cho metabolic disorders
TRANSCRIPT
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CARBOHYDRATE METABOLISM-INHERITED DISORDERS
DR.D.RAMAKRISHNA
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GALACTOSEMIA
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OUTLINE
Galactose and Galactosemia
Genetics of Galactosemia
Galactose Metabolism
Types of Galactosemia
Signs and Symptoms
Diagnosis and Treatment
Pharmacy Connection
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GALACTOSE
Galactose is a sugar that is found in many foods.
When lactose is broken down in the body, glucose
and galactose are produced.
Galactose is converted into glucose in the body forenergy in the Leloir pathway.
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GALACTOSE METABOLISM
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GALACTOSE METABOLISM: STEPS
Galactose is taken up by RBC and then converted to glucose via a 3enzyme pathway known as the Leloir Pathway
STEPS
1. -D-galactose is phoshorylated to galactose 1-phosphate by
galactokinase (GALK)
2. A UMP group is transferred from UDP-glucose to galactose 1-
phosphate, generating glucose 1-phosphate and UDP-galactose by
galactose-1-phosphate uridyltransferase (GALT)
glucose 1-phosphate proceeds into glycolysis
3. UDP-galactose is converted to UDP-glucose by UDP-galactose 4-
epimerase (GALE) to complete the pathway
Galactosemia occurs when mutations lead to a deficiency in any one
of these enzymes
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WHAT IS GALACTOSEMIA?
Means galactose in the blood
It is an inherited autosomal recessive enzyme
deficiency resulting in the inability to digest
galactose. This leads to various complications and
can result in death
Galactosemia can be confused with lactose
intolerance but galactosemia is a more serious
condition because a galactosemic individual who
consumes galactose can cause permanent damageto their bodies due to a buildup of toxins.
Lactose intolerance can develop later on in an
individuals life while galactosemia is evident at
birth.
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EPIDEMOLOGY
Incidence:
Type 1: 1/30,000 to 1/60,000 for classic galactosemia
Type 2: Less common, fewer than 1/100,000
Type 3: Very rare
Age:
Neonatal onset, some complications evident later on
in lifeSex:
M:F equal occurrence
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Genetics of
Galactosemia
Autosomal Recessive Metabolic Disorder
Genes for the 3 key enzymes are ondifferent autosomal chromosomes
( 9, 17 and 1)
Must inherit a defective allele from
both parents to get galactosemia
N - normal gene
G - defective GALT gene
1. N/N normal / wildtype
2. N/G - galactosemia carrier(reduced butsufficient amount of working enzyme)
3. G/G - galactosemia (affected - insufficientamount of working enzyme)
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TYPE I: CLASSIC GALACTOSEMIA
The most common form (95%)
Most severe form
Mutations in the GALT gene located
on short arm of chromosome 9 Codes for the enzyme galactose-1-
phosphate uridyltransferase
Most of these mutations severelydiminish or eliminate the activity of
the enzyme causing galactosemiaAccumulation of galactose 1-
phosphate becomes toxic andcauses many severe complications
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TYPE I: CLASSIC GALACTOSEMIA
More than 190 mutations in theGALT gene have been identified
Glutamine replaced with Arginine(Q188R)
- most common mutation
- most common in Caucasians
Serine replaced with Leucine(S135L)
- most common in people ofAfrican Descent
Duarte variantAsparagine replacedwith Aspartic acid (N314D)
- 5% of general population
- Reduces enzymatic activityby 50%
- Milder symptoms
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TYPE II: GALACTOKINASE DEFICIENCY
Gene:galactokinase 1(GALK1) onchromosome 17
Enzyme:galactokinase 1
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TYPE II: GALACTOKINASE DEFICIENCY
over 20 different mutations have been identified The mutations in GALK1 alter the enzyme
preventing galactose from being processed Galactose and other compounds can build up to
toxic levels and accumulate in tissues
Fewer long-termcomplications butcataracts common
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TYPE III: GALACTOSE EPIMERASE DEFICIENCY
Gene: UDP-galactose-4-epimerase(GALE) onchromosome 1
Enzyme: UDP-galactose-4-epimerase
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TYPE III: GALACTOSE EPIMERASE DEFICIENCY
The rarest of the three forms ofgalactosemia
Galactose and related
compounds can build up totoxic levels and accumulate intissues
Signs and symptoms vary frommild to severe
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TYPE III: GALACTOSE EPIMERASE DEFICIENCY
reduces the activity of theenzyme throughoutthecells ofthe body
Complications: cataracts,
intellectual disability, liverdamage, kidney damage,brain damage
reduces the activity of theenzyme in red blood cellsonly
Complications: often will
not see any of thecomplications thatcommonly occur ingalactosemia
Peripheral Form
(Mild)
Generalized Form
(Severe)
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COMPLICATIONS
Renal Dysfunction
Premature Ovarian
Failure
Poor growth and
balance
Delayed speech
development
Mental retardation
Death
Vomiting
Hepatomegaly
Lethargy Diarrhea
Increased susceptibility
to bacterial infections
Hemolytic anemia Cataracts
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SIGNS AND SYMPTOMS
At birth: Jaundice after
milk consumption
Aminoaciduria: High
levels of amino acids in
urine and/or plasma
Hepatomegaly
Hypoglycemia
Ascites - fluid
accumulation in theabdomen
High Galactose
concentrations in urine
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DIAGNOSIS
Infants are now routinely screened for galactosemia in
the US and many provinces.
