Carbohydrate disorder

xxx
 CONGENITAL DISORDER OF GLYCOSYLATION (CDG)

• DEFINITION = Genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in
the synthesis and processing of asparagine (n)-linked glycans or oligosaccharides on glycoproteins. (Involve in metabolism,
cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity)

• CLASSIFICATION
1. TYPE 1 = Defect in the assembly or transfer of the dolichol-linked glycan.
2. TYPE 2 = Defect in processing of the protein-bound glycans either late in the endoplasmic reticulum or
the golgi compartments.

• TYPE OF INHERITANCE = Autosomal recessive (both alleles are mutated)

RISK FACTOR PREVENTION OF PRIMARY AND

I. Obligate carrier parent (carry one mutant allele)
II. Mutation in glycosylation pathway
III. Environmental stress during period of growth
(infection, fever, insufficient nutrition)
SECONDARY MANIFESTATION
I. Mannose – normalize hypoproteinemia and
coagulation defect.
II. Attention to coagulation status before surgery
(increased risk of deep venous thrombosis and
bleeding)
Group 8. congenital disorder of glycosylation
47 Pathogenesis (PMM2-CDG)

1. In the case of CDG-Ia (most common subtype), there is

mutation in the gene (localized on chromosome 16p13)
that encodes for phosphomannomutase 2, the
enzyme responsible for the conversion of mannose-
6-phosphate to mannose-1-phosphate in the
cytoplasm.
2. Deficiency in PMM2.
3. Disruption of normal glycosylation causes failure of
multiple body systems.

Diagnosis
4. Isoelectrofocusing (IEF) of serum transferrin
(transferrin is a predominant serum glycoprotein)
5. Enzymatic measurements (CDGIa: Measurement of PMM2
activity in fibroblasts or leukocytes)

Reference: http://www.nature.com/pr/journal/v52/n5/full/pr2002233a.html
"Pathophysiology" of Congenital Disorder of Glycosylation (CDG) Group
48
There is NO SPECIFIC medicine to treat CDG.
 EXCEPTIONAL for CDG Ib/MPI-CDG and CDG IIc.

i. Mannose supplementation.
 Treat patients with CDG Ib.
 This reverses the hypoglycemia and coagulopathy within a few weeks
 Within 1-2 months, plasma protein levels become normal.
 Protein-losing enteropathy disappears.

ii. Fucose supplementation

 Treat patients with CDG IIc who have defective GDP-Fucose transporter and recurrent infections
 However, fucose only provide partial effect. it does not help with other symptoms of this disorder (eg. developmental delay).

How to treat CDG Ia then?

 NO CURE
However, there are some measures may be taken to improve it;
i.Get the best possible nutrition to help with growth.
ii.Early use of occupational, physical and speech therapy.
iii. Surgical or non-surgical measures (correct crossed eyes)
 Diabetic ketoacidosis is a
serious complication of
diabetes.
Body cant produce insulin
-> fat replace glucose as energy

-> produce ketone

Risk Factor Associated with

Diabetes Other Risk Factor

Type 1 Diabetes Type 2 Diabetes

Miss insulin shot
Bacterial infection and intercurrent
illness
Medical, surgical, or emotional
stress
Brittle diabetes
Intercurrent illness (eg, myocardial
Not enough insulin
infarction, pneumonia, prostatitis, Not enough food
UTI)   Insulin reaction (low blood
Medication (eg, corticosteroids, glucose)
pentamidine, clozapine)
 Diabetic Ketoacidosis
By JAIRONI BIN SATEEM & HARIARAN SUBRAMANIE

Pathophysiology
1. Excessive thirst.
2. Frequent urination.
3. Nausea and vomiting.
Treatment
4. Abdominal pain.
1. Fluid replacement.
5. Weakness or fatigue.
2. Electrolyte replacement.
6. Shortness of breath.
3. Insulin therapy.
7. Fruity-scenty breath.
8. Confusion.
9. Hyperglycemia (High blood sugar level).
10. High ketones levels in urine.
 PATHOGENESIS OFDIABETIC KETOACIDOSIS (DKA)

TYPE 1 DIABETES MELLITUS

• Due to lack of insulin no uptake of glucose into cell
(muscle).
• Lipolysis occurs and lead to excess free fatty acid(FFA) and
glycerol production.
• FFA undergo beta-oxidation to form acetyl-CoA.
• Acetyl-CoA undergoes ketogenesis and produce ketone bodies
ketoacidosis
• pH of the blood drops
Diagnosis

• Urine test - presence of ketone bodies

• Blood test - High serum ketone
- Low pH
- hyperglycemia
HOW IT RELATES TO DX:
- a)- Fructose give a positive
test for reducing sugars-
detect inborn errors of sugar
metabolism in pediatric
patients. Positive reducing
test suggest that some
substance other than glucose
is present in the urine
- negative reaction for
glucose oxidase-because this
is to determine the glucose
level
-This two means there is
fructose presence in the
urine

b) -Fructose tolerance test

:test of liver function-
provoke neither increase in
blood glucose nor
hypoglycemia
 1. The blood glucose was lower than the normal blood
glucose range which is 5.6 to 11.1 mmol/L.

