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MUSCULAR DYSTROPHY SYNDROMES ²

LGMD: General features

Inheritance Myopathy: General features Presenting features Prevalence Proteins: Subcellular location Sarcoglycans Weakness

From Bramwell: Atlas of Clinical Medicine MD: Toe walking

• Dystrophin-associated glycoprotein (DAG; Sarcoglycan) mutations: Typical features
  • Mutations in one DAG often also result in reduced amounts of the others in muscle
  • Weakness: Severe
  • Prognosis: Loss of ambulation < 18 years ¹³⁵
    • Symptom onset: During the first decade of life
    • Protein expression in muscle biopsy: < 30%
  • Very high serum CK
  • Complexes of DAGs are different in extrasynaptic muscle than at neuromuscular junctions
  
  
• Also see: Metabolic disorders
  • Lipid myopathies
  • Glycogen disorders
  • Mitochondrial disorders
    • LGMD 1H

LGMDD (LGMD 1): Dominant inheritance

• Nosology: Confused terminology
  • LGMD 1D: HUGO
  • LGMD 1E: OMIM & Some authors ³⁵
• Epidemiology
  • DNAJB6 mutations in > 100 patients
  • 3% of LGMD
  • Geography: Worldwide; US, Japan & Europe
• Genetics
  • Mutations
    • ~ 20 described
    • Locations: G/F domain (Exon 5); J domain (A50V, E54A)
    • Types
      • Missense
      • Splice site: Removes glycine/phenylalanine-rich region (G/F domain)
      • Inframe deletion: Asp98del
    • Hotspot: Phe93
    • Clinical correlations ⁹⁹
      • Severe disease & Early onset: c.346+5G>A (ΔG/F); Phe91
      • Intermediate disease: Phe100, Pro96, Phe89
      • Milder disease: Phe93
      • Limb girdle phenotype: Proximal G/F domain mutations; Phe89, Phe91, Phe93
      • Distal onset: Distal G/F mutations; Pro96, D98del, Phe100
      • Bulbar: Phe100
  • Allelic disorders
    • Distal Dystrophy with Rimmed Vacuoles
    • Myofibrillar myopathy, Distal, Late onset
    • Cardiomyopathy susceptibility
• DNAJB6 protein ¹⁵⁶
  • Cell location & Isoforms
    • A isoform: Nucleus; Longer protein
    • B isoform: Cytoplasm, M-band > Z-band & Nucleus
  • Expression
    • Muscle: Z-disk
    • CNS
      • High levels
      • Inhibits polyglutamine (PolyQ) aggregation
      • Component of Lewy bodies
    • Other tissues
  • Chaperone-related
    • Protects client proteins from irreversible aggregation
    • Interacts with BAG3; HSP70
    • HSP40/DNAJ co-chaperone family: Features
      • Regulate molecular chaperone activity by stimulating ATPase activity
      • Associate with: HSP70 ATPases (e.g., HSPA4 )
      • Stimulate protein folding & remodeling reactions in endoplasmic reticulum
    • Other chaperone-related protein disorders
  • Ligands: MLF1 ; HSPA8 ; KRT18
  • Mutation effects
    • Reduced capacity to prevent protein aggregation
    • Enhanced GSK3β signaling
  • HSP40/DNAJ family: Other DNAJ disorders
    • DNAJA1 : Degrades Huntington aggregates
    • DNAJB1 : Polyglutamine protein specificity; Degrades Ataxin-3 aggregates
    • DNAJB2: Motor neuropathy; CMT 2T
    • DNAJB4: Myofibrillar myopathy with Respiratory failure & Rigid spine
    • DNAJB5: Distal atrophy
    • DNAJB6: LGMDD1; Inhibits aggregation of Aβ₄₂ & α-synuclein
    • DNAJC3: Diabetes Mellitus & Multisystem Neurodegeneration
    • DNAJC5 : CLN4 ; Promotes release of TDP-43 & other proteins into extracellular space
    • DNAJC6 : PARK19
    • DNAJC7: ALS risk
    • DNAJC12 : Hyperphenylalaninemia, Dystonia & Intellectual Disability
    • DNAJC13 : Parkinson , Essential tremor & Tourette related
    • DNAJC19: Dilated Cardiomyopathy with Ataxia
    • DNAJC21 : Bone marrow failure
• Clinical
  • Onset age
    • Mean: 38 years
    • Range: 8 to 50 years
  • Weakness
    • Distribution: Variable
      • Proximal (Deltoid & Biceps; Hamstrings) > Distal or Distal (Grip) > Proximal
      • Legs > Arms
      • Hamstring > Quadriceps: Some patients
      • Respiratory: Some childhood onset patients
    • Progression
      • Slow: Loss of 0.5 to 1 lb/yr
      • Wheelchair: Very common after 20 to 30 years; Mean age 34 years
  • Dysphagia (50%)
  • Muscle size: Atrophy in some patients
  • Cramps: Some patients
  • Systemic features: None
• Laboratory
  • Serum CK: Normal to 5x elevated
  • EMG: Myopathic; Some with irritability
  • MRI
  • Muscle pathology
    • Myopathic
    • Small muscle fibers: Rounded & Angulated
    • Endomysial fibrosis
    • Rimmed vacuoles: Associated with autophagy markers TDP-43, LC3, SQSTM1
    • Eosinophilic cytoplasmic bodies
    • Aggregates: Protein contents
      SMI-31, TDP-43, αB-crystallin, Myotilin, Desmin, DNAJB6
      Structural, RNA-binding stress-granule, Chaperones & Cochaperones
    • Small fibers express neonatal & fetal myosin
    • NMJs: Multisegmented
• DNAJB6 variant: Distal-onset Dystrophy with Rimmed vacuoles ¹³¹
  • Epidemiology: 7 families
  • Genetics
    • Inheritance: Dominant
    • Mutations
      • General locations: G/F or J domains
      • Specific locations
        • G/F domain: Phe91Leu, Phe91Ile, Phe93Leu, Phe100Val, & c.346+5 G>A splice site
        • J domain: A50V; E54A
      • Less severe clinical phenotype: Phe93
  • DNAJB6 protein
    • Distal Dystrophy: Complete loss of G/F domain function
  • Clinical
    • Onset ages: 6 to 50 years
    • Weakness
      • Early: Legs; Distal
      • Legs: Distal then Prioximal
      • Arms: Distal & Proximal
      • Face
      • Bulbar: Dysarthria & Dysphagia
      • Progression: Loss of ambulation in 50% (4th decade); Respiratory (Mild)
      • Tongue atrophy: Few patients
    • Tendon reflexes: Reduced
    • Contractures: Ankles
  • Laboratory
    • Muscle MRI
      • Gastrocnemius,lateral & medial: Severe fatty infiltration
      • Thigh: Vasti, Adductor magnus, Semitendinosus, Semimembranosus, Biceps femoris
      • Lower trunk: Diffuse
    • Serum CK: Normal to 4x High
    • EMG: Myopathic ± Spontaneous activity
    • Muscle
      • Fiber sizes: Varied; Hypertrophy & Atrophy
      • Rimmed vacuoles
      • Inclusions: Eosinophilic; p62+ & LC3+
      • Necrosis & Regeneration
      • DNAJB6: Normal
• DNAJB6 variant: Distal Myofibrillar myopathy, Late onset, Recessive ¹⁴¹
  • Epidemiology: Chinese family
  • Genetics
    • Inheritance: Recessive
    • Mutation: c.695_699del (p.Val232Gly fs*7) in exon 9
    • Mutation effects: Only DNAJB6a nuclear isoform
  • Clinical
    • Onset age: 60 years
    • Weakness
      • Distal Legs: At disease onset; Ankle dorsiflexion & Eversion
      • Proximal: with disease progression
    • Tendon reflexes: Absent at ankles
    • Sensation: Normal
  • Laboratory
    • NCV: Normal
    • EMG: Myopathic
    • Serum CK: 400 to 500
    • Vital capacity: Mildly reduced
    • Muscle MRI & Imaging
      • Legs: Fatty replacement
      • Thigh: Biceps femoris, Semimembranosus, Quadriceps, Adductor longus, Adductor Magnus (Asymmetric)
      • Trunk: Intercostal, Paravertebral, Subscapular
    • Muscle pathology
      • Fiber sizes: Varied; atrophy, hypertrophy,
      • Internal nuclei
      • Fiber splitting
      • Rimmed vacuoles: TDP-43, p62, LC3B
      • Sarcoplasmic masses
      • Internal architecture: Moth eaten
      • Aggregates: DNAJB6 (Subsarcolemmal), Desmin, Dysferlin
      • No DNAJB6 in nuclei
      • Endomysial connective tissue: Increased
      • Ultrastructure
        • Myofibrillar network: Focal disruptions
        • Perinuclear: Electron dense material
        • Mitochondria: Abnormal

• Nosology: LGMD 1F
• Epidemiology 2 families
• Genetics
  • Mutation: c.2771delA; c.2757delC
  • Penetrance: 85%
  • Related features
    • IRF5-TNPO3 region: rs10488631 is risk locus for Systemic Lupus Erythematosus
    • c.2771delA mutation: Inhibits HIV-1 infection
• TNPO3 protein
  • Location: Nuclear
  • Transport into nucleus: Serine/arginine-rich proteins (Splicing factors)
  • HIV-1 infection cofactor: Through interaction with viral integrase & capsid
  • Karyopherin β superfamily of proteins
• Clinical
  • Weakness
    • Onset
      • Age
        • Mean: 16 years
        • Range: Congenital to 58 years
      • Hypotonia
      • Proximal leg
    • Distribution
      • Proximal: Early in disease course
      • Symmetric
      • Legs > Arms
      • Scapular winging: Some patients
      • Distal
        • Late in course
        • Muscles: Extensor digitorum, Tibialis anterior, Toe extensors
      • Face: Normal in most
      • Early-onset or More severe patients: Weakness
        • Face
        • Proximal & Distal
        • Respiratory: Younger onset patients; FVC 40%
        • Progression more rapid
      • Progression: Linear rate
        • Slow: Adult onset patients
        • More rapid: Juvenile onset patients
        • Wheelchair in 2nd or 3rd decade in younger onset patients
  • Muscle hypertrophy: Absent
  • Skeletal
    • Contractures: Occasional late; Ankles
    • Spinal deformity: Some younger onset patients
• Laboratory
  • Muscle pathology
    • Fiber size: Varied
    • Necrosis: Occasional
    • Type 1 predominance: Some patients
    • Connective tissue, Endomysial: Increased
    • Desmin: Mildly increased expression in some fibers
    • Nuclei: Abnormal morphology, Internal; TNPO3 perinuclear
    • Rimmed vacuoles (60%)
    • Ultrastructure: Autophagic vacuoles
  • Muscle MRI: Most involved muscles
    • Scapular girdle: Teres major (80%) > Pectoral (64%), Iinfraspinatus & Serratus anterior (55%), Deltoids (46%)
    • Lumbar: Paraspinal (90%) > Abdominal oblique (55%) Rectus abdominus (55%)
    • Thigh: Sartorius (100%) > Vastus lateralis, intermedius & medialis (73%), Biceps femoris, Semitendinosus (55%)
    • Lower leg: Peroneal (91%) & Gastrocnemius (91%) > Soleus (73%), Tibialis anterior (70%)
  • EMG: Myopathic or Neurogenic
  • Serum CK
    • Mean: 589
    • Normal: 40%
    • Range: 47 to 2,920
  • Cardiac: Normal EKG & Echocardiogram

