2. MYOTONIC DYSTROPHY
Myotonic dystrophy (dystrophia myotonica, DM)
is a chronic, slowly progressing, highly variable
inherited multisystemic disease. It is characterized by
wasting of the muscles (muscular dystrophy),
cataracts, heart conduction defects, endocrine
changes, and myotonia. Myotonic dystrophy can occur
in patients of any age.
3. HISTORY
First described by Hans Steinert in 1904, there are now
two types recognized (DM1 and DM2).
In 1992, a genetic mutation was discovered to cause
DM1 – also called myotonic dystrophy of Steinert, or
Steinert’s dystrophy.
In 1994, a second mutation was found and DM2 was
differentiated – also called proximal myotonic myopathy
(PROMM).
4. TYPES
The common types are:
Type 1 (DM1), also called Steinert's disease,
Type 2 (DM2) also called as proximal myotonic
myopathy (PROMM)
Other forms are
DM3
DM4
DMX
5. Comparison between myotonic
dystrophy subtypes
Type Gene Repeat Anticipation Severity
DM1 DMPK CTG Yes
Moderate-
severe
DM2 ZNF9 CCTG Minimal/none
Mild-
moderate
7. SYMPTOMS AND SIGNS
Myotonia means abnormally long muscle contractions or
slowed relaxation after a muscle contraction
A person with DM often has difficulty relaxing his or her grip,
especially in the cold. DM causes general weakness, usually
beginning in the muscles of the hands, feet, neck, or face. It
may slowly progress to other muscles, including the heart. It
also may affect the muscles of the digestive system, causing
constipation and other digestive problems
DM may affect a wide variety of other organ systems, may
adversely affect intellectual abilities, often increases sleep
needs & decreases motivation and may have other impacts on
personality and behavior.
8. SYMPTOM SEVERITY
Symptom severity forms the basis for a common
classification of DM:
1). “Mild DM” (adult onset): People with “mild DM” often
lead active lives and may even be unaware that they
have the disorder.
2). “Classical DM” (adult onset): People commonly have
muscle weakness and wasting, myotonia, hand and wrist
weakness and/or foot drop.
3). “Congenital Myotonic Dystrophy” (CMD): A very
severe form of DM1, often fatal in young children (not
seen in DM2).
9. INCIDENCE OF DM1 AND DM2
Research is contradictory in terms of how common each
type is, some studies say that 98 percent of people with
myotonic dystrophy have DM1; other sources suggest
that the prevalence of DM1 and DM2 are about equal.
Due to founder effects, DM is not evenly distributed in
populations and pockets of both disorders are seen.
Research suggests that DM2 is more common in
Northern Europeans and their descendents
In Germany, DM2 may be as common as DM1.
15. GENETIC BASIS
DM is a genetic condition which is inherited in an
autosomal dominant pattern, meaning that inheriting
a mutant gene from one parent will result in the
condition
In DM1, the affected gene is called DMPK (myotonic
dystrophy protein kinase) which codes for a myosin
kinase expressed in skeletal muscle. The gene is
located on the long arm of chromosome 19
DM2 is similarly caused by a defect of the ZNF9 gene
on chromosome 21.
16. DMPK gene
The official name of this gene is “dystrophia myotonica-protein kinase.”
FUNCTIONS:
The DMPK gene provides instructions for making a protein called
myotonic dystrophy protein kinase. Although the exact function of this
protein is not known, it appears to be important for the normal
function of muscle, heart, and brain cells. This protein may be involved
in communication within cells. It also appears to regulate the
production and function of important structures inside muscle cells.
For example, myotonic dystrophy protein kinase has been shown to
turn off (inhibit) a specific subunit (PPP1R12A) of a muscle protein
called myosin phosphatase. Myosin phosphatase is an enzyme that
plays a role in muscle tensing (contraction) and relaxation. Myotonic
dystrophy protein kinase may interact with other proteins as well.
17. DMPK gene
One region of the DMPK gene has a particular
repeating sequence of three nucleotides, CTG. The
CTG sequence is usually repeated 5 to 35 times within
the gene and is called a trinucleotide repeat
19. TYPE 1 MD AND DMPK gene
Type 1 myotonic dystrophy is caused by an expansion of the
CTG trinucleotide repeat in the DMPK gene. This
condition occurs when the CTG segment is abnormally
repeated from 50 to 5,000 times. The mutated DMPK gene
produces an altered version of messenger RNA.
Researchers have found that the altered messenger RNA
interacts with certain proteins to form clumps within the
cell. The abnormal clumps interfere with the production of
many other proteins. These changes prevent cells in
muscles and other tissues from functioning properly,
leading to the signs and symptoms of type 1 myotonic
dystrophy.
20. TYPE 1 MD AND DMPK gene
The size of the abnormally expanded CTG repeat is
associated with the severity of signs and symptoms.
