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Kuldeep Kinja et. al. / JPBMS, 2011, 5 (09)
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ISSN NO- 2230 - 7885
Original Review Article
JPBMS
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES
A REVIEW ON
Hereditary Disorders
1Kinja
Kuldeep*, 1Patel Hiten, 1Gupta Nakul
of Pharmacy, Shobha Nagar, Jaipur-303121
Rajasthan, India.
1NIMS Institute
Abstract
Genetic disorders are either hereditary disorders or a result of mutations. Some disorders may confer an advantage, at
least in certain environments. A genetic disorder is an illness caused by abnormalities in genes or chromosomes. Most
disorders are quite rare and affect one person in every several thousands or millions. Some types of recessive gene
disorders confer an advantage in the heterozygous state in certain environments. Genetic disorders rarely have effective
treatments, though gene therapy is being tested as a possible treatment for some genetic diseases.
There are mainly two types of genetic disorders are there. These are Single gene disorder and multifactorial and
polygenic (complex) disorders. Single gene disorders are again of different types- Autosomal dominant, Autosomal
recessive, X-linked dominant, X-linked recessive, Y-linked and Mitochondrial.
Currently around 4,000 genetic disorders are known, with more being discovered. Most disorders are
quite rare and affect one person in every several thousands or millions. In this article we only discussed about main four
hereditary disorders which are having a high mortality and occurrence rate. These are Neurofibromatosis, CharcotMarie-Tooth disease (CMT), Haemophilia and Sickle Cell Anaemia.
Key Words: Hereditary, Neurofibromatosis, Charcot-Marie-Tooth disease (CMT), Haemophilia and Sickle Cell
Anaemia.
Introduction:
Hereditary Disease is an illness caused by abnormalities
in genes or chromosomes. While some diseases, such as
cancer, are due in part to a genetic disorder, they can also
be caused by environmental factors. Most disorders are
quite rare and affect one person in every several
thousands or millions. Several ways or mechanisms by
which these disorders passes to subsequent generation
are[1]
Single gene order:
A single gene disorder is the result of a single mutated
gene. There are estimated to be over 4000 human
diseases caused by single gene defects. Single gene
disorders can be passed on to subsequent generations in
several ways. Achondroplasia is one of the examples.
a) Autosomal dominant:
Only one mutated copy of the gene is necessary for a
person to be affected by an autosomal dominant disorder.
Each affected person usually has one affected parent.
There is a 50% chance that a child will inherit the
mutated gene. Neurofibromatosis and colorectal cancer
are its examples.
b) Autosomal recessive:
Two copies of mutated genes are must for a person to be
affected by an autosomal recessive disorder. An affected
person usually has unaffected parents who each carry a
*Corresponding Author
Kuldeep Kinja,
Department of Pharmacology,
NIMS Institute of Pharmacy, Shobha Nagar, Jaipur-303121,
India.
1
single copy of the mutated gene (and are referred to as
carriers).For example sickle-cell anemia, spinal muscular
atrophy.
c) X-linked dominant:
X-linked dominant disorders are caused by mutations in
genes on the X chromosome. For example X-linked
hypophosphatemia rickets. The chance of passing on an
X-linked dominant disorder differs between men and
women. The sons of a man with an X-linked dominant
disorder will all be unaffected (since they receive their
father's Y chromosome), and his daughters will all inherit
the condition. A woman with an X-linked dominant
disorder has a 50% chance of having an affected foetus
with each pregnancy.
d) X-linked recessive:
X-linked recessive disorders are also caused by mutations
in genes on the X chromosome. The sons of a man with an
X-linked recessive disorder will not be affected, and his
daughters will carry one copy of the mutated gene. A
woman who is a carrier of an X-linked recessive disorder
has a 50% chance of having sons who are affected and a
50% chance of having daughters who carry one copy of
the mutated gene and are therefore carriers. Hemophilia
and Red-green color blindness are its examples.
e) Y- Linkage:
Y-linked disorders are caused by mutations on the Y
chromosome. Because males inherit a Y chromosome
from their fathers, son of an affected father will be all
affected. Because females inherit an X chromosome from
their fathers of affected fathers are never affected. Since
the Y chromosome is relatively small and contains very
few genes, there are relatively few disorders. Male
infertility is one the example.
