pricking a baby’s heel.

A urine test may also be used to diagnose this condition. Genetic testing can also help diagnose
galactosemia.

Treatment
The most common treatment for galactosemia is a low-galactose diet. This means that milk and
other foods that contain lactose or galactose can’t be consumed. There is no cure for
galactosemia or approved medication to replace the enzymes.

Although a low-galactose diet can prevent or reduce the risk of some complications, it may not
stop all of them. In some cases, children still develop problems such as speech delays, learning
disabilities, and reproductive issues.

Speech problems and delays are a common complication, so some children may benefit from
speech therapy as part of the treatment plan.

In addition, children who have learning disabilities and other delays may benefit from individual
education plans and intervention.

Galactosemia can increase the risk of infections, so controlling infections when they occur is
crucial. Antibiotic treatments or other medications may be necessary.

Genetic counseling and hormone replacement therapy may also be recommended. Galactosemia
can affect puberty, so hormone replacement therapy may help.

It’s important to talk to your doctor and address concerns early.

Diet

To follow a low-galactose diet, avoid foods with lactose, including:

 milk
 butter
 cheese
 ice cream
 other dairy products

You can replace many of these foods with dairy-free alternatives, like almond or soy milk,
sorbet, or coconut oil. Learn about almond milk for babies and toddlers.

Human breast milk also contains lactose and isn’t recommended for babies diagnosed with this
condition. Some babies with Duarte variant galactosemia may still be able to drink breast milk,
however. Talk to your doctor if you have any concerns about not being able to breastfeed your
baby.

While the Centers for Disease Control and Prevention (CDC) recommends breast milk as the
best way for infants to receive nutrients, they don’t recommend breastfeeding an infant with
galactosemia. Instead, you’ll need to use a lactose-free formula. Ask your doctor about formula
options.

If you plan to use formula, look for a lactose-free version. Many dairy products are fortified with
vitamin D. Talk to your doctor about vitamin D supplements and whether they are appropriate
for your child.
Outlook
Galactosemia is a rare inherited disorder that affects how galactose is processed in the body. If
galactosemia isn’t diagnosed at an early age, then complications can be serious.

Following a low-galactose diet is an essential part of managing this disorder.

Galactosemia is a genetic disorder in which the body is unable to convert a sugar, called
galactose, into energy. It is caused by mutations in the GALE, GALK1, and GALT genes.

What are the other Names for this Condition? (Also known
as/Synonyms)
 Epimerase Deficiency Galactosemia
 Galactose-1-Phosphate Uridyl-Transferase Deficiency Disease
 UTP Hexose-1-Phosphate Uridylyltransferase Deficiency

What is Galactosemia? (Definition/Background

Information)
 Galactosemia is a genetic disorder in which the body is unable to convert a sugar, called
galactose, into energy. It is caused by mutations in the GALE, GALK1, and GALT genes
 Galactose is a simple sugar, just like glucose. Glucose is the most common type of sugar
that the body converts into energy. Galactose is a part of lactose, which is present in milk
and milk-products, including baby formulas
 There are 3 different types of Galactosemia, caused by mutations in different enzymes
that are responsible for metabolism of galactose. They are classified as:
o Galactosemia Type I: Classic Galactosemia Type I is the most common type, with
the most severe signs and symptoms. In this type, the mutation occurs in GALT
gene
o Galactosemia Type II: Caused by mutations in the GALK1 gene, resulting in
galactokinase deficiency
o Galactosemia Type III: Caused by mutations in the GALE gene, resulting in
galactose epimerase deficiency
 Like the enzyme produced from GALT gene, the enzymes made from the GALK1 and
GALE genes play a role in processing galactose. A shortage of any of these critical
enzymes, allows galactose and related compounds to build up to toxic levels in the body.
The accumulation of these substances, damages tissues and organs, leading to the
characteristic features of Galactosemia

What are the Causes of Galactosemia? (Etiology)

 Galactosemia is caused by mutations in the GALE, GALK1, and GALT genes. These
genes are responsible for converting dietary galactose into energy, which the body can
use
 All Galactosemia types are genetic disorders inherited in an autosomal recessive pattern.
This means that both copies of the genes (one obtained from each of the parents) have to
be mutated to cause the disorder. If one gene is mutated and other is normal, then the
individual is considered to a carrier of the disorder; such carrier individuals, do not suffer
from signs and symptoms of Galactosemia
 The body's lack of ability to metabolize galactose, results in accumulation of toxic
substances in different parts of the body. These cause the signs and symptoms of
 Galactosemia, which also depend on the specific type (Type I, II, or III) of the disorder.
Higher the levels of toxic accumulation, greater are the severity of signs and symptoms
 Classic Galactosemia Type I is the most common type, with the most severe signs and
symptoms. In this type, mutation occurs in the GALT gene; there are two variants of
GALT gene mutations:
o In a majority of the cases, the mutations in GALT gene cause a total loss of
enzyme activity, leading to a complete lack of galactose metabolism in the body.
This results in life-threatening signs and symptoms
o In a minority of the cases, GALT gene mutation (called the Duarte variant)
decreases, but does not completely eliminate the activity of the enzyme.
Individuals with the Duarte variant, usually have much milder signs and
symptoms of Galactosemia
 Galactosemia Type II and Type III are caused by gene mutations, resulting in
galactokinase deficiency and galactose epimerase deficiency, respectively

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two
copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have
an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to
their children. If, however, only one mutant copy of the gene is inherited, the individual will be a
carrier of the condition, but will not be present with any symptoms. Children born to two
carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being
heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Galactosemia?

