GALACTOSEMI A

BY:

GALACTOSE


A monosaccaride contained in milk Derived from hydrolysis of lactose Identical to glucose except exchanged orientation of -H and OH on C4

GALACTOSE


Along with glucose, composes lactose Component of cerebrosides and gangliosides, glycoproteins

GALACTOSEMIA


   

Inherited disorder characterized by the inability of the body to utilize galactose Galactosemia meaning galactose in blood Rare (1 in 60,000 US) but varies internationally Recognized and diagnosed in newborns High mortality rate in infants with sepsis caused by E. coli

METABOLIC REACTION OF GALACTOSE

GALACTOSE METABOLIC PATHWAY

http://www.biocarta.com/pathfiles/lactosePathway.asp

Galactose to Glucose Step 1



Destination: Galactose to Galactose-1phosphate Enzyme: Galactokinase What Happened? Galactose undergoes phosphorylation to produce galactose-1phosphate (1 ATP)

Galactose to Glucose Step 2



Destination: Galactose-1-phosphate to UDPgalactose Enzyme: Galactose-1-phosphate uridyltransferase (GALT) What happened?: Exchange reaction where UMP is removed from UDP-glucose (leaving behind glucose-1-phosphate) and then transferred to the galactose-1-phosphate producing UDP-galactose

GALACTOSE TO GLUCOSE STEP 3

 

Destination: UDP-galactose to UDP-glucose Enzyme: Uridine diphosphogalactose-4epimerase What happened?: epimerase enzyme changes stereochemistry of C4 in UDPgalactose to UDP-glucose

What happened to UDPgalactose



The UDP-galactose goes a different route and serves as a donor of galactose units to a number of pathways including the synthesis of lactose, glycoproteins, glycolipids, and cosaminoglycans.

Galactose to Glucose


UDP-Glucose will next be released as Glucose-1-phosphate Phosphoglucomutase converts glucose-1phosphate to glucose-6-phosphate Glucose-6-phosphate enters glycolysis to generate energy

Glucose + Galactose = Lactose

http://biocarta.com/pathfiles/LactosePathway.asp

Galactose Synthesis
 

For GLYCOPROTEINS Galactosyl transferase catalyzes formation of glycosidic bond between galactose and Nacetyl-D-glucosamine to create Nacetyllactosamine (D-galactosyl-N-acetyl-Dglucosamine) found in the oligosaccharides of glycoproteins

Galactose Synthesis
 

For LACTOSE Galactosyl transferase can only be produced in mammary glands because it does not have the specificity to produce lactose. The complete lactose synthase complex includes galactosyl transferase and alpha-lactalbumin. With alpha-lactalbumin, galactosyl transferase specificity is switched to use glucose, resulting in lactose production

Types of Galactosemia
 Galactose 1-phosphate uridyl transferase 1deficiency galactosemia  Galactokinase deficiency  Uridine diphosphate galactose 44epimerase (UDP Gal 4-epimerase) 4deficiency

Galactose 1-phosphate uridyl 1transferase deficiency galactosemia

 Classic galactosemia is a serious disease with an Classic early onset of symptoms  The incidence is 1 in 60,000, therefore, it is a quite rare disease  The newborn infant normally receives up to 20% of caloric intake as lactose (from milk), which consists of glucose and galactose  Without uridyl transferase, the infant is unable to metabolize galactose 1-phosphatethe accumulation 1-phosphate of galactose 1-phosphate results in injury to 1parenchymal cells to the kidney, liver, and brain

Galactose 1-phosphate uridyl 1transferase deficiency galactosemia

 Galactosemia caused by uridyl transferase deficiency is inherited as an autosomal recessive trait, therefore, it is trait, a hereditary disease of the newborn  The gene for galactose-1-phosphate uridyl transferase is galactoselocated on chromosome 9p13.  African-American patients have milder symptoms African(despite the absence of measurable transferase activity in erythrocytes) and retain 10% of enzyme activity in the liver and intestinal mucosa  Caucasian patients have no detectable enzyme activity in any of these tissues

Galactokinase Deficiency
 In contrast to the multiple systems that are affected in uridyl transferase deficiency, cataracts are usually the sole manifestation of galactokinase deficiency.  The affected infant is otherwise asymptomatic.  This disorder is characterized by elevated blood galactose levels with normal uridyl transferase activity and an absence of galactokinase activity in erythrocytes.  Treatment is dietary restriction of galactose intake.  Mutations leading to galactokinase deficiency have been identified in the gene coding for galactokinase (located on chromosome 17q24).

Uridine diphosphate galactose 44epimerase (UDP Gal 4-epimerase) 4deficiency

 Aside from the accumulated metabolites in uridyl transferase deficiency, this type of galactosemia shows an increase in cellular UDP galactose.  2 forms of epimerase deficiency: 1. A benign form wherein the patients are healthy; the enzyme deficiency is limited to leukocytes and erythrocytes, without deranged metabolism in other tissues, and no treatment is required. 2. A rare and severe form with clinical manifestations resembling uridyl transferase deficiency with hypotonia and nerve deafness  The gene for epimerase is located in chromosome 1p35-36; 1p35mutations responsible for both forms of the epimerase deficiency have been identified.

What are the biochemical effects of galactosemia and their corresponding clinical symptoms? What are the molecular explanation for these?

