inborn errors of carbohydrate metabolism

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INBORN ERRORS OF METABOLISMTapeshwar Yadav (Lecturer) BMLT, DNHE, M.Sc. Medical Biochemistry


Inborn errors of metabolismDefinition:- These are a group of rare genetic disorders in which the body cannot metabolize food components normally. These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down very essential biochemical components.


What is a metabolic disease?Garrods hypothesis

product deficiencySubstrate excess toxic metaboliteADBC


What is a metabolic disease?According to Garrods hypothesis A genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block that may have pathologic consequences at birth (e.g. phenylketonuria) or in later life (e.g. diabetes mellitus); also called enzymopathy and genetotrophic disease.




Mitochondrial inheritance :-Lebers hereditary optic neuropathy is caused by complex-I defect in ETC, leads to blindness, cardiac conduction defects.Leighs syndrome :- Complex I defect, leads movement disorders.Mitochondrial myopathies :- Defects in mitochondrial genome will lead to mitochondrial myopathies such as myoclonic epilepsy and myopathy dementia.Complex-I defect also causes lactic acidosis, strokes and seizures.







Inborn errors of Carbohydrate Metabolism


CategoriesHemolytic anemias caused by deficiencies of-HexokinasePyruvate kinaseGlucose-6-(P)-dehydrogenasePyruvate dehydrogenase deficiency.Carbohydrate intolerance disorders-Lactose intolerance.Fructose intolerance.Fructosuria.Galactosemia.Pentosuria.Glycogen storage disorders.Mucopolysaccharidoses.


1) Hemolytic anemia caused by different enzyme deficiencies:


A. Hexokinase deficiency:This is very rare among all the hemolytic disorders.Glycolysis in the RBC is linked with 2,3-BPG production, essential for the oxygen transport.In the deficiency of the hexokinase, the synthesis and concentration of 2,3-BPG are low in RBC, so the oxygen unload to the tissues decreased, condition leads to Hemolysis.


B. Pyruvate kinase deficiency:It is an autosomal recessive disorder and most common red cell enzymopathy after G-6-PD deficiency.PK catalyses the conversion of phosphoenolpyruvate to pyruvate with the generation of ATP.Inadequate ATP generation leads to premature red blood cell death (Prickle cells).On the other hand in the patients with pyruvate kinase deficiency the level of 2,3-BPG in RBC is high, resulting in low oxygen affinity of Hb observed.


Blood film: PK deficiency: Characteristic "prickle cells" can be seen.


C. Glucose-6-phosphate dehydrogenase deficiency :G-6-PD deficiency is a X-linked recessive disorder.Frequency is 1 in 5,000 births.The deficiency occur in all the cells of affected individuals.But it is more severe in RBCs.RBCs depend only on HMP shunt for their NADPH requirement.G-6PD deficiency leads impaired NADPH production, so oxidized glutathione is not converted to its reduced form.


Low NADPH concentration also results the accumulation of methemoglobin and peroxides in RBC, causes loss of RBC membrane integrity.Till now it is mostly asymptomatic.


But when the enzyme deficient subjects exposed to severe infection, administered oxidant drugs such asAnti-malarial (Primaquine)Anti-biotic (Sulfamethoxazole)Acetanilide (Antipyretic)Favism :- Ingestion of FAVA beans.Leads to Hemolytic anemia.


2) Pyruvate dehydrogenase deficiency:-Frequency is 1 in 2,50,000 births.Main symptom is lactic acidosis.Neuronal loss in brain.Muscular hypotonia.


3) Carbohydrate intolerance disorders


A. Hereditary Lactose intolerance :-It is a rare disorder, due to the deficiency of Lactase (-Galactosidase) enzyme.Symptoms - Diarrhea, inadequate nutrition and fluid & electrolyte disturbances.Prominent feature is Lactosuria (Lactose in urine).Milk is not digested in the individuals so milk products are preferred.


B. Hereditary Fructose intolerance :-It is an autosomal recessive disorder.Incidence is 1 in 20,000.1 in 70 persons are carriers of abnormal gene.The defect is Adolase-B (fructose-1-(P) aldolase)Fructose -1(P) cannot be metabolized.Fructose-1(P)Glyceraldehyde + DHAP.


It leads to accumulation of fructose-1-(P),severe hypoglycemia, vomiting, hepatic failure and jaundice.Fructose-1-(P) allosterically inhibits liver phosphorylase and blocks glycogenolysis leading to hypoglycemia.Treatment :- Early detection and intake of diet free from fructose and sucrose, are advised to overcome fructose intolerance.


4) Essential fructosuria :-Due to the deficiency of fructokinase, fructose is not converted to fructose-1-(P).FructoseFructose-1-(P).This is an asymptomatic condition with excretion of fructose in urine.


5) Galactosemia:-It is a serious serious autosomal recessive disorder resulting from the deficiency of galactose-1-(P) uridyltransferase, leads to accumulation of Galactose-1-(P) in the liver and becomes toxic.Incidence is one in 35,000 births.Galactose -1-(P) UDP Galactose.