• Nosology: LGMD 1G
• Epidemiology: 6 families
• Genetics ⁹²
  • Mutations: Missense in same base pair; G>A (p.Asp378Asn), G>C (p.Asp378His)
• hnRPDL protein
  • HNRPDs: Participate in splicing of specific exons in premRNA of transcripts
  • Location
    • Normal muscle: Nuclei & Some cytoplasm
    • Disease: Irregular nuclei; Also present around nuclei
  • May interact with: Transportin-1 (TNPO1) in RNA-processing events
  • Regulator of pre-mRNA splicing & Nuclear export
  • Ribonuclear proteins & Disorders
• Clinical
  • Onset
    • Age
      • Range: 15 to 63 years
      • Mean 37 years
      • Some mutation carriers: Asymptomatic > age 63
    • Weakness: Legs or Arms; Proximal
    • Cramps: Legs
    • Cataracts (50%)
  • Weakness
    • Severity: Varied
    • Most patients: Proximal > Distal
    • Some patients: Distal leg weakness
    • Legs 100%; Arms 90%
    • Finger & Toe flexion: Limited
    • Scapular winging: May be asymmetric
    • Progression
      • Slow
      • 50% walking at 10 years after onset
  • Muscle, Other
    • Atrophy
    • Cramps
  • Contractures: Limited flexion of fingers & toes
  • Eye: Cataracts
  • Diabetes, Type 2: Some patients
  • Cognitive impairment: 1 family
• Laboratory
  • EKG: Normal
  • Hand X-rays: Normal
  • Serum CK: Usually high (Up to 9x normal); Normal in 20%
  • Muscle biopsy
    • Fiber size: Variation
    • Perimysial fibrosis (Discrete)
    • Necrotic fibers
    • Vacuoles
      • Rimmed
      • Stain with dystrophin & sarcoglycans
    • Cytoplasmic bodies
    • Type 2 fiber predominance
    • Denervation-like
      • Small atrophic angulated fibers
      • Fiber type groups: Scattered
    • Ultrastructure: Autophagic changes; Myofibrillar degeneration
    • Milder patients: May be normal
  • Muscle MRI
    • Involvement: Adductor magnus; Vasti
    • Sparing: Rectus femoris; Adductor longus muscles

Myofibrillar myopathy 3 (MFM3)

• Nosology: LGMD 1A
• Epidemiology
  • > 15 families described
  • Female = Male
  • 10% of myofibrillar myopathies
• Genetics
  • Mutations
    • Missense
      • Most common: Ser60Cys
      • Arg6His; Arg6Gly (Severe); Tyr4_His9 deletion (Distal); Lys36Glu; Ser39Phe (Spheroid body);
          Ser55Phe; Thr57Ile; Ser60Phe; Ser60Ile; Gln74Lys; Ser95Ile; Ala115Thr; Arg405Lys
      • Most common in: Exon 2; Serine rich region of myotilin
      • Other exon mutations: Arg6His (Exon 1); Arg405Lys (Exon 9)
    • In-frame deletion ¹⁷¹
    • Whole gene duplication ¹⁷⁹: Late onset
  • ~50% of families have no family history: Not related to specific mutation
  • Allelic disorders
    • Myofibrillar myopathy
      • MFM3: Dominant
      • Distal myopathy, Dominant, Early onset
      • Recessive
    • Homozygous Dominant mutation
    • Spheroid body myopathy
  • Also see: Myofibrillar myopathies
  • External link
    • Gene data base: Caveolin-3; Sequence variants
• Protein: Myotilin (Titin immunoglobulin domain protein; TTID)
  • Structure: Contains 2 Ig-like domains in C-terminus homologous to titin
  • Location
    • Sarcomere: In I-bands (Z-line); Bound to α-actinin
    • Sarcolemmal membrane
  • Interacts with
    • α-Actinin
    • Actin
    • Filaments: γ-Filamin; Filamin C
    • FATZ/Myozenin/Calsarcin
    • ZASP
    • Ubiquitin E3 ligases: MuRF1; MuRF2
• MFM3 Clinical features ⁴⁰
  • Onset
    • Age: Variable
      • Common: 42 to 77 years
      • Young adults (3rd & 4th decade): Thr57Ile, Inframe Tyr4_His9 deletion
    • Weakness
      • Legs
      • Distal or Proximal
    • Myalgias & Stiffness: Some patients
  • Weakness
    • Legs & Arms
    • Distal
      • Most: With disease progression
      • Many patients: Early foot drop
      • "Distal myopathy": Some mutations
    • Arms: Wrist & Finger extensors + Deltoids most common
    • Neck extensors: Some patients
    • Face: 17%
    • Symmetric: Most patients
    • Respiratory failure: Some patients; At onset in 1 patient
  • Speech: Dysarthria, nasal (30%); ? Related to palatal weakness
  • Myalgias: 25%
  • Tendon reflexes: Reduced at knees & ankles (100%); Some with diffuse loss
  • Joint Contractures: Ankles (30%)
  • Cardiomyopathy
    • Frequency: 50%
    • Onset age: 6th or 7th decade
    • All patients also have myopathy
  • Neuropathy: Occasional patient
    • Sensory loss: Distal
    • Axonal loss
    • Demyelinating features: One patient
  • Progression
    • Slow
    • Late loss of ambulation (10 years after onset)
• Laboratory
  • Serum CK: Normal to 15-fold elevated; Commonly 2x high
  • EMG
    • Myopathic
    • Fibrillations: Some patients
    • Myotonia: Some patients
  • CT: Early posterior leg involvement
• Muscle pathology
  • Myopathic
  • Muscle fiber degeneration
  • Muscle fiber size: Varied
  • Fiber splitting
  • Central nuclei
  • Sarcomere: Disorganization
  • Z-line: Streaming
  • Rimmed vacuoles: Numerous; Autophagic; No amyloid
  • Inclusions
    • Hyaline: Some congophilic; Composed of compacted, fragmented filaments
    • Rod-like inclusions: Z-band streaming
    • Spheroid bodies
    • May be PAS positive
  • Perimysium: Replaced by fat
  • Inflammation: 1 patient; Mild
  • Immunocytochemistry
    • Myotilin
      • Normal levels
      • Abnormal muscle fibers often have patches of increased immunostaining
      • Co-localizes with ubiquitin & clusterin
    • DAG: Normal staining
    • Increased staining: Other molecules in abnormal muscle fibers
      • Common to myofibrillar myopathies: Dystrophin; NCAM; Desmin; Plectin
      • More prominent than in other myofibrillar myopathies: Gelsolin; Ubiquitin
    • Reduced staining
      • Laminin γ1
  • Denervation: Small esterase positive muscle fibers
  
  
• Variant syndrome: Spheroid body myopathy ⁵²
    ● Myotilin ; Chromosome 5q31; Dominant
  • Epidemiology: Indiana & Oregon families
  • Genetics
    • Mutations: Missense; S39F in myotilin gene exon 2
  • Clinical: Variable within family
    • Onset: Teens to 80's; Mean 4th decade
    • Weakness
      • Proximal ± Distal
      • Legs
      • Symmetric
      • Dysarthria
      • Respiratory
    • Tendon reflex: Absent ankle
    • Prognosis
      • Usual: Benign; Little disability
      • Some patients: Rapid progression to wheelchair or respiratory failure
  • CK: Normal
  • Pathology
    • Variation in fiber size: Moderate
    • Inclusions
      • Aggregates of Gomori Trichrome + & Eosinophilic material
      • Contain Desmin & Ubiquitin
      • Type I > Type II fibers
      • Often subsarcolemmal; ± Associated with acid phosphatase staining
      • PAS -
• Variant syndrome: Myofibrillar myopathy, Recessive ⁹⁵
    ● Myotilin ; Chromosome 5q31; Recessive
  • Epidemiology: 1 German family, 2 patients
  • MYOT mutation: Arg6Gly, Homozygous
  • Clinical
    • Severe phenotype: Intrafamilial variability
    • Onset age: 3rd or 4th decade
    • Weakness: Proximal; Legs > Arms; Progressive
  • Laboratory
    • Serum CK: 1143
    • Muscle pathology: Myofibrillar myopathy
      • Fiber size: Varied
      • Subsarcolemmal & intracellular masses
      • Protein aggregates: Desmin; αB-crystalline; Myotilin
      • Ultrastructure: Myofibrillar damage
    • EMG: Myopathic
    • Muscle MRI: Vastus involvement
    • Cardiac: Mild EKG changes
• Variant syndrome: Homozygous Dominant disease
  • Genetics: Ser60Phe mutation
  • Clinical
    • Onset age: Adult
    • More severe disease
    • Proximal & Distal weakness

• Nosology: LGMD 1B
• Genetics
  • Lamin A/C gene mutation types
    • Missense & Deletion of codon in rod domain
    • Splice donor site: Protein lacking half of the globular tail domain
  • Lamin A/C gene mutations: Other clinical syndomes
• Lamin A/C protein
• Clinical
  • Onset: < 20 years
  • Weakness
    • Common: Symmetric; Proximal; Lower limb
    • Variant: Quadriceps with Arg377His mutation
  • Progression: Slow; Upper limbs involved by 3rd or 4th decade
  • No contractures
  • Associated systemic feature: Cardiomyopathy (62%)
    • A-V conduction block
    • Occasional dilated cardiomyopathy: Onset before weakness with Arg377His mutation
• Laboratory features
  • Serum CK: Normal to mildly elevated
  • Muscle
    • Myopathic changes, Mild
    • Aggregates: Desmin, Myotilin, α-B-Crystallin, Dystrophin
  • Lamin A subcellular localization
    • Normal: Nucleus; Co-localizes with Emerin
    • Mutated: May aggregate in nucleus & be present in cytoplasm
• Also see: Dominant myopathy with cardiomyopathy

Caveolin protein LGMD 1C   Allelic disorders   Clinical   Genetics   Laboratory   Mouse models
	Caveolin-3: Located on muscle fiber sarcolemma

