Dystrophinopathies: Duchenne + Becker muscular dystrophy

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DYSTROPHINOPATHIES

Clinical syndromes
Becker
Cardiomyopathy
Cramps
Duchenne
Female carrier
Mental retardation
Microdeletion
Outliers
Dystrophin gene
Mutations
Dystrophin protein
Associated glycoproteins
Genotype-Phenotype Correlations
Pathology
Duchenne
Becker

Dystrophinopathies: External link

From: A Kornberg

Duchenne muscular dystrophy
Standing from supine position

Dystrophinopathies: Clinical

l Dystrophin

; Chromosome Xp21; Recessive

Becker
Cardiomyopathy
Cramps
Duchenne
Female carrier
Mental retardation
Microdeletion
Outliers

From NLM
Guillaume-Benjamin
Duchenne de Boulogne

De la Paralysie Musculaire Pseudo-hypertrophique...
1868

Clinical syndromes: General
- Usually very high serum CK
- Genotype-Phenotype correlation
DMD: Hypertrophic
leg muscle
Duchenne muscular dystrophy
- Genotype: Dystrophin
  - 96% with frameshift mutation
  - 30% with new mutation
  - 10% to 20% of new mutations are gonadal mosaic
- Onset 3 to 5 yrs
- Clinical
  - Weakness
    - Distribution
      - Proximal > Distal
      - Symmetric
      - Legs & Arms
      - Most involved muscles: Adductor magnus in legs
      - Relatively spared muscles: Gracilis & Sartorius
    - Course
      - Reduced motor function by 2 to 3 years
      - Steady decline in strength: After 6 to 11 years
    - Gowers sign: Standing up with the aid of hands pushing on knees
    - Failure to walk: 9 - 13 years; Later with steroid treatment
  - Muscle hypertrophy
    - Especially calf
    - May be generalized
    - Increases with age
    - Most commonly due to muscle fibrosis
    - Some relatively spared muscles may have true hypertrophy
  - Musculoskeletal
    - Contractures
      - Especially ankles; Also hips & knees
      - Treatment
    - Scoliosis
      - Onset: After loss of ambulation
      - May be reduced if walking & standing is prolonged to 17 to 18 years
      - Treatment: Surgical insertion of spinal rod
  - Other clinical features
    - Cardiomyopathy: Dilated; Especially > 15 years
    - Mental retardation: Mean IQ ~ 88
    - Night blindness
      - Altered response to flashes of light in dark adapted state
      - ERG: b-wave, Reduced amplitude
      - Dp260: Isoform of dystrophin in retina
    - Gastrointestinal: Rare
      - Type: Pseudo-obstruction; Gastric dilatation
      - Upper GI tract
      - Late in disease course
  - Death
    - Most common between 15 - 25 years
    - Due to respiratory or cardiac failure
    - Life prolonged by ~ 6 years to 25 years with respiratory support⁸
    - Life shortened by 2 years with cardiomyopathy
- Laboratory
  - Serum
    - CK: Very high
    - Troponin I: Elevated above normal but not to levels in cardiac ischemia
    - Liver enzymes: High AST & ALT
  - Muscle biopsy
    - Endomysial fibrosis
    - Variable fiber size: Small fibers rounded
      
      Dystrophic
      muscle (Erb)
    - Hypercontracted (opaque) muscle fbers
    - Myopathic grouping
    - Muscle fiber degeneration & regeneration
    - Muscle fiber internal archetecture: Normal or immature
    - Dystrophin: Absent staining
    - Other membrane proteins
      - Sarcoglycans: Reduced
      - Aquaporin 4: Reduced; Varied levels
  - Diagnostic testing
    - Muscle: Staining for dystrophin protein absent
    - Genetic: Deletion, Duplication, Small mutation, Point mutation¹⁰
- Drug treatment: Prolongs ability to walk by 2 to 3 years
  - Prednisone
    - Doses
      - Weekly: 5 to 10 mg/kg/week starting dose⁶
      - Daily: 0.75 mg/kg/day starting dose; Less optimal than weekly regimen
    - Effects of treatment
      - Walking: Prolonged by 2 to 5 years
      - Strength: Increased
      - Falling: Reduced
      - Most beneficial
        
        While patient still ambulatory
        
        ? When started at early age (3 to 5 years)
      - Scoliosis: May prolong walking long enough to reduce likelihood or severity
  - Deflazacort: 0.9 to 1.2 mg/kg/day starting dose
  - Oxandrolone: 0.1 mg/kg/day
- External link: Duchenne biography
Becker muscular dystrophy