People with the classic features of type 1 myotonic
dystrophy, including muscle weakness and wasting
beginning in adulthood, usually have 100 to 1,000 CTG
repeats. People born with the more severe congenital
form of type 1 myotonic dystrophy tend to have a larger
number of CTG repeats, often more than 2,000. This
form of the condition is apparent in infancy and may
involve life-threatening medical problems.
21. TYPE 1 MD AND DMPK gene
As the altered DMPK gene is passed from one
generation to the next, the size of the CTG repeat
expansion often increases in size. People with 35 to 49
CTG repeats have not been reported to develop type 1
myotonic dystrophy, but their children are at risk of
having the disorder if the number of CTG repeats
increases. Repeat lengths from 35 to 49 are called
premutations
22. CNBP gene
The official name of this gene is “CCHC-type zinc finger,
nucleic acid binding protein.”
FUNCTIONS:
The CNBP gene provides instructions for making a protein
called CCHC-type zinc finger, nucleic acid binding protein.
This protein is found in many of the body's tissues, but is
most abundant in the heart and in muscles used for
movement (skeletal muscles). Although the exact function
of this protein remains unclear, it probably helps regulate
genes involved in the production and use of cholesterol.
The protein has seven regions, called zinc finger domains,
which are thought to attach (bind) to specific sites on
messenger RNA (a molecule similar to DNA that forms a
blueprint for making proteins).
23. CNBP gene
One region of the CNBP gene has a particular
repeating sequence of four DNA building blocks
(nucleotides), written as CCTG. The CCTG sequence is
usually repeated fewer than 26 times within the gene
and is called a tetranucleotide repeat.
24. TYPE 2 MD AND CNBP gene
Type 2 myotonic dystrophy is caused by an expansion of
the CCTG tetranucleotide repeat in the CNBP gene. This
condition occurs when the CCTG segment is abnormally
repeated 75 to more than 11,000 times.
Researchers have found that the mutated CNBP gene
produces an altered messenger RNA, which interacts with
certain proteins to form clumps within the cell. The
abnormal clumps interfere with the production of many
other proteins. These changes prevent cells in muscles and
other tissues from functioning normally, leading to the
signs and symptoms of type 2 myotonic dystrophy
25. DIAGNOSIS
Biopsy: Caregivers remove a small piece of tissue from
the muscle and is sent to the lab for tests.
Electromyography (EMG): Electromyography is a
test that measures the electrical activity of the
muscles. The muscles are tested at rest and while using
them. An EMG test may also check the nerves that
control the muscles.
26. DIAGNOSIS
12-lead ECG: This test, also called an EKG, helps caregivers
look for damage or problems in different areas of the heart.
Caregivers may need to prepare the skin by shaving off
some hair, or cleaning it with a gritty lotion. Sticky pads are
placed on chest, arms, and legs. Each sticky pad has a wire
that is hooked to a machine or TV-type screen. A short
period of electrical activity in the heart muscle is recorded.
Caregivers will look closely for certain problems or changes
in how the heart is working. This test takes about 5 to 10
minutes. It is important to lie as still as possible during the
test.
27. DIAGNOSIS
Magnetic resonance imaging: This test is also called
an MRI. Pictures of the muscles are taken during this
test. Caregivers use these pictures to look for changes
in the muscles.
28. MOLECULAR DIAGNOSIS
The important molecular diagnosis for myotonic
dystrophy are:
Fluorescent PCR technique
Preimplantation genetic diagnosis
Southern Blotting
32. TREATMENT
Although myotonic dystrophy cannot be cured, treatment
directed at providing symptomatic relief to affected
patients can be given.
Mild cases of myotonic dystrophy do not require any
treatment.
More severe cases might demand treatment with quinine,
phenytoin and other similar anticonvulsant drugs.
Treatment is directed at providing symptomatic relief to
affected patients.
33. TREATMENT
Muscle function may be preserved to some extent with
rehabilitation therapy or physical therapy. Such forms
of treatment can preserve muscle strength and
flexibility.
Patients with cardiac and respiratory problems can be
treated using a cardiac pacemaker and ventilator
respectively.
Urging the patient to indulge in a high fiber diet can
prevent constipation.
34. TREATMENT
Cataract surgery in the form of lens replacement may be done to
improve the vision of affected patients.
Occupational therapy can help the patient find alternatives to
loss of muscle strength and dexterity and can ensure restoration
of functionality of the affected patient to the maximum possible
extent
A speech and language specialist can provide assistance in
coherent speech and swallowing food.
Pregnant women with myotonic dystrophy should be closely
monitored during pregnancy to avoid any complications during
pregnancy, labor or delivery
35. GENE THERAPY
Though gene therapy for myotonic dystrophy is under
study, a succesful study using antisense RNA
expression was done in mouse model.
36. DRUGS
Sodium channel blockers such as procainamide,
phenytoin and mexiletine,
Antidepressant drugs such as clomipramine or
imipramine, benzodiazepines, calcium antagonists,
taurine and prednisone.