• Nosology: Rippling Muscle disease 2 (RMD2)
• Genetics
  • Caveolin-3 gene mutations
    • General: Most commonly located in scaffolding domain of protein
    • Specific mutations
      • Arg26Gln
        • Caveolin levels reduced 60% to 80%
        • Associated disorders
          • Idiopathic hyperCKemia
          • Rippling muscle disease
          • Distal myopathy, Tateyama type
      • Asp27Glu
        • Rippling muscle disease ± Weakness (Distal or Proximal)
        • Variable clinical features in family
      • Pro28Thr
        • Onset 35 years
        • Rippling muscle disease
        • Fatigue: Exercise induced muscle pain, Cramps
        • Serum CK: 1100
      • Ala45Thr
        • N-terminal domain
        • Disease associations: LGMD1C; Rippling muscle disease
        • Caveolin levels reduced > 90%
      • Ala45Val: Rippling muscle disease
      • Ala46Thr: Rippling muscle disease; Distal myopathy
      • Ala46Val: Cardiomyopathy with Rippling muscles
      • Ser52Gly
        • Domain with role in homo-oligomerization
        • Rippling muscle disease
      • Gly55Ser
        • Caveolin scaffolding domain
        • Inheritance: Recessive
        • Caveolin levels: Normal
      • Val57Met: HyperCKemia
      • T63S: Cardiomyopathy
      • Cys71Trp: ? Disease association
        • Caveolin scaffolding domain
        • Caveolin levels: Normal
      • Homozygous: L86P or A92T
        • Rippling muscle disease: Severe, Recessive
      • Pro104 Leu
        • Missense mutation in membrane-spanning region
        • Disease associations: LGMD1C; Rippling muscle disease
        • Caveolin levels reduced > 90%
      • Arg125His: ? Disease association
        • C-terminal domain
        • Caveolin levels normal
      • 186Del9
        • Microdeletion in the scaffolding domain
        • Caveolin levels reduced > 90%
      • Splicing: IVS1+2T>C ⁶⁴
        • Homozygous
        • Intronic
        • Recessive inheritance
  • Caveolin-3: Allelic disorders
    • LGMD 1C
    • Rippling muscle disease 2: Dominant or Recessive
    • Increased CK with normal strength
    • Distal myopathy
    • Cardiomyopathy, familial hypertrophic
    • Long QT syndrome 9
  • External link: Leiden database
• Caveolin proteins
  • Caveolins: General
    • Integral transmembrane proteins
    • Principal protein components of caveolae
    • Caveolin-1 & Caveolin-3 generate caveola-like vesicles
    • Most of the functional domains in caveolins located in last exon
    • Functions
      • Signaling
        • Able to bind multiple components of a signaling pathway
        • Implicated in signal transduction: By receptor tyrosine kinases (RTKs) & G-proteins
        • Mechanism: Scafolding proteins; Organize & Concentrate molecules
          • Lipids: Cholesterol; Glycosphingpolipids
          • Lipid-modified signaling molecules in caveolar membrane
            • Src-like kinases, H-ras, eNOS, G proteins
      • Vesicular trafficking events
      • ? Tumor supressor (Caveolin-1)
  • Caveolae
    • Structure: Membrane invaginations
      • Flask-shaped
      • Location: Most cell membranes
      • Size: 50 to 100 nm
      • Associations
        • Appendages or subcompartments of plasma membranes
        • Muscle: Invaginations from sarcolemma
    • Functional
      • Scaffold
        • Microdomains
        • Place members of a signal-transduction pathway in proximity to each other
      • Membrane reservoir: Allow increase in surface area during muscle fiber stretch
    • Biogenesis: Role of PACSIN3 (Syndapin III)
  • Caveolin-3 protein
    • Tissue location: Muscle specific, Striated & Smooth
    • Cell localization
      • Sarcolemma (Adult)
      • T-tubules (Development & Adult): Concentrated in subsarcolemmal regions
    • Forms homo-oligomer: 14 to 16 subunits
    • Caveolin-3 interacts with
      • G-protein α subunits
      • Signaling molecules: Gl2α; Gβγ; c-Src; Src-like kinases
      • Dystrophin & Associated glycoproteins
        • Interaction not as strong as integral members of the DAG complex
        • Direct interaction with β-dystroglycan: Via WW-like domain
      • Dysferlin: Indirect interaction
      • PFK-M
        • Prominent caveolin-3 binding protein
        • ? Regulation of glycolysis by caveolin-3
      • nNOS (muscle-specific): Interaction inhibits nNOS enzyme activity
        • Cytokine-stimulated NOS activity: Increased in myotubes transfected with mutant CAV3
        • Transgenic CAV3 mutant mice (P104L): Increased nNOS activity in skeletal muscle
        • LGMD1C: Severe reduction of nNOS expression
      • Colocalizes with Na_v1.5 (SCN5A) in myocardium
    • Muscle functions
      • Required for myoblast fusion/myotube formation
      • Regulates myostatin signaling: Suppresses activation of type I myostatin receptor
      • Sarcolemma integrity
      • Electrical transmission of contractile impulse
      • Energy metabolism
  • Disease effects: Caveolin gene mutations & Other Disorders
    • LGMD 1C mutations
      • Caveolin-3 levels in muscle
        • Reduced
        • Membrane caveolin-3 especially reduced (~95%)
      • Muscle Structure
        • Formation of unstable high molecular mass aggregates
        • Aggregates composed of normal & mutated caveolin-3: Dominant negative effect
        • Aggregates of normal & mutated caveolin-3
          • Cell location: Retained in Golgi; Not targeted to plasma membrane
          • Effect of aggregation on caveolin-3 protein: Misfolding; Degradation
          • Metabolism: Undergo ubiquitination & proteasomal degradation
          • Caveolin-3 Half-life: Shortened by 7 fold
          • ? Treatments rescue wild type caveolin-3
            • Inhibition of proteasomal degradation of caveolin-3 aggregates
            • Inhibition of caveolin-3 misfolding
        • Altered interactions of scaffolding region with muscle regulatory proteins
    • Duchenne MD
      • Caveolin-3 is upregulated
      • Muscle has increased numbers of caveolae
    • Denervation: Caveolin-3 aggregates are present inside targets
• LGMD 1C: Clinical features
  • Onset
    • Age: 4 to 71 years
    • Weakness
    • Difficulty walking
  • Weakness
    • Usual
      • Severity: Moderate
      • Pattern: Proximal
    • Distal
      • 2 families described
      • Also in recessive patients
    • Progression
      • Mild: Adults with Gower's maneuver
      • Variable among families
  • Muscle size: Calf hypertrophy
  • Exercise intolerance ± Weakness
    • Cramps: After exercise
    • Rhabdomyolysis
  • Variable clinical manifestations may occur in single family
• Caveolin-3 mutations: Variant syndromes
  • Recessive muscular dystrophy syndromes ⁶⁴
    • Mutations: Gly55Ser; Splice site (IVS1C2TOC)
    • Weakness
      • Proximal & Distal; Foot drop
      • Legs & Arms
    • Contractures: Ankles
    • Calf hypertrophy
    • MRI
      • Asymmetric
      • Muscles: Hip abductors & adductors, Rectus femoris, Hamstring, Tibialis anterior
    • Muscle biopsy
      • Chronic myopathy
      • Caveolin-3 absent: No 21 kD band on Western blot
  • Rippling muscle disease syndromes
  • Distal myopathy (MPDT)
    • Nosology: Tateyama myopathy
    • Epidemiology: 3 families
    • Genetics
      • Inheritance: Dominant
      • Mutations: Arg26Gln; N33K mutations
    • Clinical
      • Weakness
        • Onset age: 2nd to 5th decade
        • Isolated Hand & Foot muscles
        • Neck flexors: Mild
      • Muscle size
        • Calf hypertrophy
        • Distal wasting
      • Percussion induced muscle contractions: Distal hands
      • Some patients
        • Rippling
        • Myalgias
        • Pes cavus
    • Laboratory
      • Serum CK: High
      • EMG: Myopathic
      • Muscle
        • Internal nuclei
        • Type I predominance
        • Caveolin-3 nearly absent
        • Dysferlin: May be reduced or normal
  • Hyper-CKemia ⁶³
    • Mutations: Missense; Gly56Ser, Thr78Met
    • Frequency: 7% of Idiopathic Hyper-CKemia
    • Caveolin-3 staining of muscle: Normal
  • Cardiomyopathy: Varied types
    • Hypertrophic
    • Dilated
    • Long QT syndrome ⁶⁵
      • Mutations: Missense; T78M, A85T, F97C, S141R
      • Effect of mutations: 2- to 3-fold increase in late sodium current
      • Onset age: 8 to 40 years
      • Symptoms: Nonexertional syncope; Cardiac arrest; Shortness of breath
• LGMD 1C: Laboratory features
  • Serum CK: Increased 3 to 40-fold
  • Pathology ⁶⁶
    • Myopathic changes: Often mild
      • More severe with early disease onset
      • Muscle fiber size: Varied
      • Necrosis & Regeneration: Some patients
      • Endomysial connective tissue increased: Some patients
    • Caveolin-3
      • LGMD1C
        • Reduced on muscle fiber sarcolemma & by Western blot
        • May be normal or high on small, regenerating muscle fibers
      • Reduced on sarcolemma in other hereditary disorders
        • VCP myopathy (IBMPFTD)
        • Cavin-1
    • Dysferlin
      • Reduced on muscle fiber sarcolemma
      • Normal by Western blot
    • Ultrastructure
      • Reduction in caveolae
      • Loss of myofibrils
• Caveolin disorders: Mouse models
  • Overexpression of wild type caveolin-3
    • Myopathy
    • Reduced dystrophin
  • Overexpression of Pro104Leu mutant caveolin-3
    • Down regulation of wild type caveolin-3
    • Myopathy: Severe
  • Caveolin-null
    • T-tubule abnormalities
      • Mislocalized dihydropyridine receptor-1α & ryanodine receptor
      • Iregular orientation of T-tubules
    • Loss of caveolae at sarcolemmal membrane
    • Muscle fiber degeneration: Especially in soleus & diaphragm
    • No effect on dystrophin complex
• Links: Leiden

• Nosology: Confused terminology
  • LGMD 1E: HUGO
  • LGMD 1D: OMIM & Some authors ³⁵
  • Myofibrillar myopathy 1 (MFM1)
• Epidemiology: 1 Large family; French-Canadian descent
• Genetics
  • Desmin mutation: Intron splice donor site mutation (IVS3+3A>G)
  • Earlier incorrect chromosome localization at 6q23
  • Allelic disorders
• Desmin protein
• Clinical
  • Weakness
    • Onset: 2nd decade & later
    • Distribution: Proximal; Face normal
    • Calf hypertrophy: Occasional
    • Exertional dyspnea
    • Progression: Slow; All patients remain ambulatory
  • Cardiac
    • Arrhythmia: Earliest feature of cardiac disease; Onset 20 to 25 years
    • Congestive heart failure: 4 chamber enlargement; Onset 3rd to 5th decade
    • Sudden death without prior cardiac symptoms
• Laboratory
  • Muscle pathology
    • Variable fiber size
    • Increased endomysial connective tissue
    • Eosinophilic inclusions: Some reducing bodies
  • Serum CK
    • Usually increased 2x to 4x control
    • More likely high in males than females

• Epidemiology: 7 families, 14 patients
• Genetics
  • Mutation: c.292C>T (p.His98Tyr)
• Myoglobin protein
  • Cytoplasmic globular hemoprotein
  • Highly expressed in: Cardiac myocytes & Oxidative skeletal myofibers
  • Binds O₂
  • Facilitates intracellular O₂ transport
  • Controller of nitric oxide & reactive oxygen species
• Clinical
  • Onset age: 33 to 49 years
  • Weakness
    • Proximal & Axial
    • Legs > Arms
    • Distal: With disease progression; Early hands in some
    • Respiratory
    • Bulbar: Dysphagia (33%); Dysarthria; Tongue weak
    • Face: Normal or weak Orbicularis oris
    • Normal: EOM
  • Muscle atrophy: Most
  • Cardiac: Dilated cardiomyopathy (45%)
  • Course
    • Slow progression
    • Wheelchair after 15 years
    • Death in some 18 to 30 years after onset
• Laboratory
  • Serum CK: Normal to 7x high
  • EMG: Myopathic with spontaneous activity
  • Muscle MRI
    • Proximal: Paraspinal, Gluteus maximus & medius
    • Thigh: Adductor magnus, Semimembranosus, Long head of biceps femoris & Vastus intermedius
    • Leg: Soleus
  • Muscle pathology
    • Sarcoplasmic bodies: Round; Autofluorescent; Also in heart
    • Vacuoles: Acid & LAMP1 phosphatase+
    • Fiber sizes: Varied
    • Internal nuclei
    • Type 1 fiber predominance

