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A. Types [1] navigator

  1. Set of inherited muscle disorders
    1. Progressive muscle wasting
    2. Weakness of muscles with variable distribution and severity
    3. Pain is not a prominent finding
    4. Cardiac abnormalities (dilation, conduction disease) may be prominent
  2. Characterized by muscles affected and gene loci / protein defects
  3. MD Classifcation by Distribution of Muscle Groups Affected
    1. Duchenne and Becker: upper arms, neck, chest, upper legs, calves
    2. Emergy-Dreifuss: upper arms, lower legs (calves, lateral feet)
    3. Limb-Girdle (including Myotonic Dystrophy): upper arms, chest, upper legs
    4. Facioscapulohumeral: upper arms, some chest, calves
    5. Distal: lower arms and hands, lower legs and feet
  4. MD Classification by Chromosome (Chr) or Gene Loci
    1. Congenital (Autosomal Recessive, AR)
    2. Duchenne and Becker (X Linked Recessive, XR; Chr Xp21): ~300 per million per year
    3. Emery-Dreifuss (two forms: XR and AR or Autosomal Dominant, AD)
    4. Distal AD (Chr 14q, 2q; unknown genes) and AR (Chr 2p, dysferlin)
    5. Facioscapulohumeral (AD, Chr 4q; unknown gene)
    6. Oculopharyngeal (AD, Chr 14q, poly(A) binding protein 2)
    7. Limb-Girdle (two forms: AD and AR)
  5. Congenital MD (AR)
    1. Chr 6q: Laminin alpha 2 (LAMA2, merosin) [11]
    2. Chr 12q: Laminin receptor (alpha7-integrin)
    3. Chr 9q: Fukutin (Fukuyama Dystrophy)
    4. Chr 1p: Selenoprotein N1 (Rigid Spine Sydnrome)
    5. Chr 1p: Glucosyltransferase (Muscle-Eye-Brain Disease)
  6. Limb-Girdle AD
    1. Type 1A: Chr 5q, Myotilin
    2. Type 1B: Chr 1q, Laminin A/C (LMNA)
    3. Type 1C: Chr 3p, Caveolin 3
    4. Type 1D: Chr 6q
    5. Type 1E: Chr 7q
    6. Type 1F: Chr 2q
    7. Abnormalities in sarcoglycan proteins found [5]
  7. Limb-Girdle AR
    1. Type 2A: Chr 15q, Calpain 3 [10]
    2. Type 1B: Chr 2p, Dysferlin
    3. Type 1B: Chr 13q, Gamma-sarcoglycan
    4. Type 1B: Chr 17q, alpha-sarcoglycan (adhalin) [5]
    5. Type 1B: Chr 4q, ß-sarcoglycan [5]
    6. Type 1B: Chr 5q, Delta-sarcoglycan
    7. Type 1B: Chr 17q, Telethonin
    8. Type 1B: Chr 9q
    9. Type 1B: Chr 19q, Fukutin related
  8. Hereditary Myopathies - usually due to ion channel mutations [2]

B. Overview of Muscle Functionnavigator

  1. Muscle contraction depends on shortening of actin-myosin complexes
    1. These complexes form ordered repeating units
    2. Width of repeated units determines "strength"
  2. Hydrolysis of ATP is required for this process
    1. Myosin associated proteins (troponins) have ATPase activity
    2. Tropomyosin is also found in the complex
  3. Muscle contraction stimulated by calcium (Ca2+) release from internal stores
  4. Key Protein Components
    1. Actin
    2. Myosin
    3. Tropomyosin
    4. Troponin T
    5. Troponin C
    6. Troponin I
    7. alpha-actinin
    8. Dystrophin
  5. Dystrophin Complex [3]
    1. Subsarcolemmal rod-shaped protein
    2. Stabilizes sarcomere by linking actin to extracellular matrix
    3. Binds to actin cytoskeleton via dystrophin-associated glycoprotein complex (DAGC)
    4. DAGC includes dystroglycan and sarcoglycan subcomplexes
    5. Two dystroglycans link dystrophin to laminin-alpha2
    6. Sarcoglycans consist of 4 transmembrane glycoproteins with unknown function
    7. Mutations in dystrophin can disrupt interactions with other proteins

C. MD with Dilated Cardiomyopathy navigator

  1. Conduction Defects Absent
    1. Limb-Girdle 2C, 2E, 2F
    2. Duchenne
    3. Becker
  2. Conduction Defects Present
    1. Limb-Girdle Types 1B and 1D
    2. Emery-Dreifuss AD and XR Forms

D. Myotonic Dystrophy [4,9]navigator

  1. Most common type of MD affecting adults
  2. Autosomal dominant with variable expression
  3. Prevalence 13.5/100,000
  4. Genetics
    1. Most common form: myotonic dystrophy 1 due to abnormalities in DMPK gene, chr 19q13.3
    2. The DMPK (myotonic dystrophy protein kinase) abnormalities are insertions of 50-2000 CTG repeats into 3' untranslated region DMPK gene
    3. Less common form: mytotonic dystrophy 2 due to abnormal zinc finger protein ZNF9 gene
    4. ZNF9 abnormalities usually due to CCTG repeats in first intron
    5. Both DMPK and ZNF9 mutations in myotonic dystrophy form abnormal pre-messenger RNAs that form hairpin structures and disrupt normal splicing of mRNA
    6. These lead to abnormally spliced mRNAs that are similar to embryonic forms
  5. Muscle Problems
    1. Delayed skeletal muscle relaxation
    2. Progressive muscle weakness with eventual atrophy
    3. Majority of patients have problems with limb girdle muscles
  6. Other Systems Involved
    1. Cardiac
    2. Endocrine
    3. Gastrointestinal
    4. Frontal Baldness
    5. Cataracts
    6. Bilateral psosis
  7. Cardiac Abnormalities [13]
    1. Conduction abnormalities common, valve abnormalities
    2. High risk for arrhythmia and sudden death
    3. Severe abnormalities on ECG and atrial tachyarrhythmia predict sudden death
  8. Aspiration pneumonia and ventricular arrhythmias are usual causes of death

