8 / 1 4 / 2 0 1 3
Dpt. Aamir Memon
Muscular Dystrophy
Muscular Dystrophies Tables
Muscular dystrophy (MD) is a group of inherited diseases in which the muscles that control
mov...
to swallow and emaciation from lack of
food; progression is slow.
Muscular dystrophies are of nine types but more importan...
functioning copy of the dystrophin gene is generally sufficient for normal muscle
function.
2. Congenital MD (CMD)
 The t...
Age of onset
 2 to 6 years (Early childhood)
 affects only males; females are carriers.
Cause
 An absence of dystrophin...
 DMD primarily affects boys, who inherit the disease through their mothers.
 Women can be carriers of DMD but usually ex...
Symptoms
 Weakness and wasting of shoulder, upper arm and calf muscles;
 Muscle shortening (contractures) occurs early i...
 About 50% of of those with facioscapulohumeral MD can walk throughout their
lives, and most live a normal life span.
Rat...
8. Myotonic (also called MMD or Steinert's disease)
 The most common form of muscular dystrophy in adults.
Age of onset
...
Cause
 A faulty gene for poly(A)-binding protein nuclear 1 (PABPN1), which is suspected to
lead to production of extra ch...
 There is now a new DNA test, called single condition amplification/internal primer
(SCAIP) sequencing, which allows doct...
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Muscular dystrophies

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Muscular dystrophies

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Muscular dystrophies

  1. 1. 8 / 1 4 / 2 0 1 3 Dpt. Aamir Memon Muscular Dystrophy
  2. 2. Muscular Dystrophies Tables Muscular dystrophy (MD) is a group of inherited diseases in which the muscles that control movement (called voluntary muscles) progressively weaken. In some forms of this disease, the heart and other organs are also affected. Type Age at onset Symptoms, rate of progression, and life expectancy Becker adolescence to early adulthood Symptoms are almost identical to Duchenne, but less severe; progresses more slowly than Duchenne; survival into middle age. Congenital birth Symptoms include general muscle weakness and possible joint deformities; disease progresses slowly; shortened life span. Duchenne 2 to 6 years Symptoms include general muscle weakness and wasting; affects pelvis, upper arms, and upper legs; eventually involves all voluntary muscles; survival beyond 20s is rare. Distal 40 to 60 years Symptoms include weakness and wasting of muscles of the hands, forearms, and lower legs; progression is slow; rarely leads to total incapacity. Emery-Dreifuss childhood to early teens Symptoms include weakness and wasting of shoulder, upper arm, and shin muscles; joint deformities are common; progression is slow; sudden death may occur from cardiac problems. Facioscapulohumeral childhood to early adults Symptoms include facial muscle weakness and weakness with some wasting of shoulders and upper arms; progression is slow with periods of rapid deterioration; life span may be many decades after onset. Limb-Girdle late childhood to middle age Symptoms include weakness and wasting, affecting shoulder girdle and pelvic girdle first; progression is slow; death is usually due to cardiopulmonary complications. Myotonic 20 to 40 years Symptoms include weakness of all muscle groups accompanied by delayed relaxation of muscles after contraction; affects face, feet, hands, and neck first; progression is slow, sometimes spanning 50 to 60 years. Oculopharyngeal 40 to 70 years Symptoms affect muscles of eyelids and throat causing weakening of throat muscles, which, in time, causes inability
  3. 3. to swallow and emaciation from lack of food; progression is slow. Muscular dystrophies are of nine types but more importantly include:  X-linked inheritance: Duchenne and Becker  Autosomal recessive: Limb girdle  Autosomal dominant: Fascioscapulohumeral and oculopharyngeal 1. Becker MD (BMD) Age of onset  Occurs at 2 to 16 years but can appear as late as age 25  Becker muscular dystrophy affects only males (1 in 30,000) Cause  Mutations in dystrophin gene resulting in decreased amount of dystrophin, usually of abnormal molecular weight Symptoms  Generalized weakness and wasting first affecting the muscles of the hips, pelvic area, thighs and shoulders.  Calves are often enlarged (pseudohypertrophy).  BMD is similar to Duchenne MD but often much less severe.  There can be significant heart involvement.  Usually, patients affected by Becker's MD are able to walk until at least age 15, and often well into their twenties and thirties.  Serum CK (creatinine kinase) levels decline as muscle tissue is progressively replaced by fat and fibrous tissue. Rate of Progression  Disease progresses slowly and with variability but can affect all voluntary muscles.  Slower than Duchenne MD Expected Lifespan  Well into middle age.  Most with BMD survive well into mid- to late adulthood. Inheritance  X-linked recessive.  BMD primarily affects boys and men, who inherit the disease through their mothers.  Women can be carriers but usually exhibit no symptoms-, because the dystrophin gene is located on the X chromosome - of which women have 2 copies - and one