• Epidemiology: 4 families, 12 patients
• Genetics
  • Mutations: Coiled-coil domain; Glu529Lys, Gln523_Glu529del
  • More weakness: Gln523_Glu529del
  • Allelic disorder
• DTNA protein
  • Mutation effect: Abnormal interaction between DTNA & Syntrophin
• Clinical
  • Onset age: Early childhood to 4th decade
  • Weakness (25%): Proximal; Legs
  • Myalgia
  • Exercise intolerance
  • Cramps (50%)
  • Autism (40%)
  • Rhabdomyolysis: 1 patient
  • Cardiac: Normal
• Laboratory
  • Serum CK: High in 90%
  • EMG: Myopathic; Fasciculations
  • Muscle pathology
    • Fiber sizes: Varied
    • Nuclei: Internal
    • NMJs: Thin in 1 patient
    • Endomysial connective tissue: Mild increase
    • Dystrophy proteins reduced by IHC: α-dystrobrevin; Sarcoglycans; Dystrophin; Dystroglycans
    • Western blot: α-dystrobrevin normal

• Epidemiology: 2 families; 17 patients
• Genetics
  • Mutations: Heterozygous; Glu668X, Gln673X
  • Protein effect: Carboxy-terminal ablation; Loss of last 15 to 18 amino acids
• MAMDC2 protein
  • Locations
    • Subcellular: Cytoplasmic, Perinuclear in proliferating cells
    • Secreted
    • Extracellular matrix
  • Enables glycosaminoglycan (GAG) binding
• Clinical
  • Onset age: Most in childhood; Few > 5th decade
  • Weakness: Varied patterns
    • Arms (60%): Especially triceps; Finger extensors or flexors
    • Legs (60%)
    • Proximal (60%)
    • Distal (50%): Arms
    • Trunk: Neck flexor; Abdominals
  • Joint contractures (25%): Fingers
• Laboratory
  • Serum CK: Normal or Mildly high (< 1,000)
  • Muscle MRI
    • Limbs: Sub-fascial regions of muscles
    • Most in areas where fascias from neighbouring muscles contact
      • VL-VI
      • Gastrocnemius-Soleus
    • Other sub-fascial muscle pathology: COL6; VWA1; IMPP
    • Normal < 40 years
    • Fat
      • Near myotendinous junctions with tendons
        • Tricipital; Rectus femoris longitudinal; Thigh muscle pelvic insertion
      • Muscles: Lumbar paraspinous; Rectus abdominus & Oblique
  • Muscle pathlogy
    • Fiber sizes: Varied
    • Necrosis & Regeneration
    • Endomysial connective tissue: Increased
    • COX- fibers: 1 patient
    • Ring fibers
    • Ultrastructure: Muscle basement membrane thick
    • Normal: Collagen VI; Laminin-α2; α-Dystroglycan; MAMDC2 staining

• Nosology: LGMD 1H
• Epidemiology: Southern Italian family
• Genetics: Incomplete penetrance
• Clinical
  • Onset
    • Age: 16 to 50 years
    • Weakness: Arms & Legs
  • Phenotype: Variable onset age & severity
  • Weakness
    • Proximal
    • Legs & Arms
    • More severe with younger onset
  • Muscle hypertrophy
    • Calves
    • Younger patients with no weakness
  • Muscle atrophy: Proximal
  • Tendon reflexes: Reduced
  • Progression: Slow
• Laboratory
  • EMG: Myopathic
  • Serum CK: 98 to 2300
  • Serum lactate: Normal
  • Muscle biopsy
    • Fiber size variation
    • Endomysial fibrosis
    • Mitochondrial
      • SDH+ & COX- muscle fibers
      • mtDNA deletions: Multiple

LGMDR (LGMD2): Recessive Inheritance

Recessive   Genetics   Calpain-3 protein   Clinical   Laboratory   Muscle pathology Dominant

From: C Angelini MD

Nosology: LGMD 2A Epidemiology 30% to 40% of LGMD Most common recessive LGMD worldwide Especially: Eastern Europe, Spain, Italy Denmark: Less common than 2I (FKRP) & 2L (ANO5) Genotype & Phenotype Mutations: > 500 identified 7 Most common type: Missense Mutation patterns Private variant mutations in 70% Recurrent mutations Founder effect 1.5x more frequent than than recurrent Single base pair: 60% to 70% Missense: Most, ~80% Stop codons: Few Splicing defects: ~15% Small insertions or deletions Frequency: 30% to 40% Most cause frameshift & stop codon 1 Large genomic deletion 2° to unequal recombination between two intragenic Alu elements Overall ~45% of mutations are truncating Location: Present through most of gene Excess of mutations: Exon 21 Excess of point mutations Exons 5, 11 (11 amino acid span with multiple CpG sites) & 21 Excess of deletions/insertions: Exons 15, 17, & 22 R490Q mutation Located in catalytic site Protein Autolytic activity: Lost CAPN3 protein present by Western blot CAPN3 remains after incubation of muscle without EDTA 130 LGMD phenotype: Weakness severity = Variable G222R mutation 54 Mutations: Compound heterozygote for R110X & G222R Loss of function: Size & Abundance normal Early onset weakness Disease foci: Geography Europe Réunion island 60% have IVS6-1G>A Amish & Basque populations Digenic inheritance: ?? Guipuzcoa (Basque Country, Spain) Exon 22, 2362AG[→]TCATCT in 76% Italy Mocheni, Italian Alps: c.1193+6T>A Venetian lagoon (Chioggia): Arg490Gln Central & Eastern Europe c.1746-20C>G; Mutation frequency 1% Russia, Eastern Mediterrananean & North Italy 550delA: Mutation frequency 1/150 North America US Northern Indiana Amish: Arg769Gln Tlaxcala, Mexico: Ala116Asp Asia China: c.2120A>G Japan: c.1795_1796insA Northern India: Asp780His, c.2099-1G>T, c.2051-1G>T, c.2338G>C Large (31,012-bp) deletion (Exons 2-8) (c.309+4469_c.1116-1204del) Occurs in different ethnic backgrounds Clinical correlations Severe phenotype Homozygous null mutations: Often but not always NS1 domain mutations; S86F Least severe phenotype: Homozygous missense mutations Allelic disorder: LGMD, Dominant Mutation Databases HGMD Leiden: Sequence variants Calpain-3 (p94) protein 145 Localization Expressed prominantly in skeletal muscle: N2-line region Associates with C-terminus of titin (connectin) in muscle Filamin C Calmodulin kinase IIβ (CaMKIIβ) Cardiac ankyrin repeat protein (CARP; ANKRD1) Dysferlin Myospryn (CMYA5) AHNAK Subcellular: Nucleus ± Cytosol; Not membrane related Substrates Metabolic Myofibrils (MLC1) Functions General Ca++ activated non-lysosomal cysteine thiol-protease Relies on Na+ activation Cleaves proteins into short polypeptides, not single amino acids Activity may not be Ca++ dependent Use cysteine as active site residue Limited proteolytic cleavage of substrate Related to location in cell Nuclear: Cell survival Cytoplasm: Cell motility; Skeletal plasticity Cytoskeletal remodeling Assembly & remodelling of contractile proteins in sarcomere Can bind & cleave titin Control of Ca++-efflux from sarcoplasmic reticulum Membrane repair Muscle regeneration Mutations: Reduced affinity of calpain-3 for titin Half life Short (< 10 minutes) Rapid turnover related to insertion sequences (IS) not present in other calpains Autolysis: Not dependent on Ca++ activation Disease mutations: Effects on calpain function vary, may be selectve for Proteolytic activity vs fodrin substrate: Reduced Autolysis capacity: Reduced Titin binding: Reduced Altered maintenance & remodelling of contractile apparatus Abnormal calpain-3 proteolysis & cleavage of titin Expression in other disorders Increased: FSHD; Melanoma, Vitiligo, Cataract (Age-related) Reduced: Dystrophies (2B, 2J, Tibial, Duchenne, Ullrich); IBM; Rhabdomyolysis LGD 2A: Clinical features 21 Onset Early motor milestones: Most normal; Toe walking common Range: 2 to 65 years; Median = 14 to 20 years; 71% between 6 to 18 years Weakness: Proximal legs; Rectus abdominus No clear sex differences; ? Females slightly younger than males Disease patterns: Various phenotypes General pattern Weakness: Scapula (Symmetric), Pelvic girdle Normal: Face Differential Diagnosis: FSH; LGMD 2I HyperCKemia, asymptomatic (14%): Male > Female 3:1 Limb girdle types (76%) Early onset: < 12 year Group with most homogeneous progression Contractures more common Null mutations: Common Leyden-Mobius type Onset 13 to 29 years Weakness Early: Pelvic-Femoral girdle Later: Shoulders Late onset Age: > 30 years Weakness: Pelvic girdle Erb dystrophy type (10%): Scapular-Humeral phenotype Onset age: 16 to 37 years Weakness early: Shoulder girdle Male = Female Calpain-3 protein in muscle: Often normal Miyoshi muscular dystrophy phenotype Weakness General Symmetrical Proximal + Milder Distal Legs > Arms at onset: Most patients May be asymmetric Progressive Severity Heterogeneous: Mild to Early onset severe Mild phenotype in majority Male = Female Trunk Peri-Scapular Latissimus dorsi; Serratus magnus Scapular winging (83%): Symmetric Rectus abdominus Pelvic girdle Gluteus maximus Legs Most severe: Adductors; Knee flexion Ankle dorsiflexion: Some patients Arms Most severe: Shoulder adduction; Elbow flexion Wrist extension: Some patients Respiratory Vital capacity: Declines over time; Rarely < 80% No nocturnal hypoventilation Quadriceps: May be selectively spared Gait Inability to walk on heels Lumbar lordosis Loss of walking: Mean late 2nd or 3rd decade Normal: Face; Ocular & Bulbar Some patients are asymptomatic with elevated serum CK levels Muscle size Atrophy Early in posterior compartments of limbs Different from Quadriceps wasting in Sarcoglycanopathies May be apparent on CT Most affected: Gluteus maximus & Thigh adductors Pelvic; Shoulder; Proximal limbs; Trunk; May be scapuloperoneal Hypertrophy Some patients Earlier in disease course Especially in Brazil Most common: Calf (Not prominent); Proximal Contractures Onset: May occur early in disease course Calf: Toe walking may be presenting sign Other: Elbow, Wrist & Finger flexion Common late in disease progression: Rigid spine May be severe & require surgery Differential diagnosis: Emery-Dreifuss CNS Normal, or Mild mental retardation: Average IQ = 77 Cardiac: No involvement Progression Slow: Earlier onset more rapid Loss of walking 10 to 30 years after onset 50% in 3rd decade Most by age 40 years Many patients can still stand, even when in wheelchair Syndrome variation Intrafamilial Similar onset age & severity in some families with null mutations Onset at 15 years Variation in others with 2 Missense mutations or Compound heterozygotes for missense & null mutation Onset 2.5 to 45 years Interfamilial: Prominent LGD 2A: Lab features Serum CK: Normal to 80 times normal; 190 to 11,000 MRI Thigh: Varies with degree of function Prominent in most patients: Posterior Early involvement: Adductors; Semimembranosus Restricted ambulation Diffuse involvement: Posterolateral thigh & Vastus intermedius Sparing: Vastus lateralis, Sartorius & Gracilis Calf Involvement: Soleus; Gastrocnemius, Medial head Relative sparing: Gastrocnemius, Lateral head Muscle Biopsy Myopathic Muscle fibers Necrosis & Regeneration Active myopathic changes Eosinophils in some associated cell foci Myopathic groups May involve clusters or whole fascicles early in disease 34 Size: Variable; Small rounded to Hypertrophic Internal architecture Usually unremarkable Regenerating fibers: Coarse internal architecture Lobulation of Type I fibers: Later in disease course Nuclei: Internal; Apoptosis with altered IκBα/NF-κB pathway Groups of atrophic (type 2) muscle fibers Endomysial fibrosis: Increased with longer disease course Fiber types Type 2 hypertrophy: Some patients Type I predominance: With increasing weakness Type 2C: Common Inflammation Some biopsies May be perivascular or endomysial Dystrophy-related proteins Calpain-3: Western blot patterns Loss of all calpain-3 bands (94 kDa, 60 kDa & 30 kDa) High specificity for LGMD2A: Frequency 23% May have null or missense mutations Absence or reduction of 60 kDa bands High specificity (94%) Sensitive (64%) Absence or reduction of 30 kDa bands Specific (88%) Sensitive (58%) Increased lower MW 60 kDa region bands No mutations (92%) Suggests protein degradation artifact Normal full-sized calpain-3 protein Occurs in 23% of patients with 2 calpain-3 mutations Often have loss of autocatalytic function Abnormal Western blot with only 1 calpain-3 mutation Similar phenotype to patients with 2 mutations found Calpain-3 reduction may occur in other myopathies Dystrophin; LGMD 1C; LGMD 2B (Dysferlin); LGMD 2I (FKRP); LGMD 2J (Titin) Dysferlin: Reduced or absent in some patients; Western blot normal Sarcoglycans & Dystrophin: Normal Ultrastructure: Patchy damage to myofibrillar Z, I & A bands Diagnosis 41 Genetics Difficult due to many different mutations More common in some regions of gene 87% of mutant alleles in exons 1, 4, 5, 8, 10, 11 & 21 Some common mutations: 61% have one of eight mutations Directed mutation analysis: Geographic groups Some patients with only 1 detected mutation have Typical LGD 2A phenotype: May be dominant Western blot Calpain-3 enzyme activity: Reduced Mouse model: Calpain-3 knockout 42 Misaligned A-bands Abnormal sarcomere formation CAPN3 variant syndrome: LGMD, Dominant 4 (LGMD D4) 104 Nosology: LGMD 1I; LGMD D4 Epidemiology: 37 families Genetics Inheritance: Dominant Mutations In-frame deletions: c.643_663del21; c.598_612del15; c.759–761delGAA [Lys254del], Ala497_Glu508del Missense: c.1333G>A [p.(Gly445Arg)], Pro102Ser, Asn457Lys S86F heterozygotes: Mildly high serum CK; Normal strength Gly234Arg heterozygotes: Exertional myalgia Mutation effects: CAPN3 loss Clinical: Milder than recessive CAPN3 mutations Onset age Mean 34 years: 16 years later than Recesive LGMD 2A Range: 13 to 84 years Pain (50%) Muscle Back Exertional May occur without weakness Weakness Severity: Milder than LGMD 2A Pattern: Similar to LGMD 2A Paraspinal: Lumbar; Camptocormia Leg: Proximal Distal leg: Gastrocnemius, medial Arms: Proximal Normal strength: Some patients Course: Variable Severe disability: Some patients Asymptomatic: Some patients Muscle wasting: Proximal arms Laboratory Serum CK: High in 90%; Range 169 to 9,000 Muscle MRI: Fat replacement Trunk: Paraspinal Pelvis: Glutei Thigh: Hamstring Leg: Gastrocnemius, medial Muscle pathology Myopathic Internal nuclei Fiber size: Varied Internal architecture: Lobulated Necrosis: Scattered Endomysial connective tissue: Increased Calpain-3 protein: Reduced (< 15% of control levels) or Normal