Becker MD

Toe walking

from A Kornberg MD
Enlarged calves
- Genotype: Dystrophin mutations
  - Deletion
    - 70% of patients: Usually In-frame
    - 16% with frameshift mutation
  - New mutations rare
  - Point mutations
    - > 70 identified
    - Mutations in CpG: All C to T; None G to A
    - ? Related to direct or inverted gene repeats
  - Worse course: Additional mutation in Myogenic factor 6 (MYF6)
- Clinical features of myopathy
  - Onset > 7 yrs
  - Weakness
    - Proximal > Distal; Symmetric; Legs & Arms
    - May be especially prominent in quadriceps or hamstrings
    - Slowly progressive
    - Severity & onset age correlate with muscle dystrophin levels
  - Calf pain on exercise
  - Muscle hypertrophy: Especially calves
  - Failure to walk 16 - 80 years
- Systemic
  - Joint contractures: Ankles & Other
  - Cardiomyopathy: May occur before severe weakness
  - Mental retardation
    - Associated with deletion of Dp140 transcription unit
- Serum CK
  - Very high: 5,000 to 20,000
  - Lower levels with increasing age & disability
- Muscle biopsy
  - Myopathic
    - Varied muscle fiber size
    - Endomysial connective tissue increased
    - Myopathic grouping: < 12 years of age
    - Degeneration & Regeneration
  - Reduced dystrophin staining
    - Rule out 2° change due to Sarcoglycanopathy
- External link: Becker biography
Outliers
- Intermediate between Duchenne & Becker
- Failure to walk 12 - 16 years
Cramp & myalgia syndromes
- Onset in childhood
- Symptoms related to exercise
- Normal or near-normal strength
- Occasional rhabdomyolysis
- CK: Persistently high CK (2,000 to 20,000) in most; Rarely normal
Dystrophinopathies: Cardiomyopathy⁵
- General features
  - Nosology: X-linked Dilated Cardiomyopathy
  - Onset: Commonly in teenage years
  - Types: Dilated cardiomyopathy > Hypertrophic > Conduction defects
  - Probable pathophysiology: Dystrophin deficiency
    - Dystrophin deficient cardiomyocytes have reduced threshold for development of sarcolemmal injury under mechanical stress
    - Important location: Cardiomyocytes rather than cardiac vasculature⁹
  - Also see: Cardiomyopathies
- Two clinical types
  - Cardiomyopathy with Becker or Duchenne MD syndromes: Common
    - Common mutations: Deletions in Exons 48-53 region (Spectrin-like region)
    - Clinical features
      - Tachycardia: > 100; Common even < 10 years of age
      - Dilated cardiomyopathy: May develop after period of hypertrophy; Increased frequency with age
      - Conduction system abnormalities: Occasional patients
      - Symptomatic: 57% by age 18
      - Progression: Variable
      - Weakness: Typical Becker or Duchenne syndrome
      - May be associated with only: Myalgias after exercise & High CK
    - EKG
      - Changes due to atrophy of posterobasal region & lateral wall of left ventricle
      - Age 10: EKG changes in 60%; No clinical manifestations
      - Age 18: EKG or ECHO changes in most
    - ECHO indications: Test Duchenne MD patients at age 13 to 14
  - Selective Cardiomyopathy (CMD3B ): Minimal or mild weakness
    - Mutations
      - General features
        
        Effects: Often affect splicing
        
        Location: Most at 5' end of dystrophin gene
      - Muscle promoter & exon 1: Deletions & Point mutations
        
        Cardiac muscle dystrophin
        
        Loss of full length dystrophin M isoform
        
        No up regulation of other dystrophin isoforms
        
        Skeletal muscle dystrophin
        
        Absent dystrophin muscle (M) isoform expression
        
        Increased expression of brain (B) & cerebellar Purkinje (CP) isoforms
        
        Upregulated by dystrophin muscle enhancer 1 (DME1)⁴
        Muscle-specific enhancer in dystrophin gene
        
        B & CP isoforms are full length (427 kDa) like the M isoform
      - Intron 11: Alu-like sequence rearrangement
        
        Alu-like sequence: 136 bp
        Contains many stop codons
        Effects of mutation
        
        Cardiac muscle: Absent dystrophin splicing
        
        Skeletal muscle: Residual dystrophin splicing
      - Exon 29
        
        Nonsense mutation
        
        Exon skipping
        
        Affects dystrophin expression only in heart
      - Other mutations
        
        Exon 2-7: Duplication
        Exon 9: Hinge 1 region
    - Clinical features
      - Weakness: Minimal or Mild
      - Cardiomyopathy: Males
        
