Inborn Errors of Carbohydrate Metabolism

Submitted by:
Samaniego, Jillian U.
BSMT 3-2
Submitted to:
Mr. Jion P. Dimson, RMT

August 25, 2015

Galactosemia

Galactosemia is a condition in which the body is unable to use (metabolize) the simple
sugar galactose.
Causes
Galactosemia is an inherited disorder. This means it is passed down through families. If
both parents carry an abnormal gene that can cause galactosemia, each of their children has a
25% chance of being affected.
It occurs in approximately 1 of every 60,000 births among Caucasians. The rate is different for
other groups.
There are three forms of the disease:

Galactose-1 phosphate uridyl transferase deficiency (classic galactosemia,

the most common and most severe form)
Deficiency of galactose kinase
Galactokinase deficiency, also known as Galactosemia type 2 or GALK deficiency, is
an autosomal recessivemetabolic
disorder marked
by
an
accumulation
of galactose and galactitol secondary to the decreased conversion of galactose to galactose-1phosphate by galactokinase. The disorder is caused by mutations in the GALK1 gene, located
on chromosome 17q24. Galactokinase catalyzes the first step of galactose phosphorylation in the
Leloir pathway of intermediate metabolism. Galactokinase deficiency is one of the three inborn
errors of metabolism that lead to hypergalactosemia. The disorder is inherited as
an autosomal recessive trait. Unlike classic galactosemia, which is caused by deficiency of
galactose-1-phosphate uridyltransferase, galactokinase deficiency does not present with severe
manifestations in early infancy. Its major clinical symptom is the development
of cataracts during the first weeks or months of life, as a result of the accumulation, in the lens,
of galactitol, a product of an alternative route of galactose utilization. The development of early
cataracts in homozygous affected infants is fully preventable through early diagnosis and
treatment with a galactose-restricted diet. Some studies have suggested that, depending on milk
consumption later in life, heterozygous carriers of galactokinase deficiency may be prone to
presenile cataracts at 2050 years of age.

Deficiency of galactose-6-phosphate epimerase

Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III
and UDP-galactose-4-epimerase
deficiency,[2] is
a
rare, autosomal recessive form
of galactosemia associated with a deficiency of theenzyme galactose epimerase.
People with galactosemia are unable to fully break down the simple sugar galactose.
Galactose makes up half of lactose, the sugar found in milk. The other sugar is glucose.

If an infant with galactosemia is given milk, substances made from galactose build up in the
infant's system. These substances damage the liver, brain, kidneys, and eyes.
Persons with galactosemia cannot tolerate any form of milk (human or animal). They
must be careful about eating other foods containing galactose.
Symptoms
Infants with galactosemia can develop symptoms in the first few days of life if they eat
formula or breast milk that contains lactose. The symptoms may be due to a serious blood
infection with the bacteria E. coli.
Convulsions
Irritability
Lethargy
Poor feeding (baby refuses to eat formula containing milk)
Poor weight gain
Yellow skin and whites of the eyes (jaundice)
Vomiting
Exams and Tests
Signs include:
Amino acids in the urine and/or blood plasma (aminoaciduria)
Enlarged liver (hepatomegaly)
Fluid in the abdomen (ascites)
Low blood sugar (hypoglycemia)
Newborn screening in many states will test for this condition.
Tests include:
Blood culture for bacterial infection (E. coli sepsis)
Enzyme activity in the red blood cells
Ketones in the urine
Prenatal diagnosis by directly measuring the enzyme galactose-1-phosphate uridyl
transferase
"Reducing substances" in the infant's urine, and normal or low blood sugar while the
infant is being fed breast milk or a formula containing lactose
Treatment
People with this condition must avoid all milk, milk-containing products (including dry
milk), and other foods that contain galactose for life. It is essential to read product labels and be
an informed consumer.
Infants can be fed with:
Soy formula
Meat-based formula or Nutramigen (a protein hydrolysate formula)
Another lactose-free formula

Calcium supplements are recommended.

Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a hereditary condition in

which red blood cells break down when the body is exposed to certain drugs or the stress of
infection.
Causes
G6PD deficiency occurs when a person is missing or doesn't have enough of an enzyme
called glucose-6-phosphate dehydrogenase, which helps red blood cells work properly. Too little
G6PD leads to the destruction of red blood cells. This process is called hemolysis. When this
process is actively occurring, it is called a hemolytic episode. The episodes are usually brief,
because the body continues to produce new red blood cells, which have normal activity.
Red blood cell destruction can be triggered by infections, severe stress, certain foods (such as
fava beans), and certain drugs, including:

Antimalarial drugs
Aspirin
Nitrofurantoin
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Quinidine
Quinine
Sulfa drugs

Other chemicals, such as those in mothballs, can also trigger an episode. In the United States,
G6PD deficiency is more common among blacks than whites. Men are more likely to have this
disorder than women.
You are more likely to develop this condition if you:

Are African American

Are of Middle Eastern decent, particularly Kurdish or Sephardic Jewish
Are male
Have a family history of the deficiency
A form of this disorder is common in whites of Mediterranean descent. This form is also
associated with acute episodes of hemolysis. Episodes are longer and more severe than in
the other types of the disorder.

Symptoms

Persons with this condition do not display any signs of the disease until their red blood
cells are exposed to certain chemicals in food or medicine, or to stress.
Symptoms are more common in men and may include:
Dark urine
Enlarged spleen
Fatigue
Pallor
Rapid heart rate
Shortness of breath
Yellow skin color (jaundice)
Exams and Tests

A blood test can be done to check the level of G6PD.

Other tests that may be done include:
Bilirubin level
Complete blood count, including red blood cell count
Hemoglobin - blood
Hemoglobin - urine
Haptoglobin level
LDH test
Methemoglobin reduction test
Reticulocyte count

Treatment

Treatment may involve:

Medicines to treat an infection, if present
Stopping any drugs that are causing red blood cell destruction
Transfusions, in some cases

Hereditary Fructose Intolerance

Hereditary fructose intolerance is a disorder in which a person lacks the protein needed to
break down fructose. Fructose is a fruit sugar that naturally occurs in the body. Man-made
fructose is used as a sweetener in many foods, including baby food and drinks.
Causes

This condition occurs when the body is missing an enzyme called aldolase B. This
substance is needed to break down fructose. If a person without this substance eats fructose and
sucrose (cane or beet sugar, table sugar), complicated chemical changes occur in the body. The
body cannot change its energy storage material, glycogen, into glucose. As a result, the blood
sugar falls and dangerous substances build up in the liver. Hereditary fructose intolerance is
inherited, which means it is possible to be passed down through families. If both parents carry an
abnormal adolase B gene, each of their children has a 25% chance of being affected. The
condition may be as common as 1 in 20,000 people in some European countries.
Symptoms
Symptoms can be seen after a baby starts eating food or formula. The early symptoms of
fructose intolerance are similar to those of galactosemia. Later symptoms relate more to liver
disease.
Symptoms may include:
Convulsions
Excessive sleepiness
Irritability
Jaundice
Poor feeding as a baby
Problems after eating fruits and fructose/sucrose-containing foods
Vomiting
Exams and Tests

Physical examination may show:

Enlarged liver and spleen (hepatosplenomegaly)
Yellow skin or eyes
Tests that confirm the diagnosis include:
Blood clotting tests
Blood sugar test
Enzyme studies
Genetic testing
Kidney function tests
Liver function tests
Liver biopsy
Uric acid blood test
Urinalysis
Blood sugar will be low, especially after receiving fructose or sucrose. Uric acid levels
will be high.

Treatment

Removing fructose and sucrose from the diet is an effective treatment for most patients.
Complications are treated. For example, some patients can take medication to lower the level of
uric acid in their blood and decrease their risk for gout.