LGD 2A: Erb phenotype From: C Angelini

Gene Protein Clinical   Variants Laboratory Pathology Mouse models

No calf hypertrophy From: C Angelini

Boule du Biceps From: Dejerine, J. Semiologie des affections du systeme nerveux.   Paris: Masson et Cie (pub.) 1914

Nosology: LGMD 2B Epidemiology Prevalence: 0.5 to 71/1,000,000 3% to 30% of LGMD 33% to 70% of Distal myopathies Genetics 25 Gene: 55 exons > 450 different mutations described Dysferlin deficiency: 18% with only 1 (heterozygous) mutation identified on 1 allele Mutation types Types: Missense (26% to 46%); Nonsense (18% to 26%); Deletions; Insertions; Intron; Splice Distributed over entire coding sequence + Introns: Most mutations private variants Most introduce stop codons or premature truncations of the dysferlin protein Splice site (in-frame) mutation (A3443-33G) 53 May allow some residual dysferlin protein production Clinical phenotype: Milder Mutation locations in gene: Widely dispersed over coding sequence Mutation effects: Dysferlin protein loss or abnormal function Geographic distribution Japanese G2997T (Trp999Cys); G3370T: Mild disease phenotype; Later onset G3510A: More severe disease; Earlier onset; High CK Other common mutations: 3746delG; 4870delT 3373delG: Japanese Miyoshi Sueca, Spain: Arg1905X 50 Portugal: Glu353_Leu429del (c.1180_1180+7AGTCGTG); c5492G>A Canada: Pro791Arg Italy: Arg959Trp Caucasian Jewish: c.2779delG Libyan Jews: 1624delG; Carrier frequency up to 10% Lebanese Jews: c.4872_4876delinsCCCC Brazil: c.5979dupA Allelic disorders LGMD R2 Late onset MD, Distal, CK high, Dominant Late onset MD, Recessive Miyoshi myopathy Distal anterior dysferlinopathy Congenital myopathy CK high, asymptomatic Chronic pain + High CK 177 Genotype-Phenotype Variations in phenotype not well explained by mutation type Same spectrum of mutations in LGMD & Miyoshi distal myopathy 1 diagnoses External links Mutation Databases: Leiden Jain Foundation Protein: Dysferlin 166 Tissues Skeletal muscle > Heart Ubiquitously expressed at low levels Size & Forms 237 kDa + Multiple lower weight bands 55 exons Isoforms: Alternative splicing at exon 40a Inclusion of exon 40a: Produces calpain-cleavable site Calpain cleavage at exon 40a produces: Mini-dysferlinc72 Regulates membrane repair Damage-dependent production Subcellular localization Plasma membrane: Present at periphery of muscle fibers T-tubules Cytoplasmic vesicles: Trans-Golgi network secretory vesicles Injury: Translocated to cytoplasm by endocytosis Homology to Nematode spermatogenesis factor (fer-1): Required for cell fusion Myoferlin: Plasma membrane & Nuclear envelope Otoferlin Domains Transmembrane: Short, C-terminal, hydrophobic C2 7 domains Hydrophilic Ca2+-dependent membrane binding Bind lipids Most of dysferlin protein intracellular Extracellular domain: Small Interactions 62 Protein complex Caveolin-3 Mitsugumin 53 (MG53; TRIM72) : May play role in membrane repair No direct interaction between Dysferlin & Caveolin-3 T-tubules RyR-1: Skeletal muscle triad RyR-2: Cardiac muscle Dihydropyridine receptor (DHPR; L-type Ca++ channel) Other proteins AHNAK Interaction mediated by calpain-3 Levels reduced in dysferlinopathies Annexins A1 & A2 : Regulate dysferlin localization S100 Calcium binding protein A10 Calpain 3 (CAPN3) β-Parvin (Affixin) CD82 (Tetraspanin 27) Other: Ca++; Lipids Functions Membrane repair: Sarcolemma & T-tubules General membrane actions Vesicle Fusion Repair Ca++-triggered fusion of nearby vesicles Provides source of membrane: To restore membrane barrier Facilitates aggregation of exocytotic repair vesicles into repair patches Ca++-mediated muscle membrane processes Homeostasis processes Signal transduction events Excitation-Contraction coupling Modulated molecules: L-type Ca++ channels; RyR Buffers Ca++ in triadic cleft via C2A domain T-tubule growth & morphology May act synergistically with BIN-1 Tissue growth Myogenesis Angiogenesis Microtubule dynamics Dysferlin turnover & levels Half-life in membrane: ~ 3 hours Upregulation: LARGE (myd) mouse Dysferlin: LGMD 2B patients Immunohistochemistry (IHC) Sarcolemma: Absent or Reduced Cytoplasm: Reduced or Increased Western blot Absence: Has more specificity for LGMD 2B than IHC changes Dysferlin amount: Often reduced; May be normal or increased Disease relation: Dysferlin reduced to ~ < 10% of normal Some mutations produce cytoplasmic aggregates of normal sized dysferlin protein Disease mechanisms Sarcolemmal membrane repair: Reduced 178 Ryanodine receptor 1 Ca++ leak: Increased 175 Clinical: Milder LGMD phenotype 85 Onset Age Mean 19 to 27 years Range General: 10 to 39 years Congenital & 8th decade onsets reported Heterogeneity in single family may occur Leg weakness Proximal May be associated with period of exercise Weakness Mild Asymmetry: Common Legs Distal: Posterior muscles Especially gastrocnemius Early inability to walk on toes Differential diagnosis: Distal myopathy with anterior leg sparing Proximal Anterior & Posterior muscle groups Especially adductors, also psoas "Diamond on Quadriceps": Asymmetric 164 Gait Tendency to place entire foot on ground, especially lateral aspect Foot: Inversion, mild; Great toe extended; Lateral 4 toes flexed Course: Lower limbs involved 9 years before upper limbs Arms Especially biceps Weakness Atrophy: Distal predominant (boule du biceps) (MRC ≥ 4) 126 Deltoid: Often spared Trunk: Glutei, Erector spinae, Shoulder girdle involved Face: Generally normal Loss of ambulation: > 30 years Respiratory 167 More with longer disease duration Overall: 50% have VC < 80% Wide inter- & intrafamilial variation Progression: Slow; Most walk until > 33 years, some into 6th decade Calf size Hypertrophy: Some patients Deltoid hypertrophy with biceps atrophy Posterior leg (Calf): May be early in disease course Occasional distal onset patients Subacute, painful enlarged calves early in course 60 Cramps & muscle discomfort: Some patients No cardiomyopathy: Clinically preserved; EF generally > 50% Same mutations may also produce Miyoshi distal myopathy ? Modifier genes determine phenotype Laboratory features CK Typical Very high Range: 10x to 72x normal; Up to 27,000 Lowest: Normal Presymptomatic: 343 to 3,000 ? Age-dependent increase EMG: Myopathic Motor units: Small amplitude; Short duration No spontaneous activity Imaging Early involvement on MRI or CT Posterior leg: Gastrocnemius atrophy, especially medial heads; soleus Thigh: Hamstrings Erector spinae Late or minimal involvement: Gracilis; Sartorius; Glutei Skeletal Muscle Pathology: Dystrophic Muscle Necrosis & degeneration of muscle fibers Endomysial connective tissue: Increased in more involved muscles Muscle fibers: Size variation, may appear bimodal; Splitting No vacuoles Inflammation: Some mutations 22 Perimysial & perivascular cell infiltrates: Some muscles T-lymphocytes No MHC class I antigen on muscle fibers Complement: Membrane attack complex (but not C3) on muscle fiber surface Amyloid Present in muscle in some patients Mutation locations: N-terminal or other regions Location: Muscle fiber surface; Endomysial connective tissue; Perivascular Amyloid may contain dysferlin Ultrastructure Sarcolemmal defects Replacement of membrane by layers of small vesicles 23 Dysferlin tissue staining 30 Levels Absent, Reduced or Normal Absent staining: More specific for LGMD 2B than reduced, but present, staining Retained staining: May be related to splice site mutations in dysferlin gene No correlation between level of staining and clinical severity Staining may be patchy among muscle fibers Reduced dysferlin staining: Differential diagnosis Not specific for dysferlinopathy: 30% to 60% with no DYSF mutation Other disorders: CAPN3 (10%); CAV3 (2%); GNE; MYH2; ANO5 Dysferlin Western blot Common & specific change in LGMD 2B: Dysferlin reduced to 0% to 20% of normal Absent dysferlin on Western blot: Dysferlin gene mutations very common Good correlation on WB between results in Skeletal muscle (234 kDa) Monocytes (doublet 224 to 234 kDa) Increased dysferlin expression: Mutatons in exons 36 or 37 Other molecules Calpain-3: Reduced especially with C2 domain mutations Sarcoglycans & Dystrophin: Present Aquaporin-4: Reduced Cardiac 167 EKG P-wave abnormalities (58%) Indicates delayed trans-atrial conduction Left ventricle function: Normal Variant syndromes: Different phenotypes may occur in same family General Late in disease course: Varying weakness phenotypes merge Distal myopathy: Miyoshi Distal myopathy: Distal Myopathy Anterior Tibial, Dysferlinopathy (DMAT; DACM) Genetics Mutation: Homozygous; 5966delG Clinical Onset: Foot drop; Steppage gait Weakness Legs Anterior: Ankle > Knee Distal > Proximal Arms: Proximal Muscle pathology: Absent dysferlin Myopathy: Proximal + Distal Onset: Proximal weakness; Calf atrophy Weakness: More rapidly progressive Muscle pathology: Inflammation more common Myopathy: Later onset, Proximal, Arms > Legs 85 Genetics Inheritance: Recessive Mutation: Trp999Cys; Homozygous Onset Age: Mean 38 years; 16 years later than others average Arm symptoms Weakness: Proximal Serum CK: High but lower than average Pain syndrome Onset: Distal leg (calf) painful swelling without weakness or atrophy Unilateral or Bilateral No weakness or atrophy Asymptomatic with elevated serum CK levels 176 Frequency: 5% of dysferlinopathies Mutations: Missense or Stop Age: 28 & 50 years MRI: Mild gastrocnemius pathology Dysferlinopathy: Congenital myopathy 70 Genetics Mutation: p.Ala927LeufsX21 frameshift Same mutation associated with: Asymptomatic high CK & LGMD syndromes Clinical Onset age: Congenital Weakness Birth: Hypotonia Legs & Neck flexor ± Arms Walking: At 19 to 30 months Motor milestones: Delayed Contractures: Ankles & Hips; Onset 3 years CNS: Normal Laboratory Serum CK: Up to 5000; Normal or mildly high early MRI: Pathology (STIR) in hamstring & gastrocnemius Muscle Myopathic: Fiber size varied; Endomysial connective tissue increased Dysferlin absent; α-dystroglycan normal Dysferlin variant: Late onset MD with High CK 162 Epidemiology: 1 family, 4 patients Genetics Inheritance: Dominant Mutation: c.6207del Clinical Onset age: 4th to 6th decade Weakness: Legs, Distal & Posterior Discomfort: Myalgias, Fatigue Laboratory Serum CK: 800 to 3,400 MRI: soleus, Gastrocnemius, medial Muscle pathology Immature fibers, scattered Fiber sizes: Varied Internal nuclei Dysferlin staining: Reduced Dysferlin: Mutation carriers 74 May be symptomatic Mutations: G519R; D625Y Clinical Weakness: Legs; Proximal or Distal; Progressive Calf myalgias: 1 patient Serum CK: High; 600 to 3000 Muscle Myopathy Dysferlin expression: Reduced & Patchy Mouse model: SJL Mutation Genomic: 141 bp intronic deletion involving tandem repeat Effects of mutation Alters 3' splicing site Causes deletion of exon 45 in cDNA: 171-bp in-frame deletion Protein results Deletion of 57 amino acids Reduced amount to 15% of normal Pathology: Myopathy ± Inflammation Mouse model: A/J Retrotransposon insertion in intron 4 (5' end) of dysferlin gene Progressive myopathy: Proximal > Distal Perivascular inflammation Dysferlin: Absent by Western blot

