CHO Metabolic Disorders

8/3/2019 CHO Metabolic Disorders

1/23

CARBOHYDRATE METABOLISM-INHERITED DISORDERS

DR.D.RAMAKRISHNA


2/23

GALACTOSEMIA


3/23

OUTLINE

Galactose and Galactosemia

Genetics of Galactosemia

Galactose Metabolism

Types of Galactosemia

Signs and Symptoms

Diagnosis and Treatment

Pharmacy Connection


4/23

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.


5/23

GALACTOSE METABOLISM


6/23

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


7/23

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.


8/23

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


9/23

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)


10/23

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


11/23

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


12/23

TYPE II: GALACTOKINASE DEFICIENCY

Gene:galactokinase 1(GALK1) onchromosome 17

Enzyme:galactokinase 1


13/23

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


14/23

TYPE III: GALACTOSE EPIMERASE DEFICIENCY

Gene: UDP-galactose-4-epimerase(GALE) onchromosome 1

Enzyme: UDP-galactose-4-epimerase


15/23


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


16/23


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)


17/23

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


18/23

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


19/23

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


20/23

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.


21/23

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


22/23

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


23/23

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

Documents

CHO Metabolic Disorders