Symptoms:The build up of galactose and the other chemicals can cause serious health problems likeSwollen and inflamed liver, Kidney failure, Stunted physical and mental growth, and Cataracts in the eyes.If the condition is not treated there is a 70% chance that the child could die. Treatment :- Galactose free diet is preferred i.e. milk will be avoided.



6) Essential pentosuria :It is a rare autosomal recessive disorder and benign condition, asymptomatic.Individuals does not show any ill-effects.Incidence is one in 2,500 births.Primarily in Jewish population.


Lack Xylitol dehydrogenase leads to excretion of larger amounts of L-Xylulose in urine.L-XyluloseXylitolIt is also reported after administration of drugs such as,Aminopyrine.Antipyrine.


7) Glycogen storage diseases :The metabolic defects concerned with the glycogen synthesis and degradation are collectively called as GSD.All Glycogen storage disorders are Autosomal recessive disorders (except Type-VIII)Incidence estimated to be between 1 in 1 lack to 1 million births per year in all ethnic groups.


DisorderEnzymeAffected TissueType I(von Gierkes disease)Glucose-6-phosphataseLiver, kidney, intestine

Type II (Pompes disease)Lysosomal 1,4- glucosidase (Acid maltase)All organsType III(Coris disease)Amylo 1,6- glucosidase (debranching enzyme)Liver, muscle, heart, leukocytesType IV(Andersons disease)Glucosyl 4,6-transferaseMost tissuesType V(Mc Ardles disease)Muscle glycogen phosphorylaseSkeletal muscleType VI(Hers disease)Liver glycogen phosphorylaseLiverType VII(Tauris disease)PhosphofructokinaseSkeletal muscle, erythrocytes.


DisorderIncidence in births (1 out of) Chromosome locationType I(von Gierkes disease)1,00,00017Type II (Pompes disease)1,75,00017Type III(Coris disease)1,25,0001Type IV(Andersons disease)1 million3Type V(Mc Ardles disease)1 million11Type VI(Hers disease)1 million14Type VII(Tauris disease)1 million1


DisorderFeaturesType I(von Gierkes disease)Hypoglycemia, Hepatomegaly, Cirrhosis, Ketosis, Hyperuricemia. Type II (Pompes disease)Generalized glycogen deposit; lysosomal storage disease.Type III(Coris disease)Hepatomegaly, CirrhosisType IV(Andersons disease)Hepatomegaly, CirrhosisType V(Mc Ardles disease)Exercise intoleranceType VI(Hers disease)Hepatomegaly, Hyperuricemia.Type VII(Tauris disease)


GSD Type-VIII :It is an X linked recessive disorder.Frequency is one in 1,25,000 births.Enzyme deficiency is Phosphorylase kinase.


Clinical Features Hepatomegaly and fibrosis in childhood, these symptoms improve with age and usually disappear after puberty. Fasting hypoglycemia (40-50 mg/dl) Hyperlipidemia Growth retardation, Growth often normalizes by adulthood as well. Elevated serum transaminase levels (Aspartate aminotransferase and alanine aminotransferase > 500 units/ml)


8) MucopolysaccharidosesType I Hurlers syndrome L-Iduronidase.Type II Hunters Iduronate sulphatase.Type III Sanfilippos N-Acetylglucosaminidase, Heparin sulphatase.Type IV Morquios Galactosamine sulphatase.Type V Scheies L-Iduronidase.Type VI Maroteaux-Lamys N-Acetyl--D-galactosamino-4-sulphatase.Type VII Slys -Glucuronidase.


Symptoms :- All mucopolysaccharidoses show skeletal deformity, corneal clouding and corneal opacity.Mental retardation (except type V &VI).Urinary excretion of respective mucopolysaccharides (C.S, D.S, H.S and K.S) observed.C.S = Chondroitin sulphateD.S = Dermatan sulphateH.S = Heparan sulphateK.S = Keartin sulphate.


Overview of Carbohydrate metabolismEnzyme DeficiencyDiseaseHexokinasePyruvate kinaseGlucose-6-(P) dehydrogenaseHemolytic AnemiaPyruvate dehydrogenaseMuscular hypotonia,Lactic acidosis.LactaseAldolase B (fructose-1-(P) aldolase)Hereditary Lactose intoleranceHereditary fructose intoleranceFructokinaseEssential FructosuriaGalactose-1-(P)-Uridyl transferaseGalactokinaseUridine di-(P)-galactose-4-epimeraseGalactosemiaL-Xylitol dehydrogenaseEssential PentosuriaGlycogen storage disordersAnd Mucopolysaccharidoses


Wernicke-Korsakoff syndrome :-This is a genetic disorder associated with HMP shunt.But it is not an inborn error.An alteration in transketolase activity that reduces affinity with TPP(a Biochemical lesion).Symptoms are mental disorder, loss of memory and partial paralysis.These symptoms manife


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