Dysferlin staining in normal muscle

• Nosology
  • LGMD2C
  • Severe Childhood Autosomal Recessive (SCARMD)
• γ Sarcoglycan gene
  • Promoters: Muscle, Brain & ? Heart-type
  • Mutations
    • Many mutations disrupt carboxyl-terminus
    • Common
      • c.525delT: Espeically Tunisia, North Africa & Europe ³⁶
      • c.848G-A: Europe
    • One Japanese patient with 73 base pair deletion
    • Gypsies: Cys283Tyr
    • Severe phenotype: May have null or missense mutation
    • Databases: Leiden; HGMD
• γ Sarcoglycan protein
  • 35 kD Dystrophin-associated glycoprotein
    • Peptide mass: 32 kDa
  • Acidic
  • Location: Subsarcolemmal
  • mRNA expressed
    • Strongly: Skeletal & cardiac muscles
    • Moderately: Lungs, Skin, Spinal cord & Olfactory bulb
    • Weakly: Cerebrum & Aorta
  • Sarcoglycan binding: Moderately to β-sarcoglycan
  • Homologous sarcoglycan: δ-sarcoglycan
  • See: Sarcoglycan complex
• Clinical features
  • Severity
    • Some with Duchenne-like course
    • Others intermediate between Duchenne & Becker phenotype
    • Mild Becker phenotype in occasional family
    • Variable: Interfamilial; Intrafamilial may be homogeneous or heterogeneous
    • Gypsies with C283Y mutation
      • Early Duchenne-like course but longer survival (50%)
      • Becker phenotype (13%)
      • Overall: More severe than North Africans with out of frame del521-T mutation
  • Weakness
    • Onset
      • Mean 5 to 6 years
      • C283Y mutation: < 2 years
    • Proximal > Distal
    • Patchy distribution with some mutations (C283Y)
      • Affected: Glutei, Adductors, Hamstrings, Spinalis, Abdominals, Subscapularis, Soleus
      • Spared: Quadriceps
    • Respiratory: Failure in 3rd decade
  • Muscle hypertrophy: Some patients (C283Y); Calf & Tongue
  • Hearing loss: Neurosensory
  • Cardiac
    • Occasional involvement: Especially late in disease course
    • C283Y mutation: Subclinical; EKG changes 60%; RVH; Diastolic dysfunction
  • Skeletal (C283Y): Lumbar hyperlordosis; Scapular winging
  • Intelligence: Normal
  • Course
    • Loss of ambulation: 10 to 37 years; Mean 16 years
    • No relation between severity of disease & age of onset
    • Death: Common in 2nd decade
• Laboratory features
  • Serum CK: Very high
  • Muscle pathology
    • Myopathic
    • Inflammation: Occasional
    • Sarcoglycan staining
      • Severe disease: Absent γ-sarcoglycan
      • Slowly progressive disease: Reduced γ-sarcoglycan
      • Other sarcoglycans: Levels not related to clinical phenotype
        • General: Reductions may be partial and diffuse or varied among muscle fibers
        • α: Normal or Reduced
        • δ: Normal or Reduced
        • β: Variable; May be reduced most or absent
    • Dystrophin: May be normal or reduced

• Nosology: LGMD 2D
• Genetics: α-Sarcoglycan gene
  • Promoters: 2
  • Mutations
    • Most mutations: Missense: In extracellular domain of SGCA
    • Arg77Cys (c.229C>T) most common mutation, independent of ethnicity
    • Common mutations, other: c.739G>A, c.850C>T
    • Mutation Databases: HGMD; Leiden
  • Allelic disorders
    • Exercise intolerance
    • LGMD miniature dachsund dogs ¹³⁸
• α-Sarcoglycan protein
  • 50 kD dystrophin-associated glycoprotein
    • Peptide size: 40.4 kDa
    • Homologous sarcoglycan: ε-sarcoglycan
    • Features distinct from non-homologous sarcoglycans
      • Cadherin-like domain: ? Function by associating with other glycoproteins
      • Calcium-binding pockets
  • Sarcoglycan binding: Moderately to β- & δ- sarcoglycans
  • Location: Expressed only in skeletal & cardiac muscle
  • See: Sarcoglycan complex
  • α-Sarcoglycan gene abnormalities
    • May produce absent or reduced level of α-Sarcoglycan in muscle
    • Levels of α-Sarcoglycan correlate roughly with gene structure
      • Null mutations: Often absent α-Sarcoglycan
      • Missense mutations: Reduced α-Sarcoglycan
    • Severity of myopathy correlates best with level of α-Sarcoglycan in muscle
      • Absent α-Sarcoglycan: Duchenne-like phenotype
        
      • Reduced α-Sarcoglycan: Later onset; Milder weakness
  • Other myopathies: α-Sarcoglycan may be reduced in other dystrophies
    • Especially other sarcoglycan disorders
    • Reduced α-Sarcoglycan in muscle (? gene defect): ? Related to dilated cardiomyopathy
      
• Clinical features: Severe or Mild phenotype
  • Onset
    • Variable: 2 to 15 years
    • Earlier onset
      • More rapidly progressive weakness
      • Absent α-Sarcoglycan
    • Later onset
      • Ambulation may be preserved
      • Occasional patients with only high CK, but no weakness
      • Reduced but present α-Sarcoglycan
    • vs Other Sarcoglycanopathies: Later onset; Slower progression
  • Weakness
    • Proximal > Distal
    • Symmetric
    • Quadriceps: Severe phenotype
    • Scapular weakness & winging: Severe phenotype
  • Calf hypertrophy: Some patients
  • Systemic: Rare associated cardiomyopathy
• Laboratory features
  • Serum CK: Very high; Often > 5,000
  • Muscle biopsy
    • Myopathic
      • Fiber size variation
      • Endomysial connective tissue: Increased
      • Degeneration & Regeneration of muscle fibers
      • Myopathic grouping of degeneratiing & regenerating muscle fibers
    • Sarcoglycan staining
      • Absent α-sarcoglycan
      • Other sarcoglycans: Reduced or absent
• Treatment: Prednisone inproves motor function (Anecdotal reports)
• Heterozygotes (Ile124Thr missense mutation): Some patients have a clinical phenotype ³⁸
  • Myalgias
  • Scapular winging: 60%
  • Calf hypertrophy: 15%
  • Serum CK: Normal
  • Muscle biopsy: Fiber-size variability; Atrophic fibers; Normal α-sarcoglycan by IHC
• α-Sarcoglycan variant disorder: Exercise intolerance & Myalgias ¹⁰¹
  • α-Sarcoglycan genetics
    • Inheritance: Recessive
    • Mutations: V247M; R284C
  • Clinical
    • Onset age: 1st or 2nd decade
    • Myalgias: With exercise
    • Strength: Normal or Biceps weak
    • Scapular winging
  • Laboratory
    • Serum CK: 700 to 12,000; Higher with exercise
    • Muscle pathology
      • Histology non-diagnostic: Atrophic muscle fibers
      • α-Sarcoglycan: Reduced by Western blot
    • EMG: Normal

