Protein Related

Disorders
College of Pharmacy
Marasmus
Marasmus
❑ Marasmus occurs when calorie
deprivation is relatively greater than
the reduction in protein.
❑ It usually occurs in developing
countries in children younger than age
1 year when breast milk is
supplemented with watery gruels of
native cereals that are usually deficient
in both protein and calories.
Marasmus

❑ Typical symptoms include

-arrested growth
-extreme muscle wasting
-loss of subcutaneous fat (emaciation),
-weakness, and
-anemia
Kwashiorkor
❑ Kwashiorkor occurs when protein deprivation is
relatively greater than the reduction in total calories.
❑ Protein deprivation is associated with severely decreased
synthesis of visceral protein.
❑ Kwashiorkor is commonly seen in developing countries in
children after weaning at about age 1 year, when their
diet consists predominantly of carbohydrates.
Kwashiorkor
❑ Typical symptoms include
-stunted growth, -skin lesions, -anorexia,
-depigmented hair, -enlarged fatty liver,
-edema (results from the lack of adequate blood proteins,
primarily albumin,to maintain the distribution of
water between blood and tissues) It may mask muscle
loss.
-decreased serum albumin concentration.

Therefore,chronic malnutrition is reflected in the level of

serum albumin. [Note : Because caloric intake from
carbohydrates maybe adequate, insulin levels suppress lipolysis
and proteolys is. Kwashiorkor is nonadapted malnutrition.]
Kwashiorkor vs Marasmus
 PRION DISEASES
The prion protein (PrP) has been strongly implicated as the
causative agent of transmissible spongiform
encephalopathies (TSEs), including:

-Creutzfeldt-Jakob disease in humans

-scrapie in sheep
-bovine spongiform encephalopathy in cattle
(popularly called “mad cow” disease).
 ALZHEIMER DISEASE
-normal protein assumes a conformation that is cytotoxic

normal proteins, after abnormal chemical processing, take

on a
unique conformational state that leads to the formation of
neurotoxic amyloid
β peptide (Aβ) assemblies consisting of β-pleated sheets.
HEMOGLOBINOPATHIES
-are defined a s a group of genetic disorders caused by
production of a structurally abnormal hemoglobin molecule;
synthesis of insufficient quantities of normal hemoglobin; or,
rarely, both.
Result from production of hemoglobin with an altered amino
acid sequence (qualitative hemoglobinopathy)
-Sickle cell anemia (HbS),
-hemoglobin C disease (HbC)
-hemoglobin SC disease (HbS + HbC = HbSC)
caused by decreased production of normal hemoglobin
(quantitative hemoglobinopathy).
-thalassemias
Sickle cell anemia
(hemoglobin S disease )
-most common of the RBC sickling diseases, is a genetic
disorder of the blood caused by a single nucleotide
substitution in the gene for β-globin.
-is an autosomal recessive disorder.
-It occurs in individuals who have inherited two
mutant genes (one from each parent) that code for synthesis of
the β chains of the globin molecules.
-is characterized by lifelong
episodes of pain (“crises”); chronic hemolytic anemia with
associated hyperbilirubinemia; and increased susceptibility to
infections, usually beginning in infancy. [Note: The lifetime of a
RBC in sickle cell anemia is less than 20 days, compared with
120 days for norma l RBC, hence , the anemia.]
Sickle cell anemia
(hemoglobin S disease )
symptoms include:
-acute chest syndrome
-stroke
-splenic
-renal dysfunction
-bone changes due to marrow hyperplasia.
Hemoglobin C disease

hemoglobin variant that has a single amino acid substitution in

the sixth position of the β-globin chain

however, a lysine is subs tituted for the glutamate (as

compared with a valine substitution in HbS).
Hemoglobin SC disease
is another of the RBC sickling diseases.

In this disease,
some β-globin chains have the s ickle cell mutation, whereas
other β-globin cha ins carry the mutation found in HbC disease.

The clinical course of adults with HbSC anemia differs from that
of s ickle cell anemia in that symptoms such a s painful crises a
re less frequent and less severe.
Methemoglobinemias
Oxidation of the heme iron in hemoglobin to the ferric (Fe3+)
state forms methemoglobin, which cannot bind O2.

The methemoglobinemias are characterized by “chocolate

cyanosis” (a brownish blue coloration of the skin and mucous
membranes and brown-colored blood) as a result of the
dark-colored HbM.
Methemoglobinemias
Symptoms are related to the degree of tissue hypoxia and
include

-anxiety
-headache
-dyspnea
In rare cases
-coma and death can occur

Treatment is with methylene blue, which is oxidized as Fe+3 is

reduced.
Thalassemias
are hereditary hemolytic diseases in which an imbalance occurs
in the synthesis of globin chains.
are the most common single gene disorders in humans.
A thalassemia can be caused by a variety of mutations,
including entire gene deletions, or substitutions or deletions of
one to many nucleotides in the DNA.

[Note: Each thalassemia can be classified as either a disorder in

which no globin chains are produced (αo- or βo-thalassemia), or
one in which some chains are synthesized but at a reduced level
(α+- or β+-thalassemia).]
β-Thalassemias
In these disorders, synthesis of β-globin chains is decreased or
absent, typically as a result of point mutations that affect the
production of functional mRNA.

those infants born with β-thalassemia major are seemingly

healthy at birth but become severely anemic, usually during the
first or second year of life due to ineffective erythropoiesis.
Skeletal changes as a result of extramedullary hematopoiesis
also are seen.These patients require regular transfusions of
blood.
β-Thalassemias
are hereditary hemolytic diseases in which an imbalance occurs
in the synthesis of globin chains.
are the most common single gene disorders in humans.
A thalassemia can be caused by a variety of mutations,
including entire gene deletions, or substitutions or deletions of
one to many nucleotides in the DNA.

[Note: Each thalassemia can be classified as either a disorder in

which no globin chains are produced (αo- or βo-thalassemia), or
one in which some chains are synthesized but at a reduced level
(α+- or β+-thalassemia).]
β-Thalassemias
are hereditary hemolytic diseases in which an imbalance occurs
in the synthesis of globin chains.
are the most common single gene disorders in humans.
A thalassemia can be caused by a variety of mutations,
including entire gene deletions, or substitutions or deletions of
one to many nucleotides in the DNA.

[Note: Each thalassemia can be classified as either a disorder in

which no globin chains are produced (αo- or βo-thalassemia), or
one in which some chains are synthesized but at a reduced level
(α+- or β+-thalassemia).]
α-Thalassemias
synthesis of α-globin chains is decreased or absent, typically as
a result of deletional mutations.
Because each individual’s genome contains four copies of the
α-globin gene (two on e a ch chromosome 16), there are
several levels of α-globin chain deficiencies.
✔ If one of the four genes is defective, the individual is termed
a silent carrier of α-thalassemia, because no physical
manifestations of the disease occur.
✔ If two α-globin genes are defective, the individual is
designated as having α-thalassemia trait.
α-Thalassemias
✔ If three α-globin genes are defective , the individual has
hemoglobin H (β4) dise ase,a hemolytic anemia of variable
severity.

✔ If all four α-globin genes are defective, hemoglobin Bart (γ4)

disease with hydrops fetalis and fetal death results, because
α-globin chains are required for the synthesis of HbF.
Collagenopathies
Defects in any one of the many steps in collagen fiber
synthesis can result in a genetic disease involving an inability
of collagen to form fibers properly and, therefore, an inability
to provide tis sue s with the needed tensile s trength
normally provided by collagen.

-Ehlers -Danlos s yndrome

-Osteogenesis imperfecta: Type I and Type II
Ehlers -Danlos syndrome
is a heterogeneous group of connective tis sue disorders that
result from inheritable defects in the metabolism of fibrillar
collagen molecules.EDS can be caused by a deficiency of
collagen-processing enzymes
Osteogenesis imperfecta:
known as brittle bone disease, is a genetic disorder of bone
fragility characterized by bones that fracture easily, with minor
or no trauma.
TYPE I OI-most common form, is characterized by mild bone
fragility, hearing loss , and blue sclerae.
Type II, the most severe form,is typically lethal in the perina
tal period as a result of pulmonary complications.
Type III is also a severe form. It is characterized by multiple
fractures at birth, short stature , spinal curvature leading to a
“humped-back”(kyphotic) appearance , and blue sclerae.
*Dentinogenesis imperfecta , a disorder of tooth
development, may be seen in OI.
Disorders of elastin
degradation
α1-Antitryps in (AAT) deficiency
α1-antitryps in deficiency
In the alveoli, elastase released by a ctivated and degenera
ting neutrophils is normally inhibited by AAT.

Genetic defects in AAT can lead to emphysema (lung) and

cirrhos is (liver).

Smoking increases risk.

The deficiency of elastase inhibitor can be reversed by wee

kly intravenous administration of AAT.
Case Study No. 1
For the child shown a t right, which of the
statements is true and supports a diagnosis of
kwashiorkor? The child:

A. appears plump due to increased

deposition of fat in adipose tissue .
B. displays abdominal and peripheral edema.
C. has a serum albumin level above normal.
D. has markedly decreased weight for height.
Case Study No. 1
ANSWER
Case Study No. 2

An 80-year-old man presented with impairment of higher intellectual function and

alterations in mood and behavior. His family reported progres s ive disorientation and
memory loss ove r the la st 6 months. There is no family history of dementia. The pa
tient was tentatively diagnosed with Alzheimer diseas e. Which one of the following
best describes Alzheimer disease?

A. It is a ssociate d with β-amyloid, an abnormal protein with an altered amino acid

sequence .
B. It re sults from a ccumula tion of dena tured proteins that have random
conformations.
C. It is a s socia ted with the accumulation of amyloid precursor protein.
D. It is a s s ocia te d with the deposition of neurotoxic amyloid β peptide aggregates.
E. It is an environmentally produced disease not influenced by the genetics of the
individual.
F. It is caused by the infectious β-sheet form of a hostcell protein.
Case Study No. 2
ANSWER
Case Study No. 3

A 67-year-old man presented to the emergency department

with a 1-week history of angina and shortness of
breath. He complained that his face and extremities had
a “blue color.” His medical history included chronic stable
angina treated with isosorbide dinitrate and nitroglycerin.
Blood obtained for analysis was brown colored. Which
one of the following is the most likely diagnosis?
A. Carboxyhemoglobinemia
B. Hemoglobin SC disease
C. Methemoglobinemia
D. Sickle cell anemia
E. β-Thalassemia
Case Study No. 3
ANSWER
Case Study No. 4

A 30-ye ar-old woman of Northe rn European ancestry presents with progre s s

ive dyspne a (shortnes s of bre a th). She denies the use of cigarettes . Family
history revea ls that her sister also has problems with her
lungs . Which one of the following e tiologie s most likely explains this
patient’s pulmonary symptoms?

A. Deficiency in dietary vitamin C

B. Deficiency of α1-antitryps in
C. Deficiency of prolyl hydroxyla se
D Decreased elastase activity
E. Increased collagenase activity
Case Study No. 4
ANSWER