  4. 4. functioning copy of the dystrophin gene is generally sufficient for normal muscle function. 2. Congenital MD (CMD)  The two forms that have been identified -- Fukuyama and congenital muscular dystrophy Age of onset  Already present at or near birth  affect males and females Cause  Genetic mutations affecting some of the proteins (especially myosin deficiency) necessary for muscles and sometimes for the eyes and or brain. Symptoms  General muscle weakness and possible joint stiffness or deformities.  Depending on the type, it may involve scoliosis (spinal curvature), respiratory problems, mental retardation or learning disabilities, eye defects or seizures  Severe and early contractures (shortening or shrinking of muscles resulting into joint problems)  Fukuyama congenital muscular dystrophy causes abnormalities in the brain and often seizures Rate of Progression  Slow Expected Lifespan  Varies, but is generally a bit shorter than normal people Inheritance:  Autosomal recessive or autosomal dominant; these diseases are sometimes inherited through both parents and sometimes inherited from one parent. They can also occur spontaneously because of a newly developed genetic flaw (mutation) 3. Duchenne Muscular Dystrophy  It is most common in young males and is the most common form of dystrophinopathy in children
  5. 5. Age of onset  2 to 6 years (Early childhood)  affects only males; females are carriers. Cause  An absence of dystrophin (Abnormalities in a gene encoding dystrophin--located in the Xp21 region), a protein that helps keep muscle cells intact.  Deletion (most common), point mutation also seen.  Dystrophin and dystrophin-associated protein complex anchors actin to membrane glycoprotein; absence of dystrophin causes transfer of the force of contraction to connective tissue and myocyte degeneration Symptoms  General and severe muscle weakness and wasting, beginning from the upper arms, hips, pelvic area, thighs and shoulders  Weakness begins in the pelvic girdle muscles, and then shoulder girdle is affected which manifests by 5 years.  Weakness eventually progresses to all voluntary muscles.  Characterized by a positive Gowers’ maneuver (requiring the assistance of upper extremities to stand up) and pseudohypertrophy (enlargement of calf muscles with weakness).  In most cases, the arms, legs, and spine become progressively deformed,  May be associated with intellectual impairment or cognitive impairment.  Severe breathing and heart problems causing (arrhythmias and heart failure) mark the later stages of the disease.  Disease progression varies, but many people with Duchenne (1 in 3,500 boys) need a wheelchair by the age of 12.  Serum CK (creatinine kinase) levels decline as muscle tissue is progressively replaced by fat and fibrous tissue. Rate of Progression  Fast  DMD eventually affects all voluntary muscles, and the heart and breathing muscles Expected Lifespan  Survival is rare beyond the early 30s (as much as 25 years, survival past the twenties is very rare).  Those with Duchenne MD usually die in their late teens or early 20s.  Paralysis and death by second to third decade.  Death results from respiratory insufficiency, pulmonary infection, and cardiac failure. Inheritance  X-linked recessive.
  6. 6.  DMD primarily affects boys, who inherit the disease through their mothers.  Women can be carriers of DMD but usually exhibit no symptoms. 4. Distal MD (DD) Cause  A mutation in any of at least eight genes that affect proteins necessary to the function of muscles. Age of Onset  40 to 60 years Symptoms  Weakness and wasting of distal muscles (those farthest from the center) of the forearms, hands, lower legs, and feet.  affects fewer muscles than other forms of muscular dystrophy Rate of Progression  Slow progression;  not life-threatening. Expected Lifespan  Rarely leads to life-threatening situations Inheritance  May be autosomal dominant (a faulty gene is inherited from one parent), or autosomal recessive (a faulty gene is inherited from each parent). 5. Emery-Dreifuss Muscular Dystrophy Age of onset  Usually by 10 years of age  affects only males Cause  Mutations in the genes that produce emerin, lamin A or lamin C, proteins in the membrane that surrounds the nucleus of each muscle cell.
  7. 7. Symptoms  Weakness and wasting of shoulder, upper arm and calf muscles;  Muscle shortening (contractures) occurs early in the disease  Often causes joint stiffening or deformities; fainting (because of cardiac abnormalities).  Life-threatening heart problems are common and can also affect carriers Rate of Progression  Disease usually progresses slowly of all  Cardiac complications are common and sometimes require a pacemaker. Expected Lifespan  Due to this disease affecting cardiac muscle fibers, sudden death is possible because of cardiac complications Inheritance  Can be X-linked recessive, primarily affecting males, who inherit the disease through their mothers.  Another type is autosomal dominant, meaning it can be inherited through either parent; an autosomal recessive type occurs when a faulty gene is inherited from each parent. 6. Facioscapulohumeral MD (FSHD) Age of onset  Usually by age 20.  affects males and females Cause  A missing piece of DNA on chromosome 4. Symptoms  Weakness and wasting of the muscles around the eyes and mouth, and of the shoulders, upper arms and lower legs initially, with later weakness of abdominal muscles and sometimes hip muscles.  Walking, chewing, swallowing, and speaking problems can occur.