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Kuldeep Kinja et. al. / JPBMS, 2011, 5 (09)
Mitochondrial:
This type of inheritance, also known as maternal
inheritance and caused due to mutation in genes in
mitochondrial DNA. Only females can pass on
mitochondrial conditions to their children. Hereditary
Optic Neuropathy is one of the examples.
•
•
•
Multifactorial and Polygenic disorders:
These disorders are also known as complex disorders
means that they are likely associated with the effects of
multiple genes in combination with lifestyle and
environmental factors. Multifactorial disorders include
heart disease and diabetes. They do not have a clear-cut
pattern of inheritance that makes them difficult to
determine a person’s risk of inheriting or passing on
these disorders. Complex disorders are also difficult to
study and treat because the specific factors that cause
most of these disorders have not yet been identified.
• asthma
• autism
• autoimmune diseases such as multiple sclerosis
• cancers
• diabetes
• heart disease
• hypertension
• inflammatory bowel disease
• mental retardation
• obesity
(i.e. bones of the leg, potentially resulting in bowing
of the legs)
Lisch nodules (hamartomas of iris), freckling in the
iris.
Tumors on the optic nerve, also known as an optic
glioma
A first-degree relative with a diagnosis of NF1.
(Figure 2)
Figure 1 : Plexiform neurofibroma
Figure 2: Patient with multiple small cutaneous
neurofibromas
Neurofibromatosis:
Neurofibromatosis (commonly abbreviated NF) is a
genetically-inherited disease in which nerve tissue grows
tumors known as neurofibromas that may be harmless or
may cause serious damage by compressing nerves and
other tissues. The disorder affects all neural crest cells
(Schwann cells, melanocytes, endoneurial fibroblasts).
Cellular elements from these cell types proliferate
excessively throughout the body forming tumors and the
melanocytes function abnormally resulting in disordered
skin pigmentation. The tumors may cause bumps under
the skin, colored spots, skeletal problems, pressure on
spinal nerve roots, and other neurological[2, 3].
Diagnostic Criteria:
Neurofibromatosis type 1:
Neurofibromatosis type 1 - mutation of neurofibromin
chromosome 17q11.2. The diagnosis of NF1 is made if
any two of the following seven criteria are met:
• Two or more neurofibromas on the skin or under the
skin or one plexiform neurofibroma (a large cluster
of tumors involving multiple nerves); Neurofibromas
are the subcutaneous lumps that are characteristic of
the disease and increase in number with age. (Figure
1)
• Freckling of the groin or the axilla (arm pit).
• Café au lait spots (pigmented, most often a shade of
brown birthmarks). Six or more measuring 5 mm in
greatest diameter in prepubertal individuals and
over 15 mm in greatest diameter in postpubertal
individuals
• Skeletal abnormalities, such as sphenoid dysplasia or
thinning of the cortex of the long bones of the body
2
Neurofibromatosis type 2:
Following symptoms may be there:o Bilateral tumors, acoustic neuromas on the
vestibulocochlear nerve (the eighth cranial nerve)
leading to hearing loss
o In fact, the hallmark of NF2 is hearing loss due to
acoustic neuromas around the age of twenty
o The tumors may cause:
Headache
Balance problems, and Vertigo
Facial weakness/paralysis
Patients with NF2 may also develop other brain
tumors, as well as spinal tumors
Deafness and Tinnitus
# NF-1 and NF-2 may be inherited in an autosomal
dominant fashion, as well as through random mutation.
Neurofibromatosis type 1 is due to mutation on
chromosome 17q11.2, the gene product being
Neurofibromin ( a GTPase activating enzyme).
Neurofibromatosis type 2 is due to mutation on
chromosome 22q, the gene product is Merlin, a
cytoskeletal protein.
Both NF1 and NF2 are autosomal dominant disorders,
meaning that only one copy of the mutated gene need be
inherited to pass the disorder [4].
Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05
Kuldeep Kinja et. al. / JPBMS, 2011, 5 (09)
Treatment:
Because there is no cure for the condition itself, the only
therapy for those people with neurofibromatosis is a
program of treatment by a team of specialists to manage
symptoms or complications. Surgery may be needed
when the tumors compress organs or other structures.
Less than 10% of people with neurofibromatosis develop
cancerous growths; in these cases, chemotherapy may be
successful. A new clinical trial at NIH uses a drug called
Peg-intron. There are some accounts of cures in foreign
countries. Though nothing has proved by the American
FDA to be effective, alternative resources would say
otherwise. Some people may find something in the herbal
remedies that can slow down the growth of these tumors.
Peg-Intron (peginterferon alfa-2b) Powder for Injection
has been approved by the FDA as a once-weekly
monotherapy for the treatment of Neurofibromatosis. It
is indicated for patients with compensated liver disease
who were not previously treated with alpha interferon.
Peg-Intron is the first pegylated interferon to be
approved in the United States, and therefore offers a new
treatment option.
disease is one of the most common inherited neurological
disorders, with 37 in 100,000 affected.
Description:
The disorder is caused by the absence of proteins that are
essential for normal function of the nerves due to errors
in the gene coding molecules. The absence of these
chemical substances gives rise to dysfunction either in
the axon or the myelin sheath of the nerve cell. Most of
the mutations identified result in disrupted myelin
production.
The different classes of this disorder have been divided
into the primary demyelinating neuropathies (CMT1,
CMT3, and CMT4) and the primary axonal neuropathies
(CMT2). Recent studies, however, show that the
pathologies of these two classes are frequently
intermingled, due to the dependence and close cellular
interaction of Schwann cells and neurons. Schwann cells
are responsible for myelin formation, enwrapping neural
axons with their plasma membranes in a process called
“myelination”[6, 7].
Symptoms:
Side Effects:
Peg-Intron may cause serious neuropsychiatric,
autoimmune, ischemic and infectious disorders. As a
result, patients receiving treatment should be closely
monitored, and those with persistently severe or
worsening signs or symptoms of these conditions should
discontinue therapy.
In clinical trials, nearly all subjects experienced one or
more adverse events. The most common adverse events
associated with Peg-Intron were "flu-like" symptoms,
which occurred in approximately 50% of subjects.
Injection site irritation or inflammation was seen in 47%
of subjects, and depression was reported in
approximately 29% of subjects.
Mechanism of Action:
Peg-Intron utilizes proprietary PEG technology
developed by Enzon. By linking recombinant interferon
to a 12,000 Dalton polyethylene glycol (PEG) molecule,
the anti-viral properties of interferon can be sustained
for a longer period of time.
Interferon bind to specific cell surface membrane
receptors and have been shown to exert antiviral and
immunomodulatory effects. After binding to the cell
membrane, the glycoproteins initiate intracellular events
including the suppression of cell proliferation, the
enhancement of macrophage activity, and the inhibition
of viral replication in infected cells. (From Intone
Prescribing Information)[5].
Charcot-Marie-Tooth Disease:
Charcot-Marie-Tooth disease (CMT), known also as
Hereditary Motor and Sensory Neuropathy (HMSN),
Hereditary Sensorimotor Neuropathy (HSMN), or
Peroneal Muscular Atrophy, is a heterogeneous inherited
disorder of nerves (neuropathy) that is characterized by
loss of muscle tissue and touch sensation, predominantly
in the feet and legs but also in the hands and arms in the
advanced stages of disease. Presently incurable, this
3
Symptoms usually begin in late childhood or early
adulthood. Usually, the initial symptom is foot drop early
in the course of the disease. This can also cause hammer
toe, where the toes are always curled. Wasting of muscle
tissue of the lower parts of the legs may give rise to
"stork leg" or "inverted bottle" appearance. Weakness in
the hands and forearms occurs in many people later in
life as the disease progresses.
Symptoms and progression of the disease can vary.
Breathing can be affected in some; so can hear, vision,
and the neck and shoulder muscles. Scoliosis is common.
Hip sockets can be malformed. Gastrointestinal problems
can be part of CMT, as can chewing, swallowing, and
speaking (as vocal cords atrophy). A tremor can develop
as muscles waste. Pregnancy has been known to
exacerbate CMT, as well as extreme emotional stress [8, 9].
Treatment:
Although there is no current standard treatment, the use
of ascorbic acid has been proposed, and has shown some
benefit in animal models. A clinical trial to determine the
effectiveness of high doses of ascorbic acid (vitamin C) in
treating humans with CMT type 1A has been conducted.
The results of the trial upon children have shown that a
high dosage intake of ascorbic acid is safe but the efficacy
endpoints expected were not met [10, 11].
People who have CMT are advised to maintain a healthy
weight, because extra weight can limit mobility and
places additional stress on the joints. They are also
advised to be moderately physically active, and to pay
special attention to the maintenance of their strength and
flexibility. Water therapy is particularly beneficial, since
the stress put on the joints is minimized.
The Charcot-Marie-Tooth Association classifies the
chemotherapy drug vincristine as a "definite high risk"
and states that "vincristine has been proven hazardous
and should be avoided by all CMT patients, including
those with no symptoms"[12].
There are also several corrective surgical procedures that
can be done to improve physical condition.
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Haemophilia:
It is a group of hereditary genetic disorders that impair
the body's ability to control blood clotting or coagulation,
which is used to stop bleeding when a blood vessel is
broken. In its most common form, haemophilia A, clotting
factor VIII is absent. In Haemophilia B, factor IX is
deficient. Haemophilia A occurs in about 1 in 5,000–
10,000 male births, while Haemophilia B occurs at about
1 in about 20,000–34,000.
These genetic deficiencies may lower blood plasma
clotting factor levels of coagulation factors needed for a
normal clotting process. The bleeding with external
injury is normal, but incidence of late re-bleeding and
internal bleeding is increased, especially into muscles,
joints, or bleeding into closed spaces. Major
complications include haemarthrosis, haemorrhage,
gastrointestinal bleeding, and menorrhagia.
Haemophilia A is caused by coagulation factor VIII (FVIII)
deficiency, haemophilia B by deficiency of coagulation
factor IX (FIX), and haemophilia C by deficiency of
coagulation factor XI. These clotting factor deficiencies
are caused by recessive mutations of the respective
clotting factor genes. As the recessive mutant FVIII and
FIX genes are located on the X chromosome, both
haemophilia A and haemophilia B are inherited in an Xlinked pattern[13].
Haemophilia B results from a wide range of
heterogeneous mutations spread throughout the FIX
gene. Most of these mutations are single-base
substitutions. Studies in various populations have found
evidence of a founder effect, where large numbers of
cases of mild haemophilia B are due to a small number of
founder mutations[17-19].
Probability:
If a female gives birth to a haemophiliac child, either the
female is a carrier for the disease or the haemophilia was
the result of a spontaneous mutation. Until modern direct
DNA testing, however, it was impossible to determine if a
female with only healthy children was a carrier or not.
Generally, the more healthy sons she bore, the higher the
probability that she was not a carrier.
If a male is afflicted with the disease and has children
with a female who is not even a carrier, his daughters will
be carriers of haemophilia. His sons, however, will not be
affected with the disease. The disease is X-linked and the
father cannot pass haemophilia through the Y
chromosome. Males with the disorder are then no more
likely to pass on the gene to their children than carrier
females, though all daughters they sire will be carriers
and all sons they father will not have haemophilia (unless
the mother is a carrier). (Figure 3)
Figure 3: Genetics of Hemophilia.
Causes:
Haemophilia A is an X-linked genetic disorder
involving a lack of functional clotting Factor VIII and
represents 90% of haemophilia cases.
• Haemophilia B is an X-linked genetic disorder
involving a lack of functional clotting Factor IX. It is
more severe but less common than haemophilia A.
• Haemophilia C is an autosomal genetic disorder (i.e.
not X-linked) involving a lack of functional clotting
Factor XI. Haemophilia C is not completely recessive:
heterozygous individuals also show increased
bleeding.
A mother who is a carrier has a 50% chance of passing
the faulty X chromosome to her daughter, while an
affected father will always pass on the affected gene to
his daughters. A son cannot inherit the defective gene
from his father.
Haemophilia A has a prevalence of about 1 in 10 000
males, while haemophilia B is less common, with a
prevalence of about 1 in 35 000 males.7 The combined
prevalence of both haemophilia A and B has been
estimated as approximately 1 in 5 000 live male births.
The most common mutation in haemophilia A is a large
inversion and translocation of exons 1 - 22 (together with
introns) away from exons 23 - 26, the mechanism of
which is homologous recombination between the F8A
gene in intron 22 and one of the F8A copies located
outside the FVIII gene.9,10 This intron 22 inversion
results in no FVIII protein being produced and is
responsible for about 40% of cases of severe haemophilia
A.11 This inversion arises almost exclusively in male
germ cells.12 A similar inversion involves intron 1 of the
FVIII gene, and has a prevalence of approximately 5% in
patients with severe haemophilia A[14-16].
•
4
Treatment:
Though there is no cure for haemophilia, it can be
controlled with regular infusions of the deficient clotting
factor, i.e. factor VIII in haemophilia A or factor IX in
haemophilia B. Factor replacement can be either isolated
from human blood serum, recombinant, or a combination
of the two. Some haemophiliac develop antibodies
(inhibitors) against the replacement factors given to
them, so the amount of the factor has to be increased or
non-human replacement products must be given, such as
porcine factor VIII.
Commercially produced factor concentrates such as
Advate, a recombinant Factor VIII produced by Baxter
International, come as a white powder in a vial which
must be mixed with sterile water prior to intravenous
injection.
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In early 2008, the US Food and Drug Administration
(FDA) approved Xyntha (Wyeth) anti-haemophiliac
factor, genetically engineered from the genes of Chinese
hamster ovary cells. Since 1993 (Dr. Mary Nugent)
recombinant factor products (which are typically
cultured in Chinese hamster ovary (CHO) tissue culture
cells and involve little, if any human plasma products)
have been available and have been widely used in
wealthier western countries.
In Western countries, common standards of care fall into
one of two categories: prophylaxis or on-demand.
Prophylaxis involves the infusion of clotting factor on a
regular schedule in order to keep clotting levels
sufficiently high to prevent spontaneous bleeding
episodes. On-demand treatment involves treating
bleeding episodes once they arise. In 2007, a clinical trial
was published in the New England Journal of Medicine
comparing on-demand treatment of boys (< 30 months)
with haemophilia A with prophylactic treatment
(infusions of 25 IU/kg body weight of Factor VIII every
other day) in respect to its effect on the prevention of
joint-diseases. When the boys reached 6 years of age,
93% of those in the prophylaxis group and 55% of those
in the episodic-therapy group had a normal index jointstructure on MRI.
It is recommended that people affected with haemophilia
do specific exercises to strengthen the joints, particularly
the elbows, knees, and ankles. Exercises include elements
which increase flexibility, tone, and strength of muscles,
increasing their ability to protect joints from damaging
bleeds. These exercises are recommended after an
internal bleed occurs and on a daily basis to strengthen
the muscles and joints to prevent new bleeding problems.
Many recommended exercises include standard sports
warm-up and training exercises such as stretching of the
calves, ankle circles, elbow flexions, and Quadriceps sets.
Alternative and complementary treatments:
While not a replacement for traditional treatments,
preliminary scientific studies indicate that hypnosis and
self-hypnosis can be effective at reducing bleeds and the
severity of bleeds and thus the frequency of factor
treatment. Herbs which strengthen blood vessels and act
as astringents may benefit patients with haemophilia;
however there is little or no peer reviewed research to
support these claims. Suggested herbs include: Bilberry
(Vaccinium myrtillus), Grape seed extract (Vitis vinifera),
Scotch broom (Cytisus scoparius), Stinging nettle (Urtica
dioica), Witch hazel (Hamamelis virginiana), and yarrow
(Achillea millefolia) [20, 21].
Sickle-Cell Disease:
Sickle-cell disease, or sickle-cell anaemia (or
drepanocytosis), is a life-long blood disorder
characterized by red blood cells that assume an
abnormal, rigid, sickle shape. Sickling decreases the cells'
flexibility and results in a risk of various complications.
The sickling occurs because of a mutation in the
hemoglobin gene. Life expectancy is shortened, with
studies reporting an average life expectancy of 42 and 48
years for males and females, respectively.
Sickle-cell disease, usually presenting in childhood,
occurs more commonly in people (or their descendants)
from parts of tropical and sub-tropical regions where
5
malaria is or was common. One-third of all indigenous
inhabitants of Sub-Saharan Africa carry the gene.
The prevalence of the disease in the United States is
approximately 1 in 5,000, mostly affecting African
Americans, according to the National Institutes of Health.
Signs and symptoms:
Sickle-cell disease may lead to various acute and chronic
complications, several of which are potentially lethal.
Vaso-occlusive crisis:
The vaso-occlusive crisis is caused by sickle-shaped red
blood cells that obstruct capillaries and restrict blood
flow to an organ, resulting in ischemia, pain, and often
organ damage. (Figure 4)
Figure 4: Shape of the RBC in Sickle cell anemia
Aplastic crises:
These are acute worsening of the patient's baseline
anemia, producing pallor, tachycardia, and fatigue. This
crisis is triggered by parvovirus B19, which directly
affects erythropoiesis (production of red blood cells).
Most patients can be managed supportively; some need
blood transfusion.
Splenic sequestration crises:
These are acute, painful enlargements of the spleen. The
abdomen becomes bloated and very hard. Management is
supportive, sometimes with blood transfusion.
Haemolytic crises:
These are acute accelerated drops in hemoglobin level.
The red blood cells break down at a faster rate. This is
particularly common in patients with co-existent G6PD
deficiency. Management is supportive, sometimes with
blood transfusions.
Pathophysiology:
Sickle-cell anaemia is caused by a point mutation in the βglobin chain of haemoglobin, causing the amino acid
glutamic acid to be replaced with the hydrophobic amino
acid valine at the sixth position. The β-globin gene is
found on the short arm of chromosome 11. The
association of two wild-type α-globin subunits with two
mutant β-globin subunits forms haemoglobin S (HbS).
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Healthy red blood cells typically live 90-120 days, but
sickle cells only survive 10–20 days[22, 23].
Inheritance:
•
•
1.
2.
Sickle-cell conditions are inherited from parents in
much the same way as blood type, hair color and
texture, eye color, and other physical traits.
The types of hemoglobin a person makes in the red
blood cells depend on what hemoglobin genes are
inherited from his parents.
If one parent has sickle-cell anaemia (SS) and the
other has sickle-cell trait (AS), there is a 50% chance
of a child's having sickle-cell disease (SS) and a 50%
chance of a child's having sickle-cell trait (AS).
When both parents have sickle-cell trait (AS), a child
has a 25% chance (1 of 4) of sickle-cell disease (SS),
as shown in the diagram.
Treatment:
Cyanate:
Hydroxyurea:
The first approved drug for the causative treatment of
sickle-cell anaemia, hydroxyurea, was shown to decrease
the number and severity of attacks in a study in 1995 and
shown to possibly increase survival time in a study in
2003. This is achieved, in part, by reactivating fetal
haemoglobin production in place of the haemoglobin S
that causes sickle-cell anaemia. Hydroxyurea had
previously been used as a chemotherapy agent, and there
is some concern that long-term use may be harmful, but
this risk has been shown to be either absent or very small
and it is likely that the benefits outweigh the risks.
Bone marrow transplants:
Dietary cyanate, from foods containing cyanide
derivatives, has been used as a treatment for sickle- cell
anemia. In the laboratory, cyanate and thiocyanate
irreversibly inhibit sickling of red blood cells drawn from
sickle cell anemia patients. However, the cyanate would
have to be administered to the patient for a lifetime, as
each new red blood cell created must be prevented from
sickling at the time of creation. Cyanate also would be
expelled via the urea of a patient every cycle of treatment.
Painful (vaso-occlusive) crisis:
Most people with sickle-cell disease have intensely
painful episodes called vaso-occlusive crises. The
frequency, severity, and duration of these crises,
however, vary tremendously. Painful crises are treated
symptomatically with analgesics; pain management
requires opioid administration at regular intervals until
the crisis has settled. For milder crises, a subgroup of
patients manages on NSAIDs (such as diclofenac or
naproxen). For more severe crises, most patients require
inpatient management for intravenous opioids; patientcontrolled analgesia (PCA) devices are commonly used in
this setting. Diphenhydramine is also an effective agent
that is frequently prescribed by doctors in order to help
control any itching associated with the use of opioids.
Folic acid and penicillin:
Children born with sickle-cell disease will undergo close
observation by the pediatrician and will require
management by a hematologist to assure they remain
healthy. These patients will take a 1 mg dose of folic acid
daily for life. From birth to five years of age, they will also
have to take penicillin daily due to the immature immune
system that makes them more prone to early childhood
illnesses.
Acute chest crisis:
Management is similar to vaso-occlusive crisis, with the
addition of antibiotics (usually a quinolone or macrolide,
since wall-deficient ["atypical"] bacteria are thought to
contribute to the syndrome), oxygen supplementation for
hypoxia, and close observation. Should the pulmonary
infiltrate worsen or the oxygen requirements increase,
6
simple blood transfusion or exchange transfusion is
indicated. The latter involves the exchange of a significant
portion of the patient’s red cell mass for normal red cells,
which decreases the percent of haemoglobin S in the
patient's blood.
Bone marrow transplants have proven to be effective in
children.
Future treatments:
Various approaches are being sought for preventing
sickling episodes as well as for the complications of
sickle-cell disease. Other ways to modify hemoglobin
switching are being investigated, including the use of
phytochemicals such as nicosan. Gene therapy is under
investigation[24,25].
Another treatment being investigated is Senicapoc.
References:
1Kuliev A, Verlinsky Y “Preimplantation diagnosis:A
realistic option for assisted reproduction and genetic
practice”. Curr. Opin. Obstet. Gynecol.2005: 17 (2): 179–
83.
2.Fauci, et al. Harrison's Principle Small Text of Internal
Medicine 16th Ed. p 2453.
3.Korf BR, Rubenstein AE. Neurofibromatosis: A
Handbook for Patients, Families, and Health Care
Professionals.2005
4.Feldkamp MM, Angelov L, Guha A Neurofibromatosis
Type 1 Peripheral Nerve Tumors: Aberrant Activation of
the Ras Pathway. Surgical Neurology.1999; 51:211-18
5.Neurofibromatosis. JAMA patient page.2008: Vol. 300
No. 3.
6.Krajewski KM, Lewis RA, Fuerst DR, et al. “Neurological
dysfunction and axonal degeneration in Charcot MarieTooth Disease type 1A".2000: Brain 123 (Pt 7): 1516–27.
