INBORN ERRORS OF METABOLISM

Tapeshwar 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?

Garrod’s hypothesis

product deficiencySubstrate excess

toxic metabolite

AD

B C

What is a metabolic disease?According to Garrod’s 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.

Classification

Mitochondrial inheritance :- Leber’s hereditary optic neuropathy is caused by

complex-I defect in ETC, leads to blindness, cardiac conduction defects.

Leigh’s 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

Categories1) Hemolytic anemia’s caused by deficiencies of-

A. Hexokinase

B. Pyruvate kinase

C. Glucose-6-(P)-dehydrogenase

2) Pyruvate dehydrogenase deficiency.

3) Carbohydrate intolerance disorders-

A. Lactose intolerance.

B. Fructose intolerance.

4) Fructosuria.

5) Galactosemia.

6) Pentosuria.

7) Glycogen storage disorders.

8) 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 as– Anti-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

(β-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). Fructose Fructose-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-Xylulose Xylitol It 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.

Disorder Enzyme Affected TissueType I

(von Gierke’s disease)

Glucose-6-phosphatase Liver, kidney, intestine

Type II (Pompe’s disease)

Lysosomal α 1,4- glucosidase (Acid maltase)

All organs

Type III(Cori’s disease)

Amylo α 1,6- glucosidase (debranching enzyme)

Liver, muscle, heart, leukocytes

Type IV(Anderson’s disease)

Glucosyl 4,6-transferase Most tissues

Type V(Mc Ardle’s disease)

Muscle glycogen phosphorylase

Skeletal muscle

Type VI(Her’s disease)

Liver glycogen phosphorylase Liver

Type VII(Tauri’s disease)

Phosphofructokinase Skeletal muscle, erythrocytes.

Disorder Incidence in births (1 out of)

Chromosome location

Type I(von Gierke’s disease)

1,00,000 17

Type II (Pompe’s disease)

1,75,000 17

Type III(Cori’s disease)

1,25,000 1

Type IV(Anderson’s disease)

1 million 3

Type V(Mc Ardle’s disease)

1 million 11

Type VI(Her’s disease)

1 million 14

Type VII(Tauri’s disease)

1 million 1

Disorder FeaturesType I

(von Gierke’s disease)Hypoglycemia, Hepatomegaly,

Cirrhosis, Ketosis, Hyperuricemia.

Type II (Pompe’s disease)

Generalized glycogen deposit; lysosomal storage disease.

Type III(Cori’s disease)

Hepatomegaly, Cirrhosis

Type IV(Anderson’s disease)

Hepatomegaly, Cirrhosis

Type V(Mc Ardle’s disease)

Exercise intolerance

Type VI(Her’s disease)

Hepatomegaly, Hyperuricemia.

Type VII(Tauri’s 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 – Hurler’s syndrome – L-Iduronidase.Type II – Hunter’s – Iduronate sulphatase.Type III – Sanfilippo’s –N-Acetylglucosaminidase,

Heparin sulphatase.Type IV – Morquio’s – Galactosamine sulphatase.Type V – Scheie’s – L-Iduronidase.Type VI – Maroteaux-Lamy’s – N-Acetyl-β-D-

galactosamino-4-sulphatase.Type VII – Sly’s – β-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 sulphate– D.S = Dermatan sulphate– H.S = Heparan sulphate– K.S = Keartin sulphate.

Overview of Carbohydrate metabolismEnzyme Deficiency Disease

HexokinasePyruvate kinase

Glucose-6-(P) dehydrogenaseHemolytic Anemia

Pyruvate dehydrogenase Muscular hypotonia,Lactic acidosis.

LactaseAldolase B (fructose-1-(P) aldolase)

Hereditary Lactose intoleranceHereditary fructose intolerance

Fructokinase Essential Fructosuria

Galactose-1-(P)-Uridyl transferaseGalactokinase

Uridine di-(P)-galactose-4-epimeraseGalactosemia

L-Xylitol dehydrogenase Essential Pentosuria

Glycogen 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 manifested in chronic alcoholics,

whose diets are thiamin-deficient.

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