• Nosology: LGMD 2E
• Epidemiology
  • Common in Northern & Southern Indiana Amish; Bern, Switzerland
  • General incidence: 1:200,000 to 1:350,000
• β-Sarcoglycan gene
  • Promoters: 1
  • Mutations
    • Missense: Common
    • Common mutation: Ser114Phe (c.341C>T)
    • Common exon locations: 3, 4
    • Also: Nonsense, Insertion & Deletion
  • Databases: Leiden; HGMD
• β-Sarcoglycan protein
  • 43 kD dystrophin-associated glycoprotein
    • Peptide size: 34.8 kDa
    • Binds to β-dystroglycan by extracellular domain
  • Sarcoglycan binding: Strongly to δ; Moderately to γ
  • Location: Subsarcolemmal
  • Expression patterns
    • Muscle: Skeletal & Cardiac
    • Only sarcoglycan expressed outside muscle: Brain; Kidney
  • See: Sarcoglycan complex
• Clinical features: Severe; Occasional mild phenotype
  • Onset age
    • < 3 years to Teens
    • Teen onset: Similar to "outlier" dystrophinopathy
    • Intrafamilial variability
  • Myopathy
    • Proximal weakness
    • Muscle hypertrophy: Prominent; ± Tongue
    • Shoulders: Scapular winging; Muscle wasting
    • Progression
      • Often in wheelchair by 10 to 20 years, usually by 25 years
      • Worse prognosis: Onset age < 10 years; Residual protein < 30%
  • Cardiomyopathy
    • Some patients
    • More common than in other sarcoglycanopathies
    • Mutation: 8 bp duplication in exon 3 of 1 allele
• Laboratory features
  • Serum CK: High; Often > 5,000
  • Muscle biopsy
    • Myopathic
    • Sarcoglycans: All usually absent or markedly reduced
    • Dystrophin: Often reduced but not absent
  • Cardiac muscle: Sarcoglycans reduced with cardiomyopathy
• β-Sarcoglycan knockout mouse
  • Myopathy with muscle hypertrophy
  • Cardiomyopathy with focal areas of necrosis
  • Reduced Sarcoglycan-Sarcospan complex in vascular smooth muscle: Vascular δ in heart, diaphragm & kidneys

• Nosology: LGMD 2F
• Epidemiology
  • > 20 families
  • Frequency: Least common sarcoglycanopathy; ~1:1,000,000
• δ-Sarcoglycan gene
  • Promoters: 3; 1 predominantly in skeletal muscle
  • Mutations
    • Commonly homozygous for single variant
    • Frameshift
      • Deletions common
      • del656C (del657C): African-Brazilian ancestry
      • Premature truncation of protein: E93Ter; Arg165Ter; Trp30Ter
    • Missense: Glu262Lys (Near cysteine-rich region)
    • Databases: HGMD; Leiden
  • Allelic with
    • Dilated cardiomyopathy 1L (CMD 1L)
    • LGMD, Mild phenotype
• δ-Sarcoglycan protein
  • 35 kD dystrophin-associated glycoprotein
  • Basic
  • Location: Subsarcolemmal
  • Sarcoglycan binding: Strongly to β- & γ- sarcoglycans
  • Homologous sarcoglycan: γ-sarcoglycan
  • Disease severity: Correlates with abundance of ramaining protein
  • See: Sarcoglycan complex
• Clinical: Severe phenotype with most mutations producing myopathy
  • Onset: 2 to 10 years
  • Weakness: Proximal; Symmetric
  • Other muscle change: Calf hypertrophy; Cramps
  • Progression: Wheelchair 9 to 16 years in most; One patient walking at 19 years
  • Death: 9 to 19 years
  • Intelligence: Normal
  • Cardiac
    • Often Normal
    • Dilated cardiomyopathy described : May occur without skeletal myopathy
• Laboratory features
  • Serum CK: High; 10x to 50x normal
  • Muscle biopsy
    • Myopathic: Degeneration & regeneration of muscle fibers
    • Immunostaining
      • δ-Sarcoglycan: Absent or Greatly reduced
      • Other sarcoglycans: α & β Absent; γ Reduced or Absent
      • Dystrophin: Present but reduced
• Animal model
  • Syrian hamster cardiomyopathy: Deletion in promoter region of δ-Sarcoglycan gene
  • Boston terrier dogs: LGMD syndrome
• SGCD variant: LGMD, Mild phenotype

• Nosology: LGMD 2G
• Epidemiology
  • 97 patients
  • Brazil (Italian ancestry), China, South Asia & Europe
• Genetics
  • Mutations
    • Types: Point, Small deletions, Microduplications
    • Produce stop codons
    • Geography: c.157C>T (Brazil); Ser11* (c.32C>A) (Dravidian); Trp25X (Bulgarian Muslims); c.165dupG & c.26_33dupAGGTGTCG (China)
    • Other: Gln35X; g.637-640del2
  • Allelic disorders
    • Myopathy
      • LGMD R7
      • Distal myopathy
      • Congenital muscular dystrophy + Joint contractures
    • Cardiac
      • Dilated cardiomyopathy 1N (DCM 1N): ? Polymorphism
      • Hypertrophic cardiomyopathy 25 (CMH 25): Dominant; Missense mutations
• Telethonin (Titin-Cap) protein
  
  • Function
    • Substrate of serine kinase domain of titin
    • Titin phosphorylates C-terminal domain of telethonin
      • Occurs in early differentiating myocytes
  • Tissue localization: Cardiac & Skeletal muscle; GI smooth muscle
  • Cellular localization: Sarcomeric Z-disc
• Clinical features
  • Onset
    • Age: Mean 12 to 20 years; Range 1 to 35 years
    • Gait disorder: Toe walking
  • Weakness
    • Extremities: Legs > Arms
      • Legs
        • Proximal: Glutei; Hamstrings; Hip adductors
        • Distal: Foot drop; Some patients
      • Arms: Proximal
      • Asymmetry: Some patients
    • Face: Normal or mildly weak
    • Neck: Normal
    • Progression: Slow; 40% non-ambulatory in 3rd or 4th decade
  • Muscle size
    • Calf hypertrophy 50%
    • Calf atrophy 50%
  • Discomfort: Occasional patient
    • Cramps
    • Myalgias
  • Cardiac involvement 55%
  • Contractures: Ankles
• Laboratory

  Serum CK Increased 3- to 30-fold Lower with greater age Muscle imaging More involvement Quadriceps Anterior tibial Posterior pelvic Asymmetry: Some Preservation: Adductor longus; Biceps femoris Hypertrophy: Sartorius; Gracilis EMG: Small myopathic potentials ± Large potentials Muscle pathology Myopathic: Degeneration & Regeneration Rimmed vacuoles: Some patients Lobulated muscle fibers: Especially type 1 Cytoplasmic bodies Telethonin protein: Absent from muscle

  Telethonin in muscle fibers

• Variant telethonin syndrome: Congenital Muscular Dystrophy ⁸⁰
  • Epidemiology: French male
  • Genetics
    • TCAP mutation: Gln58X; Homozygous
    • Inheritance: Recessive
  • Clinical
    • Motor
      • Milestones: Delayed head control & sitting
      • Weakness
        • Proximal (Psoas; Adductors) > Distal
        • Anterior tibial
        • Neck flexion
        • Course: Minimal progression
      • Gait: Waddling; Falling
      • Muscle size: Glutei wasting; Calf hypertrophy, mild
    • Skeletal
      • Scapular winging
      • Scoliosis
      • Joint laxity: Distal arms
      • Contractures: Ankles
    • Heart: Normal
  • Laboratory
    • Pathology: Muscle
      • Fiber size: Varied
      • Internal nuclei
      • Necrosis & Regeneration: Some clusters
      • Type I fibers: Small
      • Telethonin: Absent
      • α-Dystroglycan: Normal
    • Serum CK: 600 to 1300
• TCAP variant: Distal myopathy ¹¹⁷
  • Epidemiology: 1 patient
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous; Stop; c.256C>T
  • Clinical
    • Onset age: 50 years
    • Weakness
      • Symmetric
      • Legs: Distal > Proximal; Anterior > Posterior
      • Arms: Normal
  • Laboratory
    • Serum CK: < 300
    • EMG: Myopathic
    • Muscle MRI: Involvement of adductors & hamstrings
    • Muscle: Vacuoles; Varied fiber size

• Nosology: LGMD 2H
• Epidemiology
  • Focus: Hutterite
  • Other: 86 patients
• Genetics: Mutations
  • Homozygous for D487N point mutation
    • All Hutterite patients
    • Mutation localized in NHL domain
  • Other mutations: Deletions, Frameshift, Nonsense
  • Same gene as
    • Sarcotubular myopathy: Same D487N mutation
    • Bardet-Biedl syndrome 11
• Protein
  • Function
    • E3-ubiquitin ligase
    • Labeling of proteins with ubiqutin for proteasome degradation
  • Homo-multimer: Self-association via CC regions
  • Concentrated in cytoplasmic & nuclear bodies
  • Tissue localization: Muscle; Testis; Heart; Skin
• Clinical
  • Variable phenotype
  • Onset
    • Age: 3 to 45 years; Usual 2nd or 3rd decade; Some asymptomatic in 3rd decade
    • Proximal weakness; Back pain; Fatigue; Gait change
  • Weakness
    • Proximal leg: Quadriceps & Pelvic girdle
    • Some patients with: Axial, Face, Periscapular, Distal arm
    • Severity: Mild in most; Some progress to wheelchair
    • Respiratory: Often spared
    • Progression: Slow; Ambulatory > 50 years of age
  • Other muscle
    • Fatigue
    • Myalgia
  • Heart: Not involved
• Laboratory
  • Serum CK: High; 250 to 4,500 U/L
  • EMG: Myopathic; Some with spontaneous activity
  • Muscle MRI
    • Thigh: Posterior > Anterior; Biceps femoris & Semimembranosus
    • Lower leg: Posterior; Anterior tibial; Peronei
• Muscle biopsy: Mild dystrophic changes
  • Fiber size variation
  • Muscle fiber degeneration & regeneration
  • Other: Fiber splitting; Internal nuclei
  • Endomysial fibrosis
  • Vacuoles: Few patients

• Epidemiology
  • Hutterite brothers from South Dakota
  • Non-Hutterite brothers from Germany
• Genetics
  • Mutations: Similar to LGMD 2H: Homozygous missense (D487N); Large deletion
  • Inheritance: Recessive
• Clinical
  • Onset: Congenital, Childhood or Adult (31 years)
  • Weakness
    • Proximal: Symmetric; Mild
    • Face: Mild
  • Muscle size
    • Hypertrophy: Calf
    • Atrophy: Proximal
  • Myalgias: Exercise induced
  • Scapular winging
  • Tendon reflexes: Normal or Reduced
• Pathology
  • Vacuoles
    • Multiple small rounded or slit-shaped
    • In type 2 > type 1 fibers
    • Sarcoplasmic reticulum membranes
  • Varied fiber size
  • Z-disk streaming

• Nosology
  • LGMD 2I
  • Muscular dystrophy-Dystroglycanopathy
• Epidemiology
  • > 300 familes
  • Carrier risk
    • General: ~ 1:400
    • Norway: 1:101
  • Common in Denmark, Norway & parts of England
• Genetics
  • Point mutations most common: Missense
  • Common mutations
    • US & Northern Europe: Leu276Ileu (c.826G>A)
      • Frequency in 1 allele: > 90%
      • Founder variant
    • China: c.545A>G, c.948delC, c.328C>GT
    • South India: c.1343C>T (Pro448Leu)
    • Mexico: c.1387A>G
    • Japan: c.169G>A, 3 kb insertion (c.4375_4376insAB185332.1)
    • Taiwan: c.948delC
  • Disease severity: Correlates with mutation in 2nd allele
    • Leu276Ileu (c.826C>A) homozygosity: Less severe
    • Mexico founder mutation (c.1387A>G): More severe
    • c.919T>A homozygous: Severe; CMD ¹⁴⁶
  • Allelic disorders
    • Congenital muscular dystrophy with muscle hypertrophy & Normal CNS (MDC1C)
    • Myopathy with abnormal merosin (Laminin-2)
    • Walker-Warburg syndrome: Homozygous FKRP mutations; Met1Val & Cys318Tyr
• FKRP protein ¹³⁶
  • Ubiquitous
  • Highest levels: Skeletal muscle; Heart; Placenta
  • Subcellular
    • Golgi
    • Skeletal & Cardiac muscle
      • Surrounds myonuclei
      • No change in location with disease mutations
      • Absent from: Nuclei of interstitial cells
    • Targeted by N-terminus & tm domain
    • Not secreted
  • Associated with
    • Dystroglycan: Glycosylation
      • Glycosyltransferase: Transfers ribitol-5-phosphate to α-Dystroglycan
      • Regulates: Binding to laminin
    • Fibronectin: N-glycan Sialylation ¹⁴³ & Glycosylation
      • Location: Golgi
      • Regulates: Binding affinity to Collagen
  • Colocalizes with: α-Mannosidase II
  • Binds to: Myosin-10

