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  1. 1. PRESENTED BY ; Sandhya Varma 11407042 B.Tech Genetic Engg SRM University.
  2. 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. 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. 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. 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. 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. 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. 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.
  10. 10. Picture showing cataract in myotonic dystrophy patient
  12. 12. 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.
  13. 13. 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.
  14. 14. 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
  15. 15. Location of DMPK gene
  16. 16. 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.
  17. 17. 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.
  18. 18. 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
  19. 19. 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).
  20. 20. 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.
  21. 21. 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
  22. 22. 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.
  23. 23. 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.
  24. 24. 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.
  25. 25. MOLECULAR DIAGNOSIS The important molecular diagnosis for myotonic dystrophy are:  Fluorescent PCR technique  Preimplantation genetic diagnosis  Southern Blotting
  26. 26. Fluorescent PCR technique
  29. 29. 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.
  30. 30. 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.
  31. 31. 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
  32. 32. GENE THERAPY  Though gene therapy for myotonic dystrophy is under study, a succesful study using antisense RNA expression was done in mouse model.
  33. 33. DRUGS  Sodium channel blockers such as procainamide, phenytoin and mexiletine,  Antidepressant drugs such as clomipramine or imipramine, benzodiazepines, calcium antagonists, taurine and prednisone.
  34. 34. THANK YOU