Galactosemia
   

Metabolic abnormality Inherited as an autosomal recessive trait Asymptomatic in heterozygous individuals Not a sexlinked disorder

Molecular effects of Galactose Deficiency

GALT DEFICIENCY

short arm of chromosome 9 causes UDP-hexose deficit in human galactosemic cells most common deficiency


GALACTOKINASE DEFICIENCY

long arm of chromosome 17

Symptomatic Effects of Galactosemic Deficiencies

Classical Galactosemia
    

cataract formation mental retardation liver cirrhosis jaundice impaired renal tubular transport of amino acids

Galactokinase deficiency
  

cataract no mental retardation no neonatal symptoms

UDPG-4-epimerase deficiency
 

asymptomatic usually in RBC

Effects and Symptoms of Galactosemia

EFFECTS
  

Infertility (appears to affect only women ) Learning disabilities Impairment of motor function (affict both sexes equally) Jaundice Cataracts Liver enlargement Vomiting Mental retardation

SYMPTOMS
    

Cataract Formation
When presented with accumulated galactose, this enzyme (aldose reductase) reduces the aldehydic end group and produces galactitol, the analogous sugar alcohol This compound exerts osmotic pressure within the lens because it diffuses very slowly While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most observers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation In type 1 and type 2 cataracts develop secondary to galactitol accumulation in the lens.

Cataract Formation

In transferase-deficient galactosemia, galactose-1phosphate accumulates, while in kinase deficiency, galactose-1-phosphate cannot be produced. In the mechanism that produces galactose-related cataracts, the lens contains the aldose reductase enzyme

Tests for Galactosemia

Tests for Galactosemia

Tests for Galactosemia

Tests for Galactosemia

Diagnosis of Galactosemia
 The preliminary diagnosis of galactosemia is made by demonstrating a reducing substance (by Clinitest) in urine specimens collected while the patient is receiving human or cows milk or another milk formula containing lactose. cow  The reducing substance found in the urine, which is negative in a glucose oxidase test, can be identified as galactose.  Definitive diagnosis requires the demonstration of deficient activity of galactose-1-phosphate uridyl transferase in galactoseerythrocytes or other tissues, which also exhibit increased concentrations of galactose-1-phosphate. galactose-

Discuss the treatment of galactosemia

Once the disease is recognized, the only treatment for classic galactosemia is eliminating lactose and galactose from the diet. It is very important to be aware of the ingredients in the food that is bought for the sufferer. With continued dietary management, however, many individuals with galactosemia enjoy good health, and are able to lead independent lives.

Treatment for infant

The first step in treatment is to remove the baby from breast milk and commercial formula. Soy-based formulas, meat-base formula, or Nutramigen , or other lactose-free formula, that contain no galactose should be substituted into the babys diet. Individuals with galactosemia must remain on a restricted diet and maintain low blood galactose levels throughout life.

Dietary Management of Galactosemia

The dietary treatment of galactosemia is to remove any foods containing galactose from the diet . All milk and foods containing milk products must be totally eliminated. Other foods like legumes, organ meats, and processed meats also contain considerable galactose and must be avoided.

FOOD LABELS:
The labels of all processed foods must be read carefully for ingredients which are milk products . Since actual products change on a regular bases it is imperative that you re-read every label every time you buy .

MEDICINE
Pills that use lactose as a filler must also be avoided .
Lactose is often used as a filler or inactive ingredient in medicines, and might not be listed on the package . If possible, have a pharmacist be aware of what medication ingredients are unacceptable to you. ( This is the most effective way of avoiding galactose-containing medications )

Patient Education
Dietary therapy requires both parental and patient education. Involve children in their dietary management as soon as appropriate.

Nutritional concerns

Dietary supplements should be taken only when recommended by your doctor or health care professional . Since the primary source of calcium is usually milk or milk-based foods, calcium must be supplemented.
Need to supplementary : Vit.B , ex Vit.D

Why can galactosemic patients tolerate milk and other galactose containing products once they are adults?

Galactosemia and Lactose Intolerance

Galactosemia is sometimes confused with lactose intolerance. Galactosemia
 

more serious condition galactosemic individual who consumes galactose can cause permanent damage to their bodies. Individuals have an acquired or inherited shortage of the enzyme lactase Experience abdominal pains after ingesting dairy products, but no long-term effects

Lactose intolerance
 

Why can galactosemic patients tolerate milk & other galactose containing products once they are adults?

Galactose disposal by oxidation from 13C-label enrichment in plasma galactose and expired carbon dioxide accounts for about 99% of body galactose disposal. Less then 2% of endogenous galactose were found disposed by the Kidneys In patients exhibiting GALT activity in RBC of less than 1% of control, the release of galactose from endogenous intracellular sources ranged from 10 to 20 mg/kg body weight. In addition, about 3 to 10 mg/kg body weight of galactose was obviously converted intracellular to yield galactitol prior to release into the plasma compartment and subsequent excretion by the kidneys. Thus estimates for total endogenous galactose production ranged from 12 to 25 mg/kg body weight.

Free galactose is produced from endogenous sources at a physiologically relevant rate in galactosemia. Endogenous galactose production decreases significantly with age. Normal galactose turnover rates can be achieved at low residual GALT activities.