Tishk International University

Faculty of Science

Department of Medical Analysis

Advanced Clnical Biochemistry

Inborn errors in metabolism

Grade 4-Spring 2020-2021

Dr. Rundk A. Hwaiz

Inborn errors of Carbohydrate Metabolism

1. Hemolytic anemia’s caused by deficiencies of-

a) Hexokinase

b) B. Pyruvate kinase

c) Glucose-6-(P)-dehydrogenase

2. Pyruvate dehydrogenase deficiency.

3. Carbohydrate intolerance disorders-

a) A. Lactose intolerance.

b) B. Fructose intolerance.

4. Fructosuria

5. Galactosemia

6. Glycogen storage disorders.

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-

Bisphosphoglyceric acid) 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).

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.

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)

– Antipyretic (Acetanilide)

Favism :- Ingestion of FAVA beans,

Leads to Hemolytic anemia.

2. Pyruvate dehydrogenase deficiency

Frequency is 1 in 250,000 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

B. Hereditary Fructose intolerance

It is an autosomal recessive disorder. Incidence is 1 in

20,000.

The defect is Adolase-B (fructose-1-(P) aldolase)

Fructose -1(P) cannot be metabolized.

Fructose-1(P) X Glyceraldehyde + DHAP.

It leads to accumulation of fructose-1-(P)

severe hypoglycemia, vomiting, hepatic failure and

jaundice.

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 X 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 X

Symptoms:

The build up of galactose and the other chemicals can cause

serious health problems like

Swollen and inflamed liver,

Kidney failure,

Stunted physical and mental growth

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. 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

I. (Von Gierkes disease) is rare disorder is due to glucose-6-

phosphatase deficiency causing

ineffective glycogenolysis,

hypoglycemia during fasting states,

growth retardation,

ketosis, lactic acidosis,

pronounced hepatomegaly due to accumulation of

glycogen in liver.

II. Pomp’s disease

Acid alpha-glucosidase deficiency

Hypertrophic cardiomyopathy in infants

Skeletal and respiratory muscle weakness

CK value are elevated

III. Cori’s disease

Is an autosomal recessive metabolic disorder.

inborn error of metabolism characterized by a

deficiency in glycogen de- branching enzymes

This disease principally affects the liver

slowing of growth, low blood sugar levels and,

sometimes, seizures.

Muscle weakness may develop later in life

IV. Anderson’s disease

Brancher enzyme deficiency

Extremely rare hereditary metabolic disorder produced

by absence of the enzyme amylo-1:4,1:6-

transglucosidase, which is an essential mediator of the

synthesis of glycogen.

An abnormal form of glycogen, amylopectin, is

produced and accumulates in body tissues, particularly

in the liver and heart

V. Mc Ardle’s Disease

Is a metabolic disease affecting skeletal muscle.

Severe rhabdomyolysis may lead to acute kidney injury.

Potential hyperuricaemia; overproduction of adenosine

monophosphate (AMP), with accelerated liberation of

hypoxanthine and xanthine into the blood, possibly

leading to hyperuricaemia

People with McArdle's disease develop severe muscle

cramps and fatigue in the first few minutes of activity

VI. Her’s Disease

is a type of glycogen storage disease •Caused by a

deficiency in liver glycogen phosphorylase

No specific symptoms are associated with Hers disease

(glycogen storage disease, type VI).

Hepatomegaly may be present;

Growth retardation is possible.

The liver isoform of phosphorylase is deficient

VII. Tauri’s disease

It is caused by deficient activity of the enzyme

phosphofructokinase

This disease is one of the metabolic muscle disorders

that interferes with the processing of food (in this case,

carbohydrates) for energy production

Presentation

Newborn presents with hyperglycemia, liver

dysfunction, jaundice, coagulopathy, E-coli

sepsis and cataracts

Deficiency in the enzyme

galactose-1-phosphate

uridyltransferase (GALT)

Galactosemia Galactose and galactose-

1-phosphate

Diagnosis Diagnosis reducing substances in urine

GALT enzyme activity and blood galactose-1-phosphate

values

Treatment Elimination of galactose from diet for life

Presentation

Newborn infant presents with hypoglycemia, lactic

acidosis, hyperurecemia, hyperlidimia, hepatomeagly

with elevated liver enzyme, doll like face and thin

extremities.

deficient in glucose-6-

phospahatase enzyme Inability to release

free glucose

Diagnosis • Glucagon administration produces no hyperglycemic

response

• Genetic testing

Treatment

Von Gierke

disease

For children, uncooked cornstarch will sustain blood

glucose for 4-6 h. For young children, continuous

nasogastric tube of glucose to sustain normal blood

glucose level especially at night

Presentation Strenuous exercise muscle cramps

Diagnosis • High CPK

• Myoglobinuria

Treatment

• Avoid strenous exercise to prevent rhabdomyolysis

• Oral fructose/glucose intake can improve exercise

tolerance

Myophosphorylase

deficiency Mc Ardele disease

Deficiency of fructose 1,6-

biphosphate aldolase

• Autosomal recessive

• Age 4-6 months Fructose intolerance

Reducing substance in urine

Avoid all source of fructose

and sucrose

Infant is healthy until fructose

or sucrose is ingested e.g.

juice or sweetened cereal

Jaundice, vomiting, lethargy,

seizures and irritability