Fructose 1,6-Diphosphatase Deficiency

Glucose homeostasis is essential for life. Because most of an organism's life is spent in a
fasting state (ie, between meals), no fewer than 3 major mechanisms have evolved to maintain
glucose homeostasis during a fast. These mechanisms are gluconeogenesis, glycogenolysis, and
lipolysis.
In the immediate postprandial period, glycogenolysis represents the major homeostatic
process to maintain euglycemia. In neonates, gluconeogenesis is particularly important for
maintaining euglycemia. Fructose 1,6-diphosphatase (FDPase) (also termed fructose 1,6bisphosphatase) is a focal enzyme in gluconeogenesis via its conversion of fructose 1,6diphosphate (FDP) to fructose 6-phosphate (F-6-P), which permits endogenous glucose
production from gluconeogenic amino acids (eg, alanine and glycine), glycerol, or lactate.
Deficiency of hepatic FDPase was first confirmed in 1970 by Baker and Winegrad. They
reported the dramatic clinical picture of acidosis in response to D-fructose challenge.
Of broader clinical interest, excess hepatic FDPase action contributes to hyperglycemia in
patients with type 2 diabetes. The development of specific FDPase inhibitors has opened a novel
avenue for treating patients with type 2 diabetes.
FDPase catalyzes the conversion of FDP to F-6-P, which is a central step in
gluconeogenesis. When challenged with D-fructose, patients lacking FDPase accumulate
intrahepatocellular FDP, which inhibits gluconeogenesis and, if intracellular phosphate stores are
depleted, inhibits glycogenolysis. The inability to convert lactic acid or glycerol into glucose
leads to hypoglycemia, lactic acidosis, and glyceroluria.

Pyruvate Carboxylase Deficiency

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other
potentially toxic compounds to accumulate in the blood. High levels of these substances can
damage the body's organs and tissues, particularly in the nervous system.

Researchers have identified at least three types of pyruvate carboxylase deficiency, which
are distinguished by the severity of their signs and symptoms. Type A, which has been identified
mostly in people from North America, has moderately severe symptoms that begin in infancy.
Characteristic features include developmental delay and a buildup of lactic acid in the blood
(lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme
tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic
acidosis are triggered by an illness or periods without food (fasting). Children with pyruvate
carboxylase deficiency type A typically survive only into early childhood.
Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that
become apparent shortly after birth. This form of the condition has been reported mostly in
Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia
in the blood (hyperammonemia), and liver failure. They experience neurological problems
including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with
this form of the condition usually survive for less than 3 months after birth.
A milder form of pyruvate carboxylase deficiency, sometimes called type C, has also
been described. This type is characterized by slightly increased levels of lactic acid in the blood
and minimal signs and symptoms affecting the nervous system.

Glycogen Storage Disease

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of
defects in the processing ofglycogen synthesis or breakdown within muscles, liver, and other cell
types. GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn
error of metabolism (genetically defective enzymes) involved in these processes. In livestock,
acquired GSD is caused by intoxication with the alkaloid castanospermine.
Overall, according to a study in British Columbia, approximately 2.3 children per 100
000 births (1 in 43,000) have some form of glycogen storage disease. In the United States, they
are estimated to occur in 1 per 20,000-25,000 births. A Dutch study estimated it to be 1 in
40,000.
There are eleven (11) distinct diseases that are commonly considered to be glycogen
storage diseases (some previously thought to be distinct have been reclassified).
(Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver,
it is often classified with the GSDs as type 0 because it is another defect of glycogen storage and
can cause similar problems.).

GSD type VIII: In the past, considered a distinct condition. Now classified with VI. Has
been described as X-linked recessive.

GSD type X: In the past, considered a distinct condition. Now classified with VI.

References:

Berry GT, Walter JH. Disorders of Galactose Metabolism. In: Saudubray JM, van den Berghe G,
Walter JH, eds.Inborn Metabolic Diseases: Diagnosis and Treatment

Gregg XT, Prchal JT. Red blood cell enzymopathies. In: Hoffman R, Benz Jr. EJ, Shattil SJ, et al.,
eds.Hematology: Basic Principles and Practice.

Golan DER. Hemolytic anemias: red cell membrane and metabolic defects. In: Goldman L,
Ausiello D, eds.Goldman's Cecil Medicine.

Steinmann B, Santer R. Disorders of Fructose Metabolism. In: Saudubray JM, van den Berghe G,
Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th ed. New York, NY:
Springer; 2012:chap 9.

http://dwb.unl.edu/Teacher/NSF/C11/C11Links/web.indstate.edu/thcme/mwking/non-glucosemetabolism.html