        Onset: Late teens
        
        Congestive heart failure
        
        Rapidly progressive: 1 to 2 years
        
        More severe cardiomyopathy with mutations at 5' end of dystrophin gene
      - Cardiomyopathy: Manifesting females
        
        Onset: 5th decade
        
        Congestive heart failure
        
        Chest pain: Atypical
        Slowly progressive over > 10 years
    - Differential diagnosis: X-linked Dilated Cardiomyopathy with Neutropenia
Dystrophinopathies: Manifesting female carriers
- Weakness
  - Course: Progressive; Mild to severe; Onset 16 to 48 years
  - Distribution
    - Proximal & Asymmetric
    - Often arms > legs
    - Shoulder abduction; Elbow flexion; Knee extension
  - Female Duchenne phenotype (Rare)
    - Severe weakness
    - Muscle biopsy: Absent dystrophin
    - Normal X chromosome
      - Total inactivation
      - Usually associated with chromosomal translocation
  - Frequency: Duchenne 19%; Becker 14%
  - Muscle biopsy: Scattered fibers with reduced or absent dystrophin
- Cramps & Myalgia: 70% have weakness
- Cardiomyopathy
  - Dilated: Duchenne 8%; Becker 0%
  - Left ventricle dilation (Echocardiography): Duchenne 19%; Becker 16%
  - Rare in non-manifesting children: Normal EKG & Echo⁷
- Serum testing in carriers
  - CK high: Duchenne 53%; Becker 30%
  - Troponin I & T: Rarely detectable; Not related to disease-specific cardiac disorders
- Genetics
  - Normal X chromosome: Non-random inactivation
  - No relation berween site of mutation & presence of weakness
- Muscle pathology
  - Myopathic changes: Varied fiber size
  - Dystrophin staining
    - May have variable degrees of staining in different muscle fibers
    - More likely to be abnormal in younger patients
- Muscle MRI: Mosaics may have patchy involvement of muscles
Mental retardation (Several types)
- Reduced verbal IQ
  - Type: Selective defects
    - Shorter digit span memory
    - Developmental delay
  - Present in most DMD patients
  - No clear correlations with location of deletions
- Reduced total IQ < 80: Mainly with 5' end of deletion between exons 35 to 79
  - Exon 52 deletions associated with retardation
    - Disrupts or deletes Dp140 coding sequence
    - Typical DMD cognitive change
  - S-dystrophin (116 kDa) promoter (intron 55) & exon 56
    - Severe mental retardation
    - Motor: Variable; DMD & BMD phenotype
    - Nerve conduction testing: Normal
  - C-terminal mutations
    - Disrupt Dp71 (Brain dystrophin) coding sequence: Altered Dp71 transcripts
    - In dystroglycan binding domain
    - Severe retardation
    - Absent ERG b-wave
- Contiguous gene syndromes: MR often severe
Chromosome Xp21 contiguous gene syndromes may include
- Microdeletion
  - Duchenne Muscular Dystrophy
  - Aland Island eye disease
  - Adrenal hypoplasia
  - Glycerol kinase deficiency
  - Retinitis Pigmentosa (RP3)
  - Mental retardation (MRX1) : IL1 receptor accessory-like protein (IL1RAPL)
  - Ornithine transcarbamylase deficiency
- Inversion: Pericentric Xq22
  - Disruption of RLGP gene: Ras-like GTPase in mitochondria
  - Clinical
    - Mental retardation Profound
    - Athetosis
    - Nystagmus
    - Congenital hypotonia: Severe
    - Duchenne MD

