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