Inborn errors of carbohydrate metabolic disorders

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CARBOHYDRATE METABOLISM- INHERITED DISORDERS : 

CARBOHYDRATE METABOLISM- INHERITED DISORDERS DR.D.RAMAKRISHNA

GALACTOSEMIA : 

GALACTOSEMIA

OUTLINE : 

OUTLINE Galactose and Galactosemia Genetics of Galactosemia Galactose Metabolism Types of Galactosemia Signs and Symptoms Diagnosis and Treatment Pharmacy Connection

GALACTOSE : 

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 for energy in the Leloir pathway.

GALACTOSE METABOLISM : 

GALACTOSE METABOLISM

GALACTOSE METABOLISM: STEPS : 

GALACTOSE METABOLISM: STEPS Galactose is taken up by RBC and then converted to glucose via a 3 enzyme pathway known as the Leloir Pathway STEPS α-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

WHAT IS GALACTOSEMIA? : 

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 damage to their bodies due to a buildup of toxins. Lactose intolerance can develop later on in an individual’s life while galactosemia is evident at birth.

EPIDEMOLOGY : 

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 life Sex: M:F equal occurrence

Genetics of Galactosemia : 

Genetics of Galactosemia Autosomal Recessive Metabolic Disorder Genes for the 3 key enzymes are on different autosomal chromosomes ( 9, 17 and 1) Must inherit a defective allele from both parents to get galactosemia N - normal gene G - defective GALT gene N/N – normal / wildtype N/G - galactosemia carrier (reduced but sufficient amount of working enzyme) G/G - galactosemia (affected - insufficient amount of working enzyme)

TYPE I: CLASSIC GALACTOSEMIA : 

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 severely diminish or eliminate the activity of the enzyme causing galactosemia Accumulation of galactose 1-phosphate becomes toxic and causes many severe complications

TYPE I: CLASSIC GALACTOSEMIA : 

TYPE I: CLASSIC GALACTOSEMIA More than 190 mutations in the GALT 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 of African Descent Duarte variant Asparagine replaced with Aspartic acid (N314D) - 5% of general population - Reduces enzymatic activity by 50% - Milder symptoms

TYPE II: GALACTOKINASE DEFICIENCY : 

TYPE II: GALACTOKINASE DEFICIENCY Gene: galactokinase 1 (GALK1) on chromosome 17 Enzyme: galactokinase 1

TYPE II: GALACTOKINASE DEFICIENCY : 

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-term complications but cataracts common

TYPE III: GALACTOSE EPIMERASE DEFICIENCY : 

TYPE III: GALACTOSE EPIMERASE DEFICIENCY Gene: UDP-galactose-4-epimerase (GALE) on chromosome 1 Enzyme: UDP-galactose-4-epimerase

TYPE III: GALACTOSE EPIMERASE DEFICIENCY : 

TYPE III: GALACTOSE EPIMERASE DEFICIENCY The rarest of the three forms of galactosemia Galactose and related compounds can build up to toxic levels and accumulate in tissues Signs and symptoms vary from mild to severe

TYPE III: GALACTOSE EPIMERASE DEFICIENCY : 

TYPE III: GALACTOSE EPIMERASE DEFICIENCY reduces the activity of the enzyme throughout the cells of the body Complications: cataracts, intellectual disability, liver damage, kidney damage, brain damage reduces the activity of the enzyme in red blood cells only Complications: often will not see any of the complications that commonly occur in galactosemia Peripheral Form (Mild) Generalized Form (Severe)

COMPLICATIONS : 

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

SIGNS AND SYMPTOMS : 

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 the abdomen High Galactose concentrations in urine

DIAGNOSIS : 

DIAGNOSIS Infants are now routinely screened for galactosemia in the US and many provinces. The presence of reducing substances in the infant’s urine with normal or low blood sugar while the infant is being 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

TREATMENT AND PROGNOSIS : 

TREATMENT AND PROGNOSIS Early diagnosis and treatment of classical galactosemia is imperative to prevent life threatning complications. Avoid milk products and anything containing or galactose. 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.

PHARMACY CONNECTION : 

PHARMACY CONNECTION Lactose is commonly used as a filler in oral pharmaceutical preparations (tablet, capsules etc.) These products are contraindicated for people with galactosemia Pharmacist Roles: Knowledge of ingredients Provide alternative medications Signs and symptoms of galactosemia for detection in infants in hospitals

SUMMARY : 

SUMMARY Galactosemia is an autosomal recessive enzyme deficiency resulting in an inability to digest galactose. Mechanism β-d-galactose is epimerized to α-d-galactose by galactose mutarotase. α-d-galactose is phoshorylation to form galactose 1-phosphate by galactokinase Transfer of a UMP group from UDP-glucose to galactose 1-phosphate, thereby generating glucose 1-phosphate UDP-galactose is converted to UDP-glucose by UDP-galactose 4-epimerase to complete the pathway Types of Galactosemia: Classical (Type 1): Mutation on GALT gene (galactose-1-phosphate uridylyltransferase) most mutations reduce/eliminate activity of enzyme Type 2: Mutation on GALK1 gene (galactokinase 1); complications less severe than Type 1 Type 3: Mutation on GALE gene; rare form of disease Treatment: a galactose free diet with supplemental vitamins and minerals

REFERENCES : 

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 for Galactose 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, 2010 from 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

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