The presence of reducing substances in the infants
urine with normal or low blood sugar while the infant isbeing fed breast milk or a formula containing lactose. A
simple urine test indicates the presence of a reducing
substance and a specific enzymatic study on the urine
can prove the substance to be galactose.
Measurement of enzyme activity in the red blood cells(fluorometric assay and Beutler assay)
Prenatal diagnosis by direct measurement of the
enzyme galactose-1-phosphate uridyl transferase
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TREATMENT AND PROGNOSIS
Early diagnosis and treatment of classical
galactosemia is imperative to prevent life threatning
complications.
Avoid milk products and anything containing orgalactose. For infants, milk can be substituted with
lactose-free formula or soy formula.
Calcium and vitamin supplements are
recommended.
Even with a diet lacking lactose and galactose,
afflicted individuals still encounter nervous system
damage and may develop mild intellectual
impairments such as delayed speech development.
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PHARMACY CONNECTION
Lactose is commonly used asa filler in oral pharmaceuticalpreparations (tablet, capsulesetc.)
These products arecontraindicated for people withgalactosemia
Pharmacist Roles:
1. Knowledge of ingredients
2. Provide alternativemedications
3. Signs and symptoms ofgalactosemia for detection in
infants in hospitals
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SUMMARY
Galactosemia is an autosomal recessive enzyme deficiencyresulting in an inability to digest galactose.
Mechanism1. -d-galactose is epimerized to -d-galactose by galactose mutarotase.
2. -d-galactose is phoshorylation to form galactose 1-phosphate bygalactokinase
3. Transfer of a UMP group from UDP-glucose to galactose 1-phosphate,thereby generating glucose 1-phosphate
4. UDP-galactose is converted to UDP-glucose by UDP-galactose 4-epimerase to complete the pathway
Types of Galactosemia:y Classical (Type 1): Mutation on GALT gene (galactose-1-phosphate
uridylyltransferase) most mutations reduce/eliminate activity of enzyme
y Type 2: Mutation on GALK1 gene (galactokinase 1); complications lesssevere than Type 1
y Type 3: Mutation on GALE gene; rare form of disease
Treatment: a galactose free diet with supplemental vitamins andminerals
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REFERENCES
ARUP Laboratories. 2009. Galactosemia. Retreived January 23, 2010 from
http://www.arupconsult.com/Topics/Galactosemia.html
Galactosemia. Retrieved January 20, 2010 from Genetics Home Reference website:
http://ghr.nlm.nih.gov/condition=galactosemia
Gerard T Berry, MD (2008). Galactose-1-Phosphate Uridyltransferase Deficiency
(Galactosemia). Retrieved January 20, 2010 from eMedicine website:
http://emedicine.medscape.com/article/944069-overview
Holden M. Hazel et al. 2003. Structure and Function of Enzymes of the Leloir Pathway
forGalactose Metabolism. Retrieved January 23, 2010 from
http://www.jbc.org/content/278/45/43885.full
Medline Plus. 2010. Galactosemia. Retrieved January 19, 2010 from Medline Plus
Website: http://www.nlm.nih.gov/medlineplus/ency/article/000366.htm
Merck Manual. 2010. Carbohydrate Metabolism Disorders. Retrieved January 19, 2010from Merck Website: http://www.merck.com/mmpe/sec19/ch296/ch296d.html
Stryer, L., Berg, J., & Tymoczko, J. (2007). Biochemistry (6th ed.).New York: W.H.
Freeman and Company