  Clinical Onset Age Range 0.5 to 27 years; 61% less than 5 years Birth: Congenital muscular dystrophy syndrome (MDC1C) c.826C>A homozygotes: Median 8.5 years; 2nd peak in 3rd decade Weakness: Waddling gait; Difficulty with stairs; Hypotonia Weakness Proximal > Distal Lower trunk: Gluteus Maximus Legs: Thigh adductors; Psoas; Quadriceps Arms: Periscapular; Deltoid; Biceps; Triceps Face: Mild weakness in some older patients Scapular winging Respiratory failure (30%) May occur while patient still ambulant DMD-phenotype: Onset in later teens Severity Varied DMD-like to Adult onset myopathy Severe: Onset < 2 years; Never run; Lose ambulation in teens Milder: Later onset; Cramps; Muscle hypertrophy Females more severe than males: Respiratory Cardiac: More in males Consistent phenotype within most individual families Intrafamilial variability: Few families Asymmetry: Some patients Progression Early onset: Non-ambulant by teens Later onset: Slow; Variable Some (28%) non-ambulant by 4th to 6th decade Muscle size Wasting: In regions of weakness; Arms > Legs Hypertrophy: Calves 77%; Thighs; Tongue Other occasional muscle features Exertional pain: Early symptom,: Mean 14 years, Range 2 to 45 years Cramps: Limbs & Tongue described Myoglobinuria (25%) Multiple episodes Related to physical activity Can occur at time with mild or no weakness Frequent with homozygous Leu276Ileu Tendon reflexes: Preserved; Knee mildly reduced Intellect: Normal Skeletal Contractures: Often at ankles; More common in non-ambulant patients Scoliosis More common in non-c.826C>A homozygous group Cardiomyopathy Common: 30% to 80%; Often seen on echocardiography Type: Dilated Usually mild Left ventricular failure May be isolated feature: Homozygous C826A mutation No relation to skeletal muscle severity More in males Skin: May be soft or hyperextensible

  FKRP: Homozygous Leu276Ileu

• Laboratory
  • Serum CK: Very high; 1,000 to 8,000
  • Muscle biopsy
  • Endomysial connective tissue: Mildly increased
  • Muscle fibers
    • Size: Variation
    • Necrosis & Regeneration
    • Type 1 predominance: Some patients
    • Muscle fiber staining
      • α-Dystroglycan: Reduced, especially in severe disease
        • Selective loss of higher MW forms
        • Less severe loss than in MDC1C
        • Some patients have normal staining
        • DDx: Reduced α-Dystroglycan
      • α2-laminin: Moderate loss in some patients: May be absent on Western blot
      • Normal: Dystrophin, Sarcoglycans & β-Dystroglycan
  • Nerve conduction studies: Normal
  • EKG: Normal
  • MRI: Normal CNS or minimal atrophy
  • Muscle MRI
  • Electroretinogram
    • ON/OFF bipolar cell responses: Abnormal
    • Sawtooth 30 Hz flicker waveforms

• Genetics: Allelic with LGMD 2I
• Clinical
  • Onset
    • Usually adult: 11 to 40 years
  • Female preponderance
  • Weakness
    • Cranial: Eye closure; Neck flexion
    • Upper extremity: Proximal; No scapular winging
    • Lower extremity: Especially hamstrings + hip adductor & flexors
    • Vital capacity: Reduced to 30% to 93% of normal
    • Asymmetry: Some
    • Progressive
  • Muscle hypertrophy: Calves; Brachioradialis
  • Cramps: Occasional
  • Skeletal: Lumbar lordosis; No contractures
  • CNS (MRI) & cardiac: Normal
• Laboratory
  • Serum CK: 1,100 to 3,700
  • EMG: Myopathic
  • Muscle histology
    • Variation in fiber size
    • Muscle fiber necrosis
  • Muscle merosin
    • Normal immunocytochemistry of muscle section (80 kDa & 300 kDa fragments)
    • Absent on Western blot

• Nosology: LGMD 2J
• Epidemiology
  • > 10 patients
  • May occur in families with other members having: Dominant distal weakness syndrome
• Genetics
  • Mutations
    • Homozygous or Compound heterozygous for titin mutations
    • Mutation types
      • 11 bp insertion-deletion (Finnish; FINmaj): Final exon (363)
      • Missense: Leu293,356Pro (French); Arg32,936His
      • Common patterns
        • Homozygous: Exon 364 mutations
        • Compound heterozygous: Exon 364 + Truncating mutation
    • Genotype-Phenotype corelations
      • Homozygous 11 bp deletion: Severe, Childhood onset
      • French missense mutation: Onset 3rd decade, Proximal Arms
    • Disease relevance of mutations: General ¹¹⁰
      • Truncating mutations most strongly associated with myopathy
      • Biallelic truncating mutations
        • Primary cardiac common
        • Wide range of phenotypes
      • Single heterozygous truncating mutations
        • Skeletal muscle disorders common
        • Also associated with: Dominant dilated cardiomyopathy
        • Western blot analysis: May identify further truncating variants in trans
  • Allelic disorders
    • Dominant
      • Distal myopathy, Finnish (Tibial MD)
      • Myopathy with Early Respiratory failure (HMERF)
        • Cytoplasmic aggregate myopathy
        • Cytoplasmic body myopathy
      • Dilated cardiomyopathy 1G
      • Hypertrophic cardiomyopathy (CMH 9)
    • Recessive
      • Congenital myopathies
        • Multicore disease
          • Congenital myopathy + Fatal dilated cardiomyopathy (EOMFC)
          • Ophthalmoplegia & Caps
        • Centronuclear myopathy
        • Fiber type size disproportion
      • LGMD 2J
      • Distal myopathy, Adult onset
      • Proximal adult-onset Rimmed Vacuolar Myopathy
      • Emery-Dreifuss without Cardiac involvement
      • Distal Arthrogryposis + Cardiomyopathy
      • Lethal Congenital Contracture Syndrome (LCCS)
    • Digenic
      • Myopathy with SRPK3 mutations
• Titin protein
• Clinical
  • Onset age
    • Usual: Childhood
    • Range: < 10 years to 3rd decade
  • Weakness
    • Proximal > Distal
    • More severe than in allelic distal myopathy
    • Face: Normal or Weak
    • Asymmetric: Some patients
  • Muscle size
    • Smallness: Anterior tibial
    • Hypertrophy: Some patients
  • Progression
    • Usual: Wheelchair < 30 years, within 20 years of onset
    • Some patients ambulatory at 60 years
  • Some patients
    • Cardiomyopathy
    • Developmental delay
    • Skeletal: Clinodactyly; Narrow face; Microcephaly
• Laboratory
  • Serum CK: High
  • Muscle biopsy
    • Myopathic
    • No vacuoles
    • Loss of calpain-3
    • Western blot: Severely reduced C-terminal titin fragments
    • Obscurin: Mislocalization
• Titin variant syndrome: Proximal adult-onset rimmed vacuolar myopathy
  • Genetics
    • Inheritance: Recessive
    • Mutations: Compound heterozygous; Exon 364 + Missense
  • Clinical
    • Onset age: Adult
    • Weakness: Quadriceps & Soleus; Tibial spared
  • Laboratory
    • Muscle: Rimmed vacuoles
• Titin variant syndrome: Emery-Dreifuss syndrome without cardiac involvement ¹⁰²
  • Epidemiology: 3 families; French & Algerian
  • Genetics
    • Inheritance: Recessive
    • Mutations: Truncating; Mex3 exon in sarcomeric M-band
  • Titin protein
    • Mutated protein: Truncation of M-line
  • Clinical
    • Onset age: 3 to 10 years
    • Weakness
      • Limb-Girdle: Proximal > Distal
      • Respiratory: Vital capacity reduced in some (67%)
      • Trunk: Scapular winging; Abdominal
      • Symmetric
      • Course: Progressive to wheelchair by 13 to 36 years
    • Large muscles: Calf; Tongue
    • Contractures
      • Arms & Legs
      • Proximal & Distal
      • C-spine & Masseter in some
    • Cardiac: Normal
  • Laboratory
    • Serum CK: 1.5x to 10x high; Lower with increased age
    • EMG: Myopathic
    • Muscle pathology
      • Fiber size: Varied
      • Necrosis: Scattered
      • Immature muscle fibers
      • Internal nuclei
      • Internal architecture: Irregular
      • Rimmed vacuoles
      • Rods or Cytoplasmic bodies
      • Calpain-3: Absent or very reduced
      • Ultrastructure: M-bands abnormal
    • Muscle MRI: Posterior thigh, Gastrocnemius & Glutei most involved
• Titin variant syndrome: Distal myopathy ¹⁰⁹
  • Epidemiology: Serbian families
  • Genetics
    • Inheritance: Recessive
    • Mutations
      • General: Stop-gain variants
      • Common: c.107635C4T (p.Gln35879Ter); Founder mutation
      • Other: Stop codons in TTN exons 286 to 358
    • Allelic disorders
  • Titin protein
  • Clinical: Similar to Dominant Finnish Tibial MD
    • Onset: Adult; 14 to 44 years
      • Later onset: Founder mutation, homozygous
    • Weakness
      • Distal (100%) > Proximal (60%)
      • Legs > Arms: Foot & toe dorsiflexors > plantarflexors
      • Proximal involvement: Hip & shoulder girdle
      • Asymmetry: 30%
      • Scapular winging: 40%
      • Course: Most patients remain ambulant
    • Contractures: Ankle
    • Respiratory: Normal
    • Cardiomyopathy: Uncommon
  • Laboratory
    • Serum CK: Normal to Mildly high
    • EMG: Myopathic
    • Muscle MRI: Similar to Tibial MD, Dominant
    • Muscle biopsy: Dystrophic
      • Muscle fibers: Hypertrophic; Atrophic
      • Endomysial connective tissue: Increased
• Titin variant syndrome: Distal arthrogryposis + Cardiomyopathy ¹⁷⁰
  • Genetics
    • Mutations: Ser35469Serfs*11; Arg34175*; Arg34175*; Gln35278; Asn34020Thrfs*9; Trp34072Arg
    • Inheritance: Recessive
  • Clinical
    • Distal arthrogryposis
    • Cardiomyopathy, dilated
• Titin variant syndrome: Lethal congenital contracture syndrome (LCCS) ¹¹¹
  • Epidemiology: 1 family
  • Genetics
    • Mutations: Homozygous c.36122delC (p. P12041Lfs*20) variant (Exon 167 in fetal IC isoform of TTN)
    • Inheritance: Recessive
  • Clinical
    • Intrauterine: Reduced movement; Death
    • Neonatal respiratory distress
    • Spontaneous movement: Reduced
    • Contractures: Large joints
    • Death: < 17 weeks
  • Laboratory
    • Bone: Multiple fractures
• Titin variant syndrome: Myopathy + Ophthalmoplegia & Caps ¹⁵⁸
  • Epidemiology: 1 patient
  • Genetