DMD and Thalassemia

10-02-12 Thalassemia and
Duchenne Muscular Dystrophy - a group of blood disorders passed down
through families, characterized by
a defect in the hemoglobin Thalassemia Thalassemia occurs when one
or more of the genes fail to produce
adequate amounts of proteins leading
to a shortage of one of the subunits. the oxygen-carrying component of red blood cells Hemoglobin Duchenne
Muscular Dystrophy History Consists of four subunits:
two alpha proteins, and
two beta proteins These aplha and beta proteins are produced by alpha globin genes and beta globin genes, respectively.

These genes produce equal amounts of alpha proteins and beta proteins to constitute the hemoglobin. - X - linked - Genetic Alteration in the
DMD gene Muscle degeneration Progressive loss
of strength Death of the muscle tissue Types of Thalassemia Alpha Thalassemia When the defect is on the
production of alpha protein Alpha globin is made by four genes –
2 on each strand of chromosome 16 Beta Thalassemia When the defect is on the production
of the beta protein Beta protein is made of two genes on
chromosome 11 – one on each strand Silent Carrier State Alpha Thalassemia Trait Hemoglobin H Disease Hydrops Fetalis Beta Thalassemia Trait Thalassemia Intermedia Cooley's Anemia Lack for alpha protein is insignificant

Generally no health problems

Called “silent carrier” because it is difficult to detect

Only one of the four globin genes is defective or absent Other Forms E Beta Thalassemia Sickle Beta Thalassemia Signs & Symptoms Complications Diagnosis Treatment Somewhat greater deficiency in alpha protein

Patients have smaller RBCs and can have mild anemia

Only two of the four genes are present or normal

Have two forms: cis- and trans-
Cis- form: the two genes are found on the same chromosome strand
Trans- form: the two genes are found on opposite strands cis- form trans- form Lack of alpha protein is great enough to cause severe anemia

Can also cause enlarged spleen, bone deformities and fatigue

Named for the abnormal hemoglobin H that destroys the RBC

Three of the four alpha globin genes are either defective or absent
NO alpha gene in the person’s DNA

This causes the gamma globulins produced by fetus to form hemoglobin Bart

Death occurs before or shortly after birth

In extremely rare cases, when condition is discovered before birth, in utero blood transfusions have allowed the birth of children with hydrops fetalis.
Lack for beta protein is insignificant

Generally no health problems except for mild anemia

Only one of the two globin genes is defective or abnormal
Can cause moderately severe anemia, bone deformities and enlargement of spleen

Has wide range of clinical severity

Thin borderline between Thalassemia Intermedia and Cooley’s Anemia

Patients need regular blood transfusions to improve quality of life
Calls for lifelong blood transfusions

May lead to “iron overload”

Requires chelation therapy to avoid organ failure (liver and heart) due to iron toxicity Occurs when Beta Thalassemia combines
with variant hemoglobin Hemoglobin E - one of the most common abnormal hemoglobin


Moderately severe anemia, with symptoms similar to
Thalassemia Intermedia Combination of Hemoglobin S and Beta Thalassemia

Condition varies to the amount of beta globin
produced by beta gene

The more beta globin, the less severe the condition No symptoms for:

Silent Carrier State Mild Anemia:

Alpha Thalassemia Trait and
Beta Thalassemia Trait

Mild anemia can make you
feel fatigued
Mild to Moderate Anemia
and Others
- Beta Thalassemia Intermedia
- Others:
-Slowed growth and
delayed puberty
-Bone problems
-Enlarged spleen Severe Anemia and Other Signs and Symptoms
-Hemoglobin H Disease or Beta Thalassemia Major
-Signs and symptoms occur within the first 2 years of life
-Others:
-Pale and listless appearance
-Dark urine
-Slowed growth and delayed puberty
-Enlarged spleen, liver and heart
-Bone problems Heart and Liver Diseases
-Iron overload may damage organs and tissues, especially the heart and liver.
-Heart disease such as heart failure, arrhythmias, and heart attack caused by iron overload is the main cause of death.
Infection
-Infections are a key cause of illness, and the second most common cause of death. Osteoporosis
-Many people who have thalassemias have bone problems including osteoporosis. Complete blood count (CBC) Hemoglobin electrophoresis Mutational analysis Prenatal testing
-Chorionic villus sampling
-Amniocentesis Regular Blood Transfusions
-should not take iron supplements Chelation Therapy
- remove excess iron from the body.
-Deferoxamine
-Deferasirox Folic Acid Supplements
-may be recommended in addition to treatment with blood transfusions and/or iron chelation therapy. It is a B vitamin that helps build healthy red blood cells.
Blood and Marrow Stem Cell Transplant
-replaces faulty stem cells with healthy ones from another person (a donor). Stem cells are the cells inside bone marrow that make red blood cells and other types of blood cells. ∞ first described by Neopolitan physicians Giovanni Semmola
in 1834 and Gaetano Conte in 1836

∞ named after Guillaume Benjamin Amand Duchenne
∂ described and detailed the case of a boy who had the condition.
∂ first who did a biopsy formicroscopic examination ∞DMD occurs in males when a child inherits
a mutated X chromosome from his mother.

∞It may also occur if the gene mutated from his mother’s eggs, or if the gene mutates early in the child’s embryonic development.
∞ rod shaped cytoplasmic protein
∞ group of muscles that work together to strengthen
muscle fibers and protect them from injury
∞ protects the muscle fibers from being damaged
while stressed during contraction
∞ mutations in the coding sequence for the
dystrophin gene produces a poorly
folded protein which is degraded Dystrophin Causes, Prevalence, Incidence,
Risk Factors ∞ caused by a defective gene for dystrophin which
helps maintain muscle structure
∞ worsens quickly, unlike other muscular dystrophies
∞ affects 1 in every 3,600 male births
∞ sons of carrier females have a 50% chance of having
the disease, while the daughter has a 50% chance of being a carrier
∞ risks include a family history of DMD Clinical Features of Genotype DMD ∞ gene is located on the Xp21 band of the X chromosome
∞ gene is located on the Xp21 band of the X chromosome
∞ mutations affecting the gene:
96% are frameshift mutations
30% are new mutations
10-20% of new mutations occur in the gametocyte [passed]
Associated Pathologies Delayed Developmental Milestones

Delays in early childhood stages involving muscle use
Delays in standing alone
Delays in sitting without aid
Delays in walking (12 to 24 months)
Child has a hard time climbing

Onset- before 6 years

Impaired Intelligence

Most show normal intelligence
20% are seriously retarded
5% of patients had learning difficulties
3% of patients had speech problems Muscle weakness

Unsteadiness
Difficulty in walking stairs or rising
from chairs
Leads to loss of motor skills Complications include:
-Difficulty in wearing shoes
-Foot pain
-Hypersensitivity
-Concern about foot’s appearance Characteristic Waddling Gait

Walking on toes
Tightening of the Achilles’ Tendon