E. Duchenne's Muscular Dystrophy (DMD)navigator

  1. Most severe form of progressive primary muscular degeneration
  2. 1:3,000 male births (~30% of cases are new mutations)
  3. Genetics
    1. About 90% have X-Linked disease localized to Xp2.1
    2. The gene has been cloned and is called "dystrophin" (440K molecular weight)
    3. Mutations usually lead to truncated proteins
    4. In a minority of patients, sarcoglycan mutations occur (limb girdle mainly) [3,5]
  4. Phenotypes Associated with Dystrophin Mutations [3]
    1. Duchenne or Becker Muscular Dystrophy
    2. X-linked dilated cardiomyopathy
    3. X-linked Mental Retardation
    4. Subclinical cases with elevated serum levels of creatine kinase (CK) subtype MM
  5. Symptoms
    1. Onset of disease at 3-5 years old
    2. Loss of ambulation at 9 years
    3. Very high serum creatine kinase levels
    4. Cardiac and Nervous System involvement occurs
  6. Death usually occurs by ~16 years (see below)
  7. Exon Skipping Therapy [12]
    1. Antisense oligonucleotide can induce exon skipping, thus overcoming mutant dystrophins
    2. PRO051 is an oligonucleotide relevant to ~16% of patients with DMD (skip exon 51)
    3. Injection of PRO051 into tibialis anterior muscle of 4 DMD patients induced dystrophin to 3-12% of normal levels in 64-97% of sarcolemmal fibers [12]
  8. Carriers of DMD Mutations
    1. Reports vary on effects of heterozygosity and symptoms
    2. ~90% of carriers (women) of DMD gene develop clinical or subclinical cardiomyopathy [6]
    3. In contrast, 8-18% of DMD carriers in another report had any cardiomyopathy [7]
    4. Differential X-chromosome inactivation may lead to variable symptoms

F. Becker's Muscular Dystrophy [8]navigator

  1. About 15 per million new cases annually
  2. Abnormality in same gene (dystrophin) as in DMD, but more mild forms
  3. Mutations retain open reading frame (contrast with DMD
  4. Onset begins ~12 years of age, and loss of ambulation at 20-40 years of age
  5. Death usually occurs between ages of 30 and 55, but some longer term survivors exist
  6. Calf pseudohypertrophy is common, as is CK elevation
  7. Cardiomyopathy also develops in carriers of the disease (as for DMD) [2,6]

G. General Diagnosis and Treatment Issues [1]navigator

  1. Diagnosis
    1. Serum CK is simplest method
    2. However, CK is not raised in all forms of MD
    3. Electromyography (EMG) important for establishing myopathic nature of disease
    4. EMG also to rule out neurogenic causes of weakness
    5. Muscle histology: shows variations in fiber size, necrosis, variable inflammation
    6. Cardiac function assessed with both electrocardiogram and echocardiography
  2. Types of Treatment
    1. Surgical
    2. Pharmacological
    3. Medical Supportive
    4. Experimental
  3. Surgical
    1. Early surgery generally not recommended
    2. Correction of contractures may be helpful in later stages
    3. Scoliosis correction is widely accepted (Luque technique)
    4. Surgery to improve lung function - substantial complications
  4. Pharmacological Agents
    1. Glucocorticoids showed early promise in slowing disease in short term
    2. No agents have shown long term beneficial effects
    3. Heart failure (dilated cardiomyopathy) treated as for systolic dysfunction
    4. Conduciton delays treated with pacemakers
  5. Medical Support
    1. Respiratory function is usually main problem in long term
    2. Assess for evidence of poor sleep and hypoxia due to poor muscle function
    3. Intermittent positive pressure ventilation with nasal mask may be very helpful
    4. Elective tracheostomy prior to severe respiratory decline should be considered
    5. Assess renal function as myoglobinuria can lead to renal decline
  6. Experimental stem cell and gene therapies being investigated

References navigator

  1. Emery AEH. 2002. Lancet. 359(9307):687 abstract
  2. Ackerman MJ and Clapham DE. 1997. NEJM. 336(22):1575 abstract
  3. Franz WM, Muller M, Muller OJ, et al. 2000. Lancet. 355(9217):1781 abstract
  4. Cooper TA. 2006. NEJM. 355(17):1825 abstract
  5. Duggan DJ, Gorospe JR, Fanin M, et al. 1997. NEJM. 336(9):618 abstract
  6. Politano L, Nigro V, Nigro G, et al. 1996. JAMA. 275(17):1335 abstract
  7. Hoogerwaard EM, Bakker E, Ippel PF, et al. 1999. Lancet. 353(9170):2116 abstract
  8. Jones HR Jr and De la Monte SM. 1998. NEJM. 339(3):182 (Case Record)
  9. Nanayakkara PWB, Hartdorff CM, Stehouwer CDA, et al. 2003. Lancet. 362(9389):1038 abstract
  10. Zatz M and Starling A. 2005. NEJM. 352(23):2413 abstract
  11. Brown RH Jr, Grant E, Pierson CR. 2006. NEJM. 355(20):2132 (Case Record) abstract
  12. Van Deutekom JC, Janson AA, Ginjaar IB, et al. 2007. NEJM. 357(26):2677 abstract
  13. Groh WJ, Groh MR, Saha C, et al. 2008. NEJM. 358(25):2688 abstract