The molecular basis of muscular dystrophy ( 肌营养不良 ) Wenya Hou Xue Jing Yitang Wang Jiezhong Zhang

OUTLINE  INTRODUCTION  Duchenne muscular dystrophy (DMD)  Dysfelin  Therapeutic Approaches and perspective

 a quarter of a million kids and adults are living with the disease, so chances are you may know someone who has it.

What is Muscular Dystrophy?  The muscular dystrophies (MD) are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms of MD are seen in infancy or childhood, while others may not appear until middle age or later. Muscular dystrophies in general are a group of genetic, degenerative diseases primarily affecting voluntary muscles.

 Healthy muscle tissue (left).  Muscular dystrophy (right).

HOW TO RECOGNIZE IF MUSCLE WEAKNESS IS CAUSED BY MUSCULAR DYSTROPHY  Mostly affects boys (rarely girls).  Often brothers or male relatives have same problem.  First signs appear around ages 3 to 5: the child may seem awkward or clumsy, or he begins to walk 'tiptoe' because he cannot put his feet flat. Runs strangely. Falls often.  Problem gets steadily worse over the next several years.

HOW TO RECOGNIZE IF MUSCLE WEAKNESS IS CAUSED BY MUSCULAR DYSTROPHY  Muscle weakness first affects feet, fronts of thighs, hips, belly, shoulders, and elbows. Later, it affects hands, face, and neck muscles.  Most children become unable to walk by age 10.  May develop a severe curve of the spine.  Heart and breathing muscles also get weak. Child usually dies before age 20 from heart failure.

There are probably nine types of muscular dystrophy.  Duchenne muscular dystrophy (DMD)  Becker muscular dystrophy (BMD)  Emery-Dreifuss muscular dystrophy (EDMD)  Limb-girdle muscular dystrophy (LGMD)  Facioscapulohumeral muscular dystrophy (FSHD)  Myotonic (pronounced: my-uh-tah-nick) dystrophy (MMD)  Oculopharyngeal Muscular Dystrophy (OPMD)  Distal Muscular Dystrophy (DD)  Congenital muscular dystrophy (CMD)

Duchenne muscular dystrophy (DMD)  Definition - One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - An absence of dystrophin, a protein that helps keep muscle cells intact.

DMD  Onset - Early childhood - about 2 to 6 years.  Symptoms - Generalized weakness and muscle wasting first affecting the musclesof the hips, pelvic area, thighs and shoulders. Calves are often enlarged.  Progression - DMD eventually affects all voluntary muscles, and the heart and breathing muscles. Inheritance - X-linked recessive. DMD primarily affects boys, who inherit the disease through their mothers. Women can be carriers of DMD but usually exhibit no symptoms.

Becker muscular dystrophy (BMD)  is similar to DMD but often much less severe. There can be significant heart involvement. Progression - Disease progresses slowly and with variability. Most with BMD survive well into mid- to late adulthood.

Emery-Dreifuss muscular dystrophy (EDMD).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.  Onset - Usually by 10 years of age.  Symptoms - Weakness and wasting of shoulder, upper arm and calf muscles; joint stiffening; fainting (because of cardiac abnormalities).  Progression - Disease usually progresses slowly. Cardiac complications are common and sometimes require a pacemaker.  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.

Limb-girdle muscular dystrophy (LGMD)  Definition - One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - A mutation in any of at least 15 different genes that affect proteins necessary for muscle function.  Onset -Childhood to adulthood.  Symptoms - Weakness and wasting first affecting the muscles around the shoulders and hips (limb girdles).  Progression - Usually progresses slowly, with cardiopulmonary complications sometimes occurring in later stages of the disease.  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.

Facioscapulohumeral muscular dystrophy (FSHD)  Definition - One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - A missing piece of DNA on chromosome 4.  Onset - Usually by age 20.  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.  Progression - Progresses slowly with some periods of rapid deterioration. Disease may span many decad

Myotonic (pronounced: my-uh -tah-nick) dystrophy (MMD)  Definition - One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - A repeated section of DNA on either chromosome 19 or chromosome 3.  Onset - Congenital form appears at birth. More common form may begin in teen or adult years.  Symptoms - Generalized weakness and muscle wasting first affecting the face, lower legs, forearms, hands and neck, with delayed relaxation of muscles after contraction common. Other symptoms involve the gastrointestinal system, vision, heart or respiration. Learning disabilities occur in some cases. Congenital myotonic dystrophy is the more severe form.  Progression - Progression is slow, sometimes spanning 50 to 60 years.  Inheritance - Autosomal dominant; the disease may be inherited through either the father or the mother.

Oculopharyngeal Muscular Dystrophy (OPMD)  Definition - One of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.  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.  Onset - Usually not until the 40s or 50s.  Symptoms - OPMD first causes weakness of the muscles of the eyelids and throat; weakness of facial and limb muscles often occurs later. Swallowing problems and difficulty keeping the eyes open are common problems.  Progression - Slow.

Distal Muscular Dystrophy (DD)  Definition - A class of muscular dystrophies that primarily affect distal muscles, which are those of the lower arms, hands, lower legs and feet. Muscular dystrophies in general are a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - A mutation in any of at least eight genes that affect proteins necessary to the function of muscles.  Onset - childhood to adulthood  Symptoms - Weakness and wasting of muscles of the hands, forearms and lower legs.  Progression - Slow progression; not life-threatening.  Inheritance - May be autosomal dominant, meaning a faulty gene is inherited from one parent; or autosomal recessive, occurring when a faulty gene is inherited from each parent.

Congenital muscular dystrophy (CMD)  Definition - A class of muscular dystrophies that show themselves at or near birth. Muscular dystrophies in general are a group of genetic, degenerative diseases primarily affecting voluntary muscles.  Cause - Genetic mutations affecting some of the proteins necessary for muscles and sometimes for the eyes and/ or brain.  Onset - At or near birth.  Symptoms - Generalized muscle weakness with possible joint stiffness or looseness. Depending on the type, CMD may involve spinal curvature, respiratory insufficiency, mental retardation or learning disabilities, eye defects or seizures.  Progression - Varies with type; many are slowly progressive; some shorten life span.  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).

Duchenne muscular dystrophy (DMD)

ERM family Spectrin family e.dystrophin muscular dystrophy