Dystrophin gene¹

Structure
- 79 Exons: Only 0.6% of gene
- 8 Promoters
- Introns: Large; 99.4% of gene
- Genomic DNA: 2.2 million base pairs
Dystrophin mRNA
- Size: 14kb
- Encodes 3685 amino acid 427kDa protein
7 different dystrophin transcripts with
- Different promoter regions & initial exons
  - N-terminus regions excluded in smaller dystrophins
  - C-terminus region is part of all sizes of dystrophin
- Cell type specificities: Determined by promoters
  - Muscle: 427 kDa molecular weight
    - Expressed in Skeletal, Cardiac & Smooth Muscle + Retina
  - Cortical: 427 kDa; B isoform
    - Cortical post-synaptic densities, Retina, ? Skeletal Muscle
    - Different first exon from muscle isoform
    - Functionally homologous to muscle isoform
  - Purkinje Cell: 427 kDa; Cerebellar; CP isoform
    - Different first exon from muscle isoform
    - Functionally homologous to muscle isoform
    - ? Present in adult muscle
  - Retinal: 260 kDa
    - Retinal exon 1 spliced to exon 30
    - Mouse retina: outer plexiform layer
  - Brain (Fetal) & Kidney: 140 kDa
    - Promoter & first exon: In large intron between exon 44 and 45
  - Schwann cell (S-dystrophin): 116 kDa
    - Onset exon 56
    - Schwann Cells: Submembrane of external (abaxonal) layer; Nodes of Ranvier
    - Mouse model: Reduced dystrophin in peripheral nerve causes demyelinating neuropathy
  - Glial: 71 kDa
    - Onset exon 63
    - Brain (Glia), Viscera (Lung, Liver, Kidney), Cardiac Muscle
- Alternative splicing
  - Exon 78: Muscle & brain developmental switch
  - Exons 71 to 74: Brain, heart & Purkinje
  - Exon 68: Smooth muscle
- External link: Dystrophin isoforms

Dystrophin protein ¹

Dystrophin Localization: Subsarcolemmal region in cardiac and skeletal muscle
- Organized periodically in costameres
- Enriched at myotendinous and neuromuscular junctions
- Cardiac muscle: Associated with T-tubules also
- Smooth muscle
  - Discontinuous along membranes
  - Alternates with vinculin
Dystrophin functions
- Mechanical
  - ? Stabilizaton of membrane during contraction & relaxation
  - Part of link between intracellular cytoskeleton & extracellular matrix
- Functional
  - Plays role in ability of muscle fibers to differentiate into fast glycolytic type
  - May play a role in organization of postsynaptic membrane & AChRs
Dystrophin: Structural Domains²

From: HPRD
Dystrophin
- NH₂-terminus
  - 1st 240 amino acids
  - α-actinin homology
  - Cytoskeleton binding: via F-actin
    - 3 distinct regions
    - Links dystrophin to F-actin subsarcolemmal cytoskeleton
    - "Calponin homology domain" (CH)
    - External link: SMART
- Rod: Coiled-coiled
  - 2400 amino acids
  - 3 helix segments: 109 amino acids
    - Contain 2 proline-rich turns
    - Repeated 24 times
  - Helix segments disrupted by non-helical regions
    - 4 Proline-rich regions
    - ? Act as hinges
  - Spectrin (SPEC) homology
    - Repeated domain 21 times
    - External link: Pfam
  - Function
    - Confers flexibility & elasticity to dystrophin
    - Actin binding
  - Deletion of rod region (Exons 17 to 48): Human disease & Mouse knockouts
    - Normal localization of dystrophin-associated proteins to membrane
    - Mild or no myopathy
- WW domain (AA 3056-3088)
  - Overlaps rod & cysteine rich domains
  - Contains 2 conserved tryptophan domains
  - Binds to proteins with
    - Particular proline-motifs, [AP]-P-P-[AP]-Y
    - Four conserved aromatic positions: Usually Trp
  - External link: SMART
- Cysteine-rich
  - Amino acids 3080 to 3360
  - Some homology to α-actinin carboxy-terminus
  - Contains 2 incomplete EF-hand calcium binding motifs
  - Contains ZnF_ZZ domain (AA 3307 to 3352)
    - Putative zinc-binding
    - Appears to bind calmodulin
    - Missense mutation of conserved cysteine: Duchenne muscular dystrophy phenotype
    - External link: SMART
  - Functions: Required for membrane attachment to cytoskeleton via binding
    - Directly to: β-Dystroglycan
      - via WW domain (AA 3055�3092)
      - Necessary but not sufficient
    - Indirectly to: Dystrophin-associated glycoproteins
- Carboxy-terminal domain
  - Last 420 amino acids
  - Homology to: Utrophin; Dystrobrevin
  - Contains many potential phosphorylation sites
  - Binds to
    - Dystrobrevins: Via coiled-coil motifs
    - Syntrophins (Exon 74)
    - ± DAGs
    - β-Dystroglycan: ZZ domain (AA 3307�3354), Cys 3340 ¹³
Dystrophin forms
- Full-length dystrophin (427 kDa)
  - Expressed in skeletal muscle, cardiac muscle & brain
  - Each form is initiated from a different promoter
- Short dystrophins: Share same C-terminal domain
Dystrophin phosphorylation
- Phosphorylated by
  - Kinase types: Proline-directed & Serine/threonine
  - Examples
    - Calmodulin-dependent protein kinase II
    - p44^erk1 mitogen-activated protein kinase (MAPK3)
    - p34^cdc2 kinase
    - Casein kinase
- Dephosphorylated by: Calcineurin
- Phosphorylation alters dystrophin binding to: Actin; Syntrophins
Dystrophin protein family: Other proteins with structural similarities
- Utrophin (DRP1)
  - Structure: Contains same 4 major domains as dystrophin
  - Widely expressed
    - Muscle: Localized to neuromuscular junctions
    - Myelin
  - Binds to: F-actin; β-Dystroglycan
- Dystrobrevins: α ; β
  - Homology to C-terminal region of dystrophin
  - α: Highly expressed in brain, skeletal & cardiac muscles; Concentrated at NMJs
  - β: Highly expressed in brain, kidney & pancreas
  - Subellular localization: Cytoplasmic
- Dystrophin-related protein 2 (DRP2)
  - High expression in brain & spinal cord
  - Also in kidney, ovary, epididymus
  - Homology to C-terminal region of dystrophin
- Other proteins with sequence homologies with dystrophin: Spectrins & α-actinins