2.
Fructose

Glycogen
Fructose-1-phosphate phosphorylase
Adolase B

Glyceraldehyde- Dihydroxyacetone
3-phosphate phosphate

Glucose
3. Hereditary Fructose Intolerance
Question 1.2
1. Elevated serum uric acid level
reference: Normal range in children = (0.17-0.22 mmol/L)

2. Absence or deficiency of aldolase B causes no

cleavage of hepatic fructose-1-phosphate → reduction
of ATP pool→activate AMP deaminase (convert AMP
to IMP)→increased purine synthesis →increased
purine catabolism (uric acid as final product)
→hyperuricaemia

3. Hereditary fructose intolerance

Question 1.3
1. Yellowing of the sclera or icteric sclera is due to repeated ingestion
of fructose containing food that can lead to liver and kidney
damage. Patient experience episodes of vomiting because there is
inadequate amount of aldolase B to complete phosphorylation
process in the liver which is the enzymatic process of fructose
absorption.
2. Aldolase B (Fructose-1-phosphate aldolase)

3. Isoform: Aldolase A, Aldolase B and Aldolase C. Aldolase A is

preferentially expressed in muscle and brain . Aldolase B in liver,
kidney, and in enterocytes and aldolase C in brain. Aldolases A and
C are mainly involved in glycolysis, while aldolase B is involved in
both glycolysis and gluconeogenesis. Some defects in aldolase B
cause hereditary fructose intolerance.
Question 1.4
i. According to the lab result, there is presence of fructose in her
urine because fructose cannot be metabolized and it accumulates
in the body and excreted in the urine. The prothrombin time is
prolonged because there is defect in extrinsic and common
pathway of blood clotting which may be caused by decrease in
blood clotting factors due to impaired protein synthesis.
ii. The most likely enzyme to be defective is aldolase B. Absence of
aldolase B cause fructose fail to be metabolized and accumulate in
form of fructose-1-phosphate (F-1-P) which are excreted in urine.
Accumulation of F-1-P cause a drop in the level of inorganic
phosphate (Pi) and therefore decrease in ATP. The decreased
availability of hepatic ATP affects protein synthesis thus there is
decrease in blood clotting factors and other essential proteins
causing prolonged prothrombin time. The disease is inherited in
autosomal recessive pattern which is also infecting the older sibling
that died from complications of lack coagulation factors that impair
blood clotting.
iii. The most likely diagnosis is hereditary fructose intolerance.
TASK 1.5
INTERPRET LAB RESULT
Level of serum phosphate is low which is serum phosphate (PO4) concentration < 2.5 mg/dL (0.81 mmol/L). This
condition is called hypophosphataemia. Normal range for boy age 18 years or older is 2.5-4.5 mg/dL (0.8-1.4 mmol/L)

Most likely biochemical explanation for this boy’s blood glucose level
and most likely diagnosis.
• This boy has high blood glucose level because his body does not produce
enough insulin. This condition is called diabetic ketoacidosis (DKA). This
boy symptom which is nausea, vomiting and abdominal pain indicated
that he has DKA. Hypophosphataemia is more likely in diabetic
ketoacidosis. This is because the phosphate level in blood can suddenly
fall dangerously low in people recovering from diabetic ketoacidosis
because the body uses large amounts of phosphate during recovery.
Initial treatment with intravenous fluid and insulin drives the phosphate
into cells, and plasma phosphate may be drastically decreased.
• Task 1.6

• Lab result:
• serum triglyceride 17mmol/L (very high level >6mmol/L)

• Biochemical explaination:
• 1) carbohydrate-induced HPTG results from increased production of VLDL particles
• 2) familial chylomicronemia – lack properly functioning lipoprotein lipase (LPL)
• 3) hyperlipidemia – increased VLDL production and decreased elimination

•
• Diagnosis : Hypertriglyceridemia
 G6PD DEFICIENCY
Definition : X-linked recessive disease characterized by abnormally low levels of
glucose-6-phosphate dehydrogenase production in the pentose phosphate pathway.
Classification :
 Class 1 (severe deficiency )
 Class 2 (severe deficiency )
 Class 3 (moderate deficiency)
 Class 4 (non-deficient/normal activity)
 Class 5 (increased enzyme activity).
Risk factor and preventions :
Risk factors Prevention
Diet ( eg : fava beans) Avoid consumption of the specific
bean
Drugs and chemicals that can cause Read labels of medications and take
oxidant stress ( eg: Chloramphenicol ) precaution steps before
consummation
 PATHOGENESIS
● There are TWO diagnostic testing that can be done to detect this deficiency:
● Fluorescent Spot Test (Enzyme Assay)
– A rapid fluorescent spot test detects the generation of NADPH from NADP.
– NADPH is a cofactor of G6PD that is involved in conversion of glucose-6-
phosphate to 6-phosphoglutanate.
– The test is positive if the blood spot fails to fluoresce (unable to detect
NADPH) under ultraviolet light.

● Polymerase Chain Reaction (PCR) / Restriction Fragment Length

Polymorphism (RFLP).
– To identify a change in genetic sequence that occurs at a site where a
restriction enzyme cuts.
● Restriction enzyme – proteins isolated from bacteria that recognize specific short sequence
of DNA and cut DNA at those site (detect any abnormalities)
– Blood sample is required from the adults for the diagnosis, meanwhile for
prenatal diagnosis, cord blood is needed.
 PATHOPHYSIOLOGY
• Two monomer of glucose-6-phosphate dehyrogenase (G6PD) exists as dimer that will eventually
become

tetramer in the presence of suitable pH.

• Each monomer consist of NADPH binding site which participate in reaction catalyzed by G6PD.
• Most common type of G6PD deficiency is Class 1 resulting from a missense mutation.
• Increase in oxidative stress on RBC causes damage on the haemoglobin so cells receive less oxygen,
eventually disturbing the cellular metabolism.
• Patients with G6PD deficiency usually present low red cell count due to intravascular haemolysis and

simple infection.
TREATMENT
• Oxygen therapy: To supply more
oxygen to cells for cellular metabolism.