The signs and symptoms of Galactosemia depend on the type of the disorder. Type I has more
severe signs and symptoms, compared to Type II and Type III Galactosemia.

 In Type I Classic Galactosemia, the infants fed with galactose, accumulate toxic levels of
compounds quickly, resulting in life threatening complication within weeks. Such infants
should not be given any form of galactose, right from birth
 Signs and symptoms of Type I Classic Galactosemia include:
o Difficulties in feeding
o Lack of energy (lethargy)
o Failure to gain weight and grow as expected (failure to thrive)
o Jaundice due to liver failure, resulting in yellowing of the skin and white of the
eyes
o Bone marrow failure resulting in severe bacterial infections (sepsis)
o Bleeding
o Multi-organ failure
 In less severe cases, such as in Type II and Type III Galactosemia, the presentations
include:
o Cataracts
o Short stature
o Infertility
o Mental disabilities

How is Galactosemia Diagnosed?

A diagnosis of Galactosemia would involve:

 Physical exam with evaluation of medical history; neonates are usually screened for this
disorder, if the physician suspects the same
 Urine and blood exam - blood sugar and plasma, amino acid analysis
 Blood culture test, to detect any infection (due to bacteria)
 Genetic tests and analysis for mutations, in order to determine the exact type of the
condition
 Prenatal exams, in order to measure certain enzymes
Many clinical conditions may have similar signs and symptoms. Your healthcare provider may
perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Galactosemia?

Complications due to Galactosemia could include:

 Liver enlargement - could progressively lead to liver cirrhosis and liver failure
 Visual impairment from cataract
 Mental disabilities, delayed speech development
 Severe bacterial infection
 Low blood sugar
 Uncontrollable and involuntary bouts of muscle movement, tremors, lack of coordination
 Ovarian failure, resulting in infertility
 Reduced density of bones causing frequent fractures, even on ‘minimal-impact traumas’

How is Galactosemia Treated?

Management of Galactosemia is undertaken on a case-by-case basis, depending on the disorder
type, and severity of signs and symptoms. However, Galactosemia is a genetic condition that
cannot be cured.

The treatment measures considered are dependent upon the age of the individual, the disease
stage, and acuity of the symptoms. These include:

 Avoidance of galactose and lactose (in any form) completely from the diet; the mother’s
milk is substituted by a soy-based formulaic preparation
 Calcium supplementation (along with vitamin D), which is required for the development
of bones and muscles

How can Galactosemia be Prevented?

 Currently, there are no specific methods or guidelines to prevent Galactosemia genetic
condition
 Genetic testing of the expecting parents (and related family members) and prenatal
diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the
risks better during pregnancy
 If there is a family history of the condition, then genetic counseling will help assess risks,
before planning for a child
 Active research is currently being performed to explore the possibilities for treatment and
prevention of inherited and acquired genetic disorders
 Avoiding any food item that contains galactose (in any form) is very important, in
controlling the severity of the condition
 Regular medical screening at periodic intervals with tests and physical examinations are
mandatory for those affected by Galactosemia

What is the Prognosis of Galactosemia?

(Outcomes/Resolutions)
 Galactosemia is a genetic disorder that manifests at birth and having potential life-
threatening consequences. Early detection and strict avoidance of galactose are the two
key factors, to having a normal life
 Physical impairment and mental growth delays often accompanies this disorder; however,
the severity of Galactosemia can be controlled, with timely and appropriate medical care
 A delay in diagnosis of the disorder, leading to a delay in treatment, could be fatal during
the infancy stage
Galactosemia Test
Does this test have other names?
Galactosemia newborn screening test.

What is this test?

This test is part of screening done on all newborns. It looks for high levels of galactose and low
galactose-1 phosphate uridyltransferase (GALT) in your child's blood. This may mean your child
has a condition called galactosemia.

Galactosemia is a rare inherited disorder. It keeps the body from breaking down galactose.
Galactose is a sugar found in many foods and in all dairy products. An enzyme called GALT
normally breaks down galactose. Low levels of the enzyme causes the high galactose level in the
blood. Galactosemia can cause serious problems. These include an enlarged liver, kidney failure,
and brain damage.

Why does my child need this test?

This test is part of screening done on all newborns. If the newborn screening test is positive, it
doesn't mean your child has galactosemia. More tests are needed to make the diagnosis. If your
child has galactosemia, early treatment can help to prevent serious problems.

What other tests might my child have along with this test?
If your child has a positive galactosemia test, he or she may need other tests such as:

 Galactosemia reflex test

 Other GALT enzyme tests
 GALT gene blood panel
 Other gene blood tests

What do my child's test results mean?

Positive galactosemia test results usually mean that your child needs more blood tests. Negative
results usually mean your child doesn't need more tests to check for this condition. Test results
may vary depending on the method used for the test, and other things. Your child’s test results
may not mean he or she has a problem. Ask the healthcare provider what the test results mean for
your child.

How is this test done?

This test is done with a blood sample. This is usually taken by a heel prick in the first week of
life. For a heel prick, a small needle is used to poke the bottom of your baby’s foot. A small drop
of blood is taken and tested.

Does this test pose any risks?

Taking a blood sample with a needle carries risks. These include bleeding, infection, or bruising.

What might affect my child's test results?

Factors that may affect your child's newborn screening results include age, other health
problems, and treatment such as blood transfusions or total parenteral nutrition (TPN).