  8. 8.  About 50% of of those with facioscapulohumeral MD can walk throughout their lives, and most live a normal life span. Rate of Progression  Slow and not steady, interspersed with periods of rapid worsening/ deterioration Expected Lifespan  Disease may span usually many decades after onset Inheritance  Autosomal dominant; the disease may be inherited through either the father or the mother, or it may occur without a family history. 7. Limb-Girdle MD (LGMD) Age of onset  late childhood to middle age  affects males and females Cause  A mutation in any of at least 15 different genes that affect proteins necessary for muscle function. Symptoms  Muscle wasting and weakness, beginning from the shoulder girdle and pelvic girdle  Within 20 years, walking becomes difficult or impossible Rate of Progression  Usually progresses slowly, with cardiopulmonary complications sometimes occurring in later stages of the disease. Expected Lifespan  Varies, death is usually due to cardiac or respiratory complication.  Sufferers typically live to middle age to late adulthood. Inheritance  Some types are autosomal dominant, meaning LGMD is inherited from one parent.  Other types are autosomal recessive and occur when a faulty gene is inherited from each parent.
  9. 9. 8. Myotonic (also called MMD or Steinert's disease)  The most common form of muscular dystrophy in adults. Age of onset  Occurs at any age, but usually 20 to 40 years {although it can be present at birth in Type 1 congenital myotonic dystrophy (congenital MMD)}  Affects both men and women. Cause  A repeated section of DNA on either chromosome 19 or chromosome 3. Symptoms  Generalized weakness and muscle wasting first affecting the face, lower legs, forearms, hands and neck.  Myotonia/delayed relaxation of muscles (difficulty or total incapacity of relaxing a muscle at will after a contraction resulting into prolonged spasm or stiffening of muscles after use. This symptom is usually worse in cold temperatures)  The disease causes muscle weakness and also affects the central nervous system, heart, gastrointestinal tract, eyes, respiration, and hormone-producing glands  Learning disabilities occur in some cases.  Congenital myotonic dystrophy is the more severe form. Rate of Progression  Slow Expected Lifespan  Varies a lot, but can be as much as 50 to 60 years Inheritance  Autosomal dominant; the disease may be inherited through either the father or the mother. 9. Oculopharyngeal Muscular Dystrophy Age of onset  40 to 70 years  in men and women
  10. 10. Cause  A faulty gene for poly(A)-binding protein nuclear 1 (PABPN1), which is suspected to lead to production of extra chemical material that causes formation of clumps in the muscle cells. Symptoms  OPMD first causes weakness of the muscles of the eyelids and throat; weakness of facial and limb muscles often occurs later.  Weakness in the muscles of the eye (drooping eyelids) and of the throat (accompanied generally by an inability to swallow, causing possible nutritional deficiencies and emaciation  Weakness in pelvic and shoulder muscles may occur later.  Choking and recurrent pneumonia may occur. Rate of Progression  Slow Expected Lifespan  Varies Inheritance  May be autosomal dominant (a faulty gene is inherited from one parent), or  autosomal recessive (a faulty gene is inherited from each parent). Diagnosis of MDs  A careful diagnosis also involves careful medical history and a thorough physical exam to determine the distribution of symptoms and to rule out other causes.  Family history is very important, since all the muscular dystrophies are genetic - and usually inherited - conditions (though rarely there will be new mutations which are not detectable with family history).  EMG are also useful: they stimulate muscles using electrical shocks and the reaction is abnormal in individuals with muscular dystrophy.  Muscle biopsies are among the most reliable tests: they consist of taking a small piece of muscle and examining it with a microscope (fibers affected by MD are unusually large and interspersed with dead cells).  The golden standard for MD diagnosis, however, is a DNA test: in the past, these tests were performed on blood samples and allowed diagnosis by identifying a specific mutation of the dystrophin gene.
  11. 11.  There is now a new DNA test, called single condition amplification/internal primer (SCAIP) sequencing, which allows doctors to have a much more accurate picture of the entire dystrophin gene, so they can find multiple variations, providing more than just one type of diagnosis.  In the next years this test should become more widely available to the general public  In any case, the two most reliable tests to diagnose a muscular dystrophy are a muscle biopsy or a DNA test (even if usually a blood test is sufficient)  The usual procedure is to first look for physical signs, then use a blood test. Blood tests work by determining the level of creatine phosphokinase (CPK): in children with the condition, these levels are usually 5 to 10 times greater than the maximum level found in normal individuals, but they can get as high as 100 times

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