• Blood transfusion: RBC are transfused

so more oxygen are carried to cells.
Galactosemia : literally means too much galactose in the blood
: is a disorder that affects how the body processes a simple sugar called galactose

Name Gene Locus Description

Type 1 Classic and GALT 9p13 • Classic galactosaemia  Blood shows essentially no
clinical variant detectable residual GALT activity
galactosemia • Variant galactosaemia  leave small amount of
residual GALT activity
Type 2 Galactokinase GALK1 17q24 Leading to loss of galactokinase (GALK) enzyme activity
deficiency
Type 3 Epimerase GALE 1p36-37 Leading to partial loss of UDP-galactose 4’-epimerase
deficiency (GALE) enzyme activity

Type of inheritance : Autosomal recessive

Risk factor : Family history of the disorder
Prevention : Individuals who have galactosemia may meet a genetic counselor to discuss the risks of
having children with the disease.
Pathogenesis of Galactosemia

GALK 1 gene – deficiency of GALK enzyme

GALT gene - deficiency of GALT enzyme
GALE gene - deficiency of UDP galactose
epimerase

• congenital cataract :excess of galactitol

• galactosuria :⬆ excretion of galactose

 Pathophysiology of
Galactosemia
• Type 1:GALT deficiency
• Type 2:GALK deficiency
• Type 3:GALE deficiency
• S N S:Vomitting,liver
enlargement, jaundice, vision
damage.

Treatment
Life long condition, which there is
no cure
• Galactose-restriction primarily
involve milk and other dairy
product.
• Nutritionally infant formula and
supplementary
D I S O R D E R S O F G L U C O N E O G E N E S I S

P Y R U VAT E C A R B O X Y L A S E ( P C ) D E F I C I E N C Y
A. Autosomal recessive rare disorder.
B. Missing/decreased amount of PC causes pyruvate cannot change to
Oxaloacetate.
C. Leads to lactic acid & pyruvate to accumulate in blood.

P H O S P H O E N O L P Y R U VAT E C A R B O X Y K I N A S E ( P E P C K )
DEFICIENCY
A. Autosomal recessive rare disorder.
B. Oxaloacetate cannot change to Phosphoenolpyruvate.
F R U C T O S E 1 , 6 - D I P H O S P H ATA S E ( F D PA S E ) D E F I C I E N C Y
A. Lower FDPase cause depletion of phosphate store, and it inhibits
gluconeogenesis. Consequently, ATP formation will be reduced.
B. Fructose and glycerol cannot be used by liver to maintain glucose level, will be
turned into lactate.

G L U C O S E - 6 - P H O S P H ATA S E ( G 6 P ) D E F I C I E N C Y
A. Autosomal recessive rare disorder, also known as Glycogen Storage Disease
type I (GSDI) or Von Gierke’s disease.
B. Will lead to hyperuricaemia.

S U M M A RY
A. Enzyme deficiencies stop gluconeogenesis pathway, cause hypoglycaemia.
B. Also cause accumulation of lactate, leads to lactic acidosis.
C. This in turns cause hepatomegaly and neuronal defects.
D. This deficiencies often manifests on neonates.
Glucose galactose Malabsorption(GGM) / Sodium
glucose transporter(SGLT 1) defect
• DEFINITION-GGM
• A disorder of transport clinically characterized by the neonatal
onset of profuse, a acidic, watery diarrhoea leading to severe
dehydration and death if untreated, resulting from a selective
defect in the intestinal transport of glucose and galactose.
• TYPE OF INHERITANCE
• Autosomal recessive (very rare disease)
• HOW RELATED TO PATIENT
RISK FACTOR
• GGM is an autosomal recessive disease. It manifests if the patient’s
parents each carry one copy of the mutated SLC5A1 gene.
• Consanguineous marriages.
PREVENTION
• There is no effective means of prevention for GGM. Genetic
counselling should always be available for the GGM patient.
 Pathogenesis of GGM/SGLT1 Defect

Transporter protein called SGLT1 is encoded by SLC5A1 gene. As the result of a mutation
on chromosome 22 in the SLC5A1 gene , the transport protein is unable to transport glucose
and galactose out of the intestinal lumen and results build up of glucose and galactose in
intestinal tract.

The diagnosis for this defect can be done by glucose breath hydrogen test. A breath
sample will be collected and tested for the presence of hydrogen. Malabsorbtion of lactose
that eventually breakdown to glucose and galactose in the lumen will be ferment by bacteria
and thus releasing hydrogen. Those with GGM will shows positive for this test.
PATHOPHYSIOLOGY
• Lactose breaks down into galactose and glucose.
• Due to SGLT 1 defect which is a protein co-transporter
not able to transport Na+ and glucose/galactose into
the enterocyte.
• This causes water retention in the intestinal lumen.
• Since Na+ is coupled with water, a retention of Na+ also
means a retention of water.
• Increased water concentration in lumen causes
diarrhea. (osmotic diarrhea)
• No reabsorption of water into the body leads to
dehydration
• Treatment includes oral rehydration and refrain from
milk based product consumption.
Glucose Transported 1
Deficiency
Group 52,53,54
 GLUT 1 Defect
Pathogenesis
Mutation of SLC2A1 Gene on chromosome 1 which maybe caused by:-
1. Hereditary mutation from parents. Germ line mutations. May arise from the sperm, egg or
even the fertilized egg.
2. Acquired or somatic mutations due to environmental factors such as UV radiation or
mistakes made during DNA replication
As a result there will be low levels of functional GLUT-1
How it relates to diagnosis?

• We can compare the cerebrospinal fluid glucose value with the glucose concentration in the
blood.
• Genetic testing – this is done to analyse any mutation in GLUT-1 gene
 GLUT1 DEFECT
CLASSIFICATION :
DEFINITION : A mutation in the gene 1. Epileptic
encodes for GLUT 1(glucose transporter at the encephalopathies
blood brain barrier) that leads to insufficient
glucose transported through the blood brain 2. Paroxysmal exercise-
barrier which affects the nervous system.
induced dyskinesia (PED)
TYPE OF INHERITANCE : RISK/PREVENTION

Autosomal Dominant (common), • Prevention for the first

Autosomal recessive (rare) manifestation:
HOW IT RELATES TO PATIENT EDUCATION :
• Infants having unexplainable seizure.
Early initiation of ketogenic
• Child has low muscle tone, having physical diet, ideally in infancy, better
difficulties eg; jumping , crawling, running seizure control
• Having problems in speech and expression.
• Having delayed learning and development.
• May have shrunken heads. (microcephaly) • Risk: Genetic predisposition
 GLUT 1 Defect
Pathophysiology :
• Mutation on SLC2A1 gene (encoding glucose transporter type1 ) 
abnormalities of glucose transport to the brain.
• Without proper GLUT 1  body cannot transport sufficient amount of
glucose across the blood brain barrier  brain cannot grow & function
properly.

Treatment :
» Ketogenic Diet :
» use different type of transporter (MCT1)  ketone can pass BBB
(ketone use to make Actyl-coA into long chain fatty acid)
» high-fat , low-carbohydrate diet  causes the body to burn fat
instead of sugar ( glucose )
» Thioctic acid :
» alpha-lipoic acid  naturally occurring compound ( made in
human body )  help glucose transport in the body.
DEFINITION
Glycogen storage disease type I also known as von Gierke disease is an inherited
disorder caused by the buildup of a complex sugar called glycogen in the body’s cells.
The accumulation of glycogen in certain organs and tissues, especially the liver, kidneys,
and small intestines, impairs their ability to function normally

CLASSIFICATIONS
• Type 1a- deficiency of G6Pase
• Type 1b-deficiency of G6P translocase
• Type 1c
• Type 1d
TYPE OF INHERITANCE
Autosomal recessive

HOW IT RELATES TO PATIENT’S EDUCATION

• Carrier parents- 25% chance of child being affected
- 50% chance of child being a carrier
- 25% chance of child being unaffected
• Males and females equally at risk
• Prevention: Genetic counseling before marriage
Pathogenesis GLYCOGEN STORAGE DISEASE
I
(Autosomal recessive disorder)

These two enzymes

work together to help
the body break down
the glycogen into free
glucose for use when
we are not eating.
Pathogenesis GLYCOGEN STORAGE DISEASE
I
(Autosomal recessive disorder)
GSD 1a (80%)
Glucose-6-phosphatase gene (G6PC)
(17q21)
-encodes glucose-6-phosphatase
enzyme In liver and kidney
GSD 1b (20%)
Glucose-6-phosphate translocase
gene (SLC37A4)(11q23)
-encodes glucose-6-phosphate
translocase (G6PT) enzyme

MISSENSE and NONSENSE mutation

Deficiency of enzyme.
.

Glucose-6-phosphate levels increase.

Glucose cannot be release from liver causes
hypoglycaemia..
Pathophysiology
-In the absence of glucose-6-phosphatase activity, free glucose cannot be release from the liver
contibuting to severe fasting hypoglycemia.

-In addition the increased glucose-6-phosphate levels lead to increased pentose phosphate pathway
(PPP) activity .Thus,ribose-5 phosphate synthesis more purine ,and eventually break down to uric
acid.Accumulation of uric acid lead to hyperuricemia.

-The incresased levels of pyruvate lead to increased lactate produciton via lactate dehydrogenase
(LDH) and alanine via alanine transaminase (ALT). Thus ,it lead to lactic acidemia.

-In addition, the increased pyruvate is oxidized via the pyruvate dehydrogenase complex (PDHc)
leading to increased production of acetyl-CoA which is, in turn, used for the synthesis of fatty acids and
cholesterol.

-The excess glycolysis also results in increased production of glycerol-3-phosphate (G3P) from DHAP via
the action of glycerol-3-phosphate dehydrogenase (GPD1).

-Increased G3P and fatty acids leads to increased triglyceride synthesis which, in conjunction with the
increased cholesterol, leads to hyperlipidemia as well as fatty infiltration in hepatocytes contributing
to hepatomegaly and cirrhosis.
How it relates to treatment and
management:

 Frequent feedings of foods high in glucose or starch (which is

readily digested to glucose):To compensate for the inability of
the liver to provide sugar, the total amount of dietary
carbohydrate should approximate the 24-hour glucose
production rate.
 Persistent elevation of uric acid above 6.5 mg/dl warrants
treatment with allopurinol to prevent uric acid deposition in
kidneys and joints.
Glycogen Storage Disease II
Group 16
Group 17
Group 18
Definition
• Called as Pompe Disease
• Caused by lack of function of the enzyme acid
alpha- 1,4- glucosidase (acid maltase)
• Metabolic disease: lysosomal storage disorders
(LSDs)
• Acid maltase enzyme works in the lysosomes.
Classification
 Infantile- onset form:
 Age: 4-8 months
 Muscles in arms and legs appear normal, but are
very weak
 Unable to lift their head or rolling over
 Complication: die before 12 months due to heart
failure and respiratory weakness.
Type of inheritance
 Autosomal recessive inheritance
 Mutation in long arm chromosome 17
How it relates to Patient Education?
 Risk
 Hereditary disease
 Prevention
 Genetic counselling- prevent the risk of getting
GSD II for the next generation
 Early treatment- control the disease
 Late onset form:
 Age: greater than 1 or 2 year-old
 Progress more slowly
 First symptom: Decrease in muscle strength
- Starting with the legs, moving to smaller
muscles in the trunk and arms
 Complication: Respiratory failure is the most
common cause of death.
 PATHOGENESIS OF GSD TYPE II

Lack of function of the enzyme acid alpha-1,4-glucosidase (GAA) or acid maltase

No breakdown of glycogen in the lysosomes into glucose
Glycogen enters lysosomes
Continuous build up and accumulation of glycogen
Lysosomes grow larger and larger
Lysosomal breakdown
Disrupts the cells and the organs that the cells make up (heart, muscles)

RELATION WITH THE DIAGNOSIS

1. Specific enzyme testing: Diagnosis is made by estimating the acid alpha

glucosidase activity in either skin biopsy (fibroblasts), muscle
biopsy (muscle cells) or in white blood cells.
2. Histopathology: show a great increase of glycogen of normal structure, and
microscopic studies will show increased glycogen enclosed within the lysosomes
3. Genetic testing: for mutation finding and GAA gene sequencing alteration
 Treatment for GSD II
• Enzyme Replacement Therapy (ERT)
- Patient with GSD type II have deficient or absence of acid alpha-glucosidase
(also known as acid maltase) activity which required for degradation of
cellular glycogen.
- ERT provides the exogenous source of acid maltase.
- Alglucoside alfa (Myozyme), an enzyme produced by recombinant DNA
technology
> long-term therapy
> improve cardiac and skeletal muscle function
- Given through Intravenous (IV) infusion
References : emedicine.medscape.com & patient.info.com
Group 17
HEXOKINASE
DEFECT
• Definition : A rare autosomal disease due to mutation
of HK type allele that can cause non-spherolytic
haemolytic anaemia
• Classification :
 Type I : All tissue (predominant type in RBC)
 Type II : Insulin-sensitive tissue (skeletal muscle)
 Type III : All tissues, but inactive at physiologic
 Type IV (Glucokinase) : liver
• Inheritance : Autosomal recessive disorder
• Risk factor : Genetic predisposition
• Prevention : Advocating eugenics
 PATHOGENESIS
• There are four types of HK isozyme which is encoded by
different genes; HK1 (Ch10), HK2 (Ch2), HK3 (Ch5), HK4
(Ch7)
• Most cases presented with HK1 gene mutation on
chromosome 10p11.2
• HK1 isozyme is present in erythrocyte
• Cause decreased formation of 1,3-BPG which normally
converted to 2,3-BPG by a mutase in the red cell.
Hence, in hexokinase deficiency, 2,3-BPG level is
decreased
• Diagnosis: Enzymatic assay of hexokinase, hexokinase
colorimetric assay kit
 PATHOPHYSIOLOGY & RELATION
WITH TREATMENT
• Blood transfusion
• - To treat premature destruction of red blood cells
- Outside membrane of the cells is weakened
- Causing it to have an irregular non-spherical shape and to burst easily
(hemolyse)
- RBCs depend on breakdown of the sugar (glycolysis) for energy.
- Hexokinase defect cause the red blood cell cannot function properly and
hemolysis or the breakdown of the membrane that hold the cells together.
- When the RBCs cannot be replaced , it causes anaemia.
- 2,3-BPG strongly decreased cause the oxygen dissociation curve shifted to the
left
- This implied the release of oxygen to the tissue was impaired.

• Splenectomy
- Abnormally large spleen(splenomegaly) due to increase destruction of RBCs.
 HYPERGLYCEMIC HYPEROSMOLAR
SYNDROME (HHS)
Defination
 is a complication of Diabetes
Mellitus(DM) 2 in which high blood sugars
cause severe dehydration and increase in
osmolarity.
Classified by the following features :
 commonly present in patients with
Type II DM
 absence of ketones in body
Type of inheritance
 Autosomal recessive
Risk factors
Have type 2 diabetes. 
Have chronic health condition,
congestive heart failure or kidney
disease.
Have an infection, pneumonia,
a urinary tract infection or a
virus,.
Drugs such as
corticosteroids,diuretics,alcohol
and cocaine.
Prevention
 Diabetic teaching in hospital
and after discharge by a primary
care physician and a visiting
home nurse
 avoid poor glycemic control
and dehydration.
PATHOPHYSIOLOGY OF HYPEROSMOLAR
HYPERGLYCEMIC SYNDROME (HHS)
Proximal tubular
Reduce circulating Hyperglycemia transport of glucose
No further glucose
insulin (associated (glycemia reached from tubular lumen
reabsorption is
with diabetes mellitus, approximately 180 into renal renal
possible.
usually type 2). mg/dL) interstitium become
saturated.

Urine carry water and It will travel into distal Glucose remain in
Osmotic diuresis.
electrolyte with it. nephron. renal tubule.

Increase plasma
Reduce total body protein concentration
Hyperosmolar state. Dehydration.
water. after the intravascular
water loss.

Coma due to severe

electrolye disturbance
Impaired tissue
occur association with Hypotension. Hypovolemia.
perfusion.
hypotension. (one of
symptoms).
Lactose intolerance
• DEFINITION
 The inability of the body to digest lactose, a component of milk and some other dairy products. The basis for lactose
intolerance is the lack of an enzyme called lactase in the small intestine

• CLASSIFICATION
Primary lactose intolerance is environmentally induced and arises in societies that do not typically consume dairy
Secondary lactose intolerance is also environmentally induced and is a consequence of certain gastrointestinal
disorders.
Congenital lactose deficiency, is a genetic disorder present at birth that prevents individuals from producing lactase.

• TYPE OF INHERITANCE
Autosomal recessive

• RISK
Age : common as you get older
Ethnicity : african americans, asian americans are more likely than caucasian
Premature baby

• PREVENTION
There is no way to prevent lactose intolerance. Decreasing or removing milk products from the diet usually can improve
the symptoms
 
Lactose intolerance is a condition where lactase enzyme is not available means that lactose
cannot be converted into glucose and galactose . Lactose will not digested and stay in big
intestine, fermented by bacteria and release gas such as CO2 and H2. Because of that the
diagnosis which is lactose tolerance test is positive. It is where the patient is given high level
solution of lactose and after 2 hours blood glucose level is tested and low. Other test is
hydrogen breath test also positive means high level of hydrogen is being exhaled. Children
cannot undergo the two test. They will do the stool acidity test because the fermented lactose
will also produce lactic acid that can be detected in stool.
PATHOPHYSIOLOGY
• Dietary lactose (disaccharides)must be hydrolysed to a
monosaccharide in order to be absorbed by small intestines.
• A deficiency of intestinal lactase prevents the hydrolysis of lactose.
• Thus, the unabsorbed lactose causes secretion of fluid and
electrolytes by small intestine caused the dilation on intestines
and accelerate the intestinal transit.
• Within large intestines, free unabsorbed lactose is fermented by
colonic bacteria to yield fatty acids and hydrogen gas.
• The fecal water, intestinal transit and generated hydrogen gas
accounts for the GIT disturbances.
• Rx: LACTAID or Lactrase
: reduce or restrict product containing lactose.
Mucopolysaccharidosis,
Definition
MPS I
A group of inherited metabolic diseases caused by the deficiency of lysosomal enzymes
needed to degrade glycosaminoglycan(GAG).
Three subtypes according to descending severity:
Hurler syndrome (MPS IH)
Hurler- Scheie syndrome(MPS IH/S)
Scheie syndrome(MPS I S)

Classification
Source: Inherited
Type of impairment: Metabolic pathway

Risk Prevention
Family history
Genetic testing and Type of inheritance
counselling Autosomal Recessive Inheritance
 Pathogenesis of Mucopolysaccharidosis type I
• Mucopolysaccharidosis type I (MPS I) is caused by mutations in the IDUA
gene.
• This gene encodes the protein α-L-iduronidase.
• A deficiency of the lysosomal enzyme alpha-L-iduronidase.
• The alpha-L-iduronidase deficiency results in an inability of the lysosome
to break down GAG, namely dermatan sulfate (DS) and heparan sulfate
(HS).
• In this disease, GAG progressively accumulates in the lysosomes,
ultimately causing cell, tissue, and organ dysfunction.
• Alpha-L-iduronidase deficiency causes an increase in the urinary
excretion of dermatan sulfate (DS) and heparan sulfate (HS) in patients
with MPS I.
How it relates to diagnosis?
• Molecular genetic testing for mutations in IDUA gene
• Detection of deficient activity of alpha-L-iduronidase
• Urine test
 Pathophysiology-MPS1
• Abnormal accumulation of undegraded GAGS within the lysosomes result in formation of product that
cannot be eliminate by the body and most commonly are heparan,dermatan and keratan sulfate.
Continued presentation of GAGs to cell for degradation result in storage instead.

Sign and symptom:

• Accumulation of storage material enlargement of lysososme occupy more cytoplasm space
deformed nuclear outline organomegaly.
• Increase storage material within cell of heart valve changes in cell shape from fusiform into round
thickening of valve impaired cardiac function valvular slerosis.
• Storage of undegraded GAGs reflection and refraction of light corneal clouding.
• Lysosomal enlargement and swollen neuron meganeurites (at CNS level).

Treatment:
*no curative treatment for any form of mucopolysaccharidosis, only symptom is treated.
• Enzyme replacement therapy- laronidase admitted intravenously once a week (for MPS1).
• Blood stem cell transplant-trigger production of the deficient enzyme.

Management:
• Range of motion exercise-limit progression loss of motion.
 MPS II
Definition - also known as Mucopolysaccharidosis type II or Hunter Syndrome. it is a rare
disease that have deficiency of the lysosomal enzyme iduronate-2-sulfatase which is required
for degradation of Glycosaminoglycan (GAGs). It leads to accumulation of GAGs throughout
the body. Our body cannot break down sugar needed for build up cells ( brain, skin, bone, etc.)
Type of inheritance - X-linked recessive ( boys affected)
CLASSIFICATION TYPE A TYPE B
Severity Severe Mild
Presentation Late infancy Adulthood
Symptom Macrocephaly, hearing problems, Similar in type a but less severe,
cardiomyopathy neurocognitive involvement

Risk - heart disease, respiratory complication, brain and nervous system complication, mental
retard, skeletal deformity
Prevention - seek advice with genetic counsellor before having more child (carrier)
 MPS II - PATHOGENESIS
• MPS disorder is diagnosed by measuring the iduronate-2-sulfatase (I2S) enzyme activity.
• The most commonly used laboratory screening test for an MPS disorder is a urine test for
GAGs.
• A definitive diagnosis of Hunter syndrome is made by measuring I2S activity
in serum, white blood cells, or fibroblasts from skin biopsy.
• In cartilage, proteoglycans play an important role in its 'shock-absorber' function by
retaining water to form a yielding sponge-like structure. They have a complex biosynthetic
pathway and are degraded by specific enzymes, one for each particular type of
glycosaminoglycan chain. In Hunter's syndrome the deficient enzyme is iduronate 2-
sulfatase (I2S).
• This condition are called lysosomal storage disorders. 
• There is an accumulation of incompletely degraded glycosaminoglycans (acid
mucopolysaccharides) in tissues, in this case heparan and dermatan sulfate.
• Glycosaminoglycans are polysaccharide chains containing amino-sugars that are part of
the structure of proteoglycans.
 MPS II - PATHOPHYSIOLOGY
• Mutation on Xq28 gene (encoding iduronate-2-sulfatase,I2S enzymes) - deficient of
I2S enzymes -> reduce or eliminate function of I2S
• Lack of IDS enzymes activity - lead to accumulation of heparan & keratan sulfate
within the lysosomes - increases the size of lysosomes - tissues and organs enlarged
- interfere the functions of other protein inside the lysosomes & disrupt the
movement of molecules inside the cell.
Treatment
• Enzyme replacement therapy ERT : idursulfase - a purified form of the lysosomal
enzyme iduronate-2-sulfatase produced by recombinant DNA technology in a human cell
line.
 Targeting of the enzymes to lysosomes & subsequent catabolism of accumulated GAGs.

• Bone marrow transplantation : bone marrow graft, or hematopoietic stem cell

transplantation.
 Providing a new source of the missing I2S but the results have been considered imperfect at best.
 Able to improve or stop the progression of some of physical symptoms but don’t prevent the eventual cognitive regression that occurs in Hunter
syndrome patients.
(GROUP 25) MUCOPOLYSACCHARIDOSIS TYPE IV (MPS IV)
Definition:
Mucopolysaccharidosis Type IV (Morquio syndrome) is a disorder caused by deficiency of lysosomal enzyme
(N-acetylgalactosamine-6-sulphate sulphatase or β -galactosidase) required for degradation of
mucopolysaccharides/ glycosaminoglycans (GAGs), which is keratan sulphate.
Classification:
-Type IVA (deficiency of N-acetylgalactosamine-6-sulphate sulphatase)
-Type IVB (deficiency of β -galactosidase)
Type of inheritance:
Autosomal recessive
Risk
- Family history of this disorder.
Prevention
-Genetic counseling is recommended for couples who have family history of Mosquio Syndrome wanted to have
children.
-Counseling for families who have child with Morquio syndrome to help them understand the condition.
-Prenatal testing for couples who wants to have children.
GROUP 26
MUCOPOLYSACCHARIDOSIS TYPE IV (MPS IV)
PATHOGENESIS :
• Deficiency of either N -acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in Morquio syndrome type
IVA OR β -galactosidase (GLB1 gene) in Morquio syndrome type IVB, which is involve in degradation of
keratan sulfate (KS).
• The specific mechanism or mechanisms by which excess storage of KS results in the skeletal dysplasia unique
to Morquio syndrome.
• Keratan sulfate is predominantly found in cartilage and cornea, the major organs affected in Morquio
syndrome (mucopolysaccharidosis type IV).
• The normal metabolism of heparan and dermatan sulfate in patients with Morquio syndrome
(mucopolysaccharidosis type IV) spares these patients from mental retardation and disease manifestations
observed in other types of MPS.
Dx :
• Increase urinary KS excretion.

07/22/2021
(GROUP 27)
MPS IV - PATHOPHYSIOLOGY
• Inability to degrade GAGs – Keratan sulfate (KS)
• Accumulation of partially degraded GAG thickening of tissue and compromising of cell and organ function
• GAGs are degraded by lysosomal enzymes
• Enzyme deficiency catabolism of GAG may be blocked
• Morquio A : deficiency of N-acetyl-galactosamine-6-sulfate sulfatase
• Morquio B : deficiency of β-galactosidase

Treatment for MPS IV

• Enzyme Replacement Therapy
• Morquio A - elosulfase alfa (Vimizim)
• Vimizim is an exogenous recombinant human GALNS enzyme that is
• Taken up into the lysosome via mannose-6-phosphate receptor binding
• Within the lysosome, Vimizim increases catabolism of GAGs
• Restoring cell function.
• Morquio B – no found treatment

07/22/2021
Pyruvate Carboxylase
Deficiency
• Pyruvate Decarboxylase : An enzyme that convert Pyruvate to
Oxaloacetate(4 Carbon Fragment)
• Inherited Disorder : Autosomal Recessive

• Type A : North American phenotype

• Type B : French phenotype
• Type C : Benign phenotype
Pathogenesis of pyruvate carboxylase
deficiency
• In pyruvate carboxylase deficiency (PCD), an autosomal recessive condition, there is
a defect on the gene locus 11q13.4-q13.5.
• Pyruvate carboxylase is needed to convert pyruvate to oxaloacetate, which is needed
in the first step of TCA cycle, gluconeogenesis and removal of ammonia via aspartic
acid.
• PCD causes impaired cell respiration, and increased quantities of lactic acid, alanine,
ketones and acetyl-CoA are produced.
• Gluconeogenesis is also impaired, which results in poor cell function during low
glucose level, and level of ammonia circulating in the blood is increased.
• In diagnosis of PCD, serum lactate and pyruvate levels are increased, as well as
serum alanine level. There is also elevated levels of lactate and pyruvate in
cerebrospinal fluid. Hyperammonaemia is also present.
Pathophysiology
• The production of citrate , at the first substrate in the citric acid cycle is
limited which prevents the citric acid cycle from functioning .
• The precursor of oxaloacetate, pyruvate, is shunted toward alternate
metabolic pathways, leading to an increase in lactic acid, alanine, and
acetylcoenzyme A (acetyl-CoA). Acetyl-CoA cannot produce citrate without
oxaloacetate and is shunted to produce ketone bodies.
• Gluconeogenesis also cannot proceed without oxaloacetate, resulting in
hypoglycemia during times of prolonged fasting. Tissues that are solely
dependent on glucose for fuel, such as the brain are severely compromised
during fasting states. Because cells cannot use the citric acid cycle to
produce energy, energy is extracted from glucose exclusively through
glycolysis. The highly inefficient process of glycolysis causes glucose to be
degraded at a high rate, resulting in a glucose deficit, thereby compounding
the problem.
• Aspartic acid, which is derived from oxaloacetate, is required for the urea
cycle. A decrease in aspartic acid production reduces ammonia disposal
and leads to increased serum ammonia levels.
PDH defect (Pyruvate dehydrogenase complex deficiency)

•Inheritance - Autosomal recessive (rare) or X-linked dominant (common)

- most common neurodegenerative disorders associated with abnormal
mitochondrial metabolism

•Characterized by a wide range of clinical signs with metabolic and neurological components of
varying severity ( eg, short neck, slight shortening of the limbs)

•Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological
disorders

•Abnormal lactate build up results in nonspecific symptoms (eg, severe lethargy, poor feeding,
tachypnea), especially during times of illness, stress, or high carbohydrate intake

•Progressive neurological symptoms start in infancy, may be evident at birth or in later childhood

•Risk factor – genetic predisposition

•Prevention
* genetic counseling

 
 Group 38
I) NUR SYAFINA NOMA BT.MOHAMMAD FAHMI NOMA
50818
II) NURUL FATIHA ZURAIDI
53457

PDH defect-pathogenesis and diagnosis

• Majority of cases of PDH deficiency causes by a defect in the E1 enzyme which revealed
mutations only in the E1α subunit gene. The gene for this subunit is located on the X-
chromosome in the region Xp 22.1 and this may account for both the frequency E1α mutations
and differences in genetic, clinical and biochemical features between males and females with
PDH deficiency.The majority of female patients are heterozygous for frameshift mutations
which lead to complete PDH deficiency whereas males have either missense mutations or
frameshift mutations near to the C-terminal end of the protein, both of which result in some
residual enzyme activity.

• Diagnosis : screening system for identification of primary PDH E1α gene mutations based on
complementation of the enzyme defect by transfection of the normal cDNA, Genetic Testing
Registry (Pyruvate dehydrogenase E1-beta deficiency, Pyruvate dehydrogenase E2 deficiency,
Pyruvate dehydrogenase E3-binding protein deficiency, Pyruvate dehydrogenase E3-binding
protein deficiency, Pyruvate dehydrogenase phosphatase deficiency, and management
byDrug Therapy,Surgery and Rehabilitation,Genetic Counseling,Palliative Care)
 Pyruvate Dehydrogenase Complex Deficiency Treatment & Management
http://emedicine.medscape.com/article/948360-treatment#d7

Pyruvate Dehydrogenase Deficiency

(Pathophysiology)
•Administration of thiamine and lipoic acid cofactors
To optimize pyruvate dehydrogenase complex function.
Important cofactor for the pyruvate dehydrogenase complex E1
enzyme.

•Lipoic acid
•Intermediate acceptor of the acetyl group formed in the reaction.

•Carnitine
To facilitate fatty acid transport into mitochondria and to
potentially increase cellular ATP production.

•Ketogenic diets (with restricted carbohydrate intake)

 To control lactic acidosis with minimal success
Pyruvate Kinase
Defect
Definition
Pyruvate kinase deficiency is an inherited metabolic disorder of
the enyzme pyruvate kinase which affect the red blood cell.

Classification
Hereditary pyruvate kinase deficiency
Acquired pyruvate kinase deficiency

Mode of Inheritance
Autosomal recessive

How It Relates To Patients’ Education

Prevention
Patients should understand their need to use folic acid and
Vitamin B supplements regularly and to avoid salicylates.
The risk of recurrence is low.
Pathogenesis
Deficiency of PK will affect the last step of glycolysis where phosphoenolpyruvate is
converted to pyruvate.

How It Relates To the Diagnosis

Physical exam
Symptoms like fatigue, shortness of breath and palor can be the first sign the patient is
anemic. When the patient also has jaundice and dark urine, the doctors will
probably suspect the anemia is due to a higher destruction of the red blood cells (also
called hemolysis) and will do a blood test to confirm this.
Blood test
have low hemoglobin levels due to the early destruction of the red blood cells, which also
leads to high billirubin levels (a waste product of rbc). Because the body compensates for
this destruction by producing more red blood cells, there will be a higher rate of young,
immature red blood cells (also called reticulocytes)(CAN BE FOUND IN BLOOD SMEAR)
Genetic diagnosis
The best way to confirm the diagnosis of PKD is by genetic testing. The mutations affect
one single gene (the PKLR gene). This gene codes for a protein called pyruvate kinase. In
PKD, the protein does not function properly and the rbc lives considerably shorter than
normal. By testing the DNA and searching for one of these mutation(s) in the PKLR gene,
the diagnosis of PKD can be confirmed. The genetic testing is done through a blood test.
Enzyme activity
A presumption of PKD can then be confirmed through a blood test measuring the
enzyme activity rate of the pk enzyme. Since pkd is caused by a lack of the pk enzyme, a
lower activity rate can confirm the diagnosis.
Pathophysiology
1. Erythrocytes in pyruvate kinase deficiency
2. Isoenzymes
3. Iron overload

Treatment
4. Blood transfusion
5. Splenectomy
6. Supplemental folic acid and B vitamins
 Prevention : Classification:
Avoidance of sucrose and Primary sucrase- isomaltase
maltose intake (sugar cane, deficiency
rock candy, brown sugar, cotton Secondary sucrase-
candy, maple syrup) isomaltase deficiency
Definition:
Deficiency of enzyme sucrase
need for proper metabolism of
sucrose (sugar)

Risk factor: paediatrician,

chronic diarrhoea, genetic Type of inheritance: autosomal
abnormality, early weaning of recessive inheritance
infants, inappropriate diet
 PATHOGENESIS OF
SUCROSE INTOLERANCE

1. The sucrase-isomaltase gene localized 3. Diagnosis

o Endoscopic biopsy
on chromosome 3q25-q26 are mutated. o Carbon-13 breath test
2. Sucrose pass undigested through the o Genetic test of sucrase-
intestine, serve as food for bacteria isomaltase gene
Treatment of Sucrose Intolerance
(Pathophysiology)
• Oral Enzyme Replacement (for
congenital sucrose intolerance)
‫ ـ‬Sacrosidase provide
replacement therapy for the
deficient sucrase
‫ ـ‬replaced sucrase  helps to
digest sucrose to reduce
diarrhea, gas production,
bloating, vomiting, nausea &
abdominal cramps
• Glucose electrolyte mixture 
prevent dehydration d/t diarrhea
• Lower sucrose intake