Dystrophin: Genotypes & Phenotype Correlations

Mutation types & size
Point
Missense
Splice
Pseudoexons
Deletions
Chromosome
Duplications
Reading frame
Other

Dystrophin gene mutations: Types & Size
- Point mutations¹⁰
  - Locations
    - Along entire gene
    - > 40% 3' of exon 55
    - Many in splice acceptor/donor sites or regulatory domains
    - Promoter region: Associated with dilated cardiomyopathy
  - Type
    - Stop: Often cause premature truncation of translation
      - Types: Nonsense; Small (1 base pair) deletion or insertion (Frameshift)
      - May occur with Duchenne or Becker phenotype
      - Also see: Out-of-frame mutations
    - Missense
      - Frequency: Some
      - May occur with Duchenne (Cys3313Phe) or Becker (Asp165Val) phenotype
      - L54R: Mutation in actin binding domain
      - WW-cysteine-rich: β-dystroglycan-binding region
    - Splice
      - Frequency: Up to 34% of dystrophin point mutations
      - Disease phenotype: Duchenne (IVS11-9G to A) or Becker (IVS25+1G to C)
      - Becker dystrophy: Often affect cononical splice site sequences
        
        Cryptic splice site activation
        
        May produce insertion of more amino acids or pseudoexon¹¹
        
        IVS25+2036A>G in intron 25; IVS62�285A>G in intron 62
        
        Pseudo-exons¹⁵
        
        Intronic mutations
        
        Cause novel splice sites & splicing changes
        
        Effect: Intronic sequence included in mRNA
        
        Produce: Out-of-frame or stop effects
        
        Detected by: Analysis of mRNA from muscle
        
        Associated pohenotype: Duchenne or Becker
        
        Therapy: Pseudoexon skipping may increase amount of wild-type dystrophin
        
        In frame skipping of exon
        Inefficient function of mutant splice site
        
        Single base substitution: Disrupts the invariant GT dinucleotide at 5' end of intron 54
        
        Produces small amount of normal dystrophin
    - Common in CpG sequences: All C-to-T transitions
    - Many private mutations: Unique to family
  - Frequency: Detected in ~73% of patients without deletions or duplications
  - External link: Leiden database
- Deletions¹⁴
  - Location
    - Majority of deletions found at the 3' end region
    - 5' end deletions in 18%
    - Most common in large introns in NH₂-terminus & Rod domains
    - Hotspots
      - Most prominent: Around exons 45-52
        
        Starting breakpoint (5' end): Intron 44 involved most frequently (15%)
        