7.Baloh RH, Schmidt RE, Pestronk A, Milbrandt J “Altered
axonal mitochondrial transport in the pathogenesis of
Charcot Marie-Tooth disease from mitofusin 2mutations".2007: J. Neurosci. 27(2): 422–30.
8.Berger P, Young P, Suter U “Molecular Cell Biology of
Charcot Marie-Tooth disease".2002: Neurogenetics 4 (1):
1–15.
9.Latour P, Fabreguette A, Ressot C, et al. "New mutations
in the X-linked form of Charcot-Marie-Tooth
disease". Eur. Neurol.1997: 37 (1): 38–42.
10.Andrew L Harris and Darren Locke (2009). Connexins
A Guide. New York: Springer.2009: pp. 574.
11.Brewer M, Changi F, Antonellis A, et al. "Evidence of a
founder haplotype refines the X-linked Charcot-Marie-
Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05
Kuldeep Kinja et. al. / JPBMS, 2011, 5 (09)
Tooth
(CMTX3)
locus
to
a
2.5
Mb
region".2008: Neurogenetics 9 (3): 191–5.
12.Passage E, Norreel JC, Noack-Fraissignes P, et al.
"Ascorbic acid treatment corrects the phenotype of a
mouse model of Charcot-Marie-Tooth disease".2004: Nat.
Med. 10 (4): 396–401.
13.Beutter E, Lichman MA, Coller BS, Kipps TJ, Seligshon
U. Williams Haematology. NewYork: MacGraw Hill, 6th
Edition,2001: pp: 1639-1657.
14.Gitschier J, Wood WI, Goralka TM et al.
“Characterization of the human factor VIII gene”. Nature
1984; 312:36-330.
15.Rossiter JP, Young M, Kimberland ML et al. “Factor VIII
gene inversions causing severe Haemophilia. A originate
almost exclusively in male germ cells”. Hum Mol Genet.
1994; 3:1035-1039.
16.Bangall RD, Waseem N, Green Pm, Giannelli F.
“Recurrent inversion breaking intron 1 of the factor VIII
gene is a frequent cause of severe haemophilia”. Blood
2002; 99: 168-174.
17.Jayandharam G, Shaji RV, Chandy M, Srivastava A.
Identification of factor IX gene defects using a multiplex
PCR and CSGE trilogy a fast report .J Throm Haemat,2003:
1(9): 201-204.
18.Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi
K “Nucleotide sequence of the gene for human factor IX
7
(antihaemophilic factor B)” Biochemistry 1985; 24: 37363750.
19.Mukherjee S, Mukhopadhyay A, Chaudhuri K “Analysis
of Haemophilia B database and stratagies for
identification of common point mutations in the factor IX
gene” Haemophilia 2003; 9: 187-192.
20.Guidelines for Management of Haemophilia, 2005: pp1-56.
21.Santagostino, E., P.M. Mannucci, and A. Bianchi
Bonomi. Guidelines for replacement therapy for
hemophilia and inherited coagulation disorders in Italy.
Hemophilia. 2000. 6:1-10.
22.Platt OS, Brambilla DJ, Rosse WF, et al. “Mortality in
sickle cell diease Life expectancy and risk factors for early
death". N. Engl. J. Med.1994; 330 (23): 1639–44.
23.Pearson H “Sickle cell Anaemia and severe infections
due to encapsulated bacteria". J Infect Dis 1977; 136
Suppl: S25–30.
24.Wong W, Powars D, Chan L, Hiti A, Johnson C, Overturf
G “Polysaccharide encapsulated bacterial infection in
Sickle cell anaemia: a thirty year epidemiologic
experience". Am J Hematol 1992; 39 (3): 176–82.
25.Jadavji T, Prober CG “Dactylitis in a child with Sickle
cell trait”. Can Med Assoc J. 1985; 132 (7): 814–5.
Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05