        Intron 44 features
        
        Largest intron of the DMD gene
        
        Contains a hotspot for meiotic recombination
        
        Intron 44 deletion breakpoints: Distributed relatively evenly within intron 44
        
        3' end: Introns 50-55
      - Other: Exons 3-19
      - Population specific patterns of breakpoints in the dystrophin gene
  - Size: More than one exon usually deleted
  - Clinical correlations
    - Exon 1 & Promoter region: Mild weakness ± severe cardiomyopathy
    - Exon 3 to 7: Exceptions to frameshift rule
      - Out of frame deletions may produce Duchenne or Becker phenotype
    - Proximal third of rod domain: Cramps & myalgia
      - Exons 13 to 17
      - Dystrophin staining of muscle is often normal
    - Exon 19: May be prone to small mutations
    - Exon 45: Deletions can present as either Duchenne or Becker phenotype
    - Central rod domain, In frame
      - General: Mild phenotype
      - Exon 45 to 55: Mild phenotype
      - Deletions of > 36 exons: Severe phenotype
    - Double deletions in one gene¹²
      - Mutation locations: Hot spot exons 3 to 19 & 45 to 52
      - Clinical phenotype: Milder
      - Muscle: Often express some dystrophin in muscle; Partial expression at rim of fibers or Revertants
    - N-terminal (N-terminal 240 AAs): Actin-binding region
      - Critical domain
      - Mutations often result in Duchenne phenotype
    - WW-cysteine-rich (Exons 63 to 69): β-dystroglycan-binding
    - C-terminal
      - Frequency: Rare
      - Phenotype: May be varied, mild or severe even in same family
    - Also see: Frame shifting
  - Disease frequency of deletions or duplications of ≥ 1 exon
    - Duchenne
      - Deletions: 60%
      - Duplications: 5%
    - Becker
      - 55% to 85% of patients have gene deletions or duplications
      - Many Becker patients have in-frame mutations in the dystrophin rod domain
        
        Effect: Reduce or increase dystrophin length
        
        Location: Especially frequent between exons 45 and 53
        
        Mutant dystrophins retain actin- & β-dystroglycan-binding sites
  - External link: Leiden database
- Very large chromosomal deletions
  - "Xp21 chromosomal microdeletion syndromes"
  - Multisystem disorders
  - Duchenne muscular dystrophy phenotype
- Duplications¹⁴
  - Locations
    - Mostly near 5' end of dystropin gene: Exons 6 and 7 duplicated most frequently (22% of cases)
    - Exon 2 alone
      - Common single exon duplication
      - Duplications including the promoter region don't disturb the reading frame
    - Duplication frequency gradually decreases to 1% towards 3' end of dystrophin gene (exons 66�79)
    - Small local increases at exons 18, 22, 38 & 51
    - Few duplications in exon 45�55 deletion hotspot region
  - Length: Mean: 7 exons
  - Duplication effects may be complex: Reading frame rule not always applicable
  - Duchenne dystrophy: Frequency of duplications 5%
- Mutation Database: HGMD; Utah
Effects of mutation on gene reading frame
- Reading frame shifted ("Out-of-frame")
  - Results in stop codons
  - Produces small, unstable protein, ? with impaired membrane attachment
  - Severely reduced or absent levels of dystrophin
    - Some dystrophin often synthesized with:
      - Single exon deletions (e.g. 44 or 45)
      - Deletions starting or finishing with exons 3 or 51
    - Dystrophin often absent with:
      - Deletions starting or finishing with exons 46 or 52
    - Weakness
      - Severe (Duchenne): Most common
      - Moderately severe (Outliers): Exon 3 to 7, or exon 44 or 45 deletions
      - Mild with cardiomyopathy: Muscle promoter & exon 1 deletion
    - Mental retardation (Several types)
- Dystrophin reading frame not shifted ("In-frame")
  - No stop codons
  - Produces internal deletions or duplicatons in protein
  - Levels of dystrophin:
    - High (40% to 70%): Distal rod deletions (exons 45 - 48)
    - Low (10% of normal): N-terminus deletions
  - Clinical Phenotype: Correlates with amount & function of dystrophin
    - Moderate (Becker's): Distal rod (exons 45 to 47, or 48) deletions
    - More severe Becker's: N-terminus deletions
    - Severe (Duchenne): Cysteine-rich or Carboxy-terminus deletions
      - Dystrophin may not bind to β-dystroglycan
      - Loss of β-dystroglycan and sarcoglycan complex from sarcolemma
Effects of dystrophin mutations: Other
- Dystrophin absence
  - DMD phenotype: Severe
  - Reduction in sarcoglycans & other proteins in dystrophin-glycoprotein complex
  - Dysferlin increased in cytoplasm
- Functional consequences of loss of dystrophin on muscle fibers
  - Increased movement of membrane impermeant molecules into and out of muscle cells
  - Force production: Decreased; Hypersensitive to lengthening, or eccentric contraction
  - Force decrement with eccentric contraction correlates with acutely increased sarcolemmal permeability
  - Disorganized costameres

Patient fact sheet

Return to Myopathy & NMJ Index
Return to Neuromuscular Syndromes

References
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15. Ann Neurol 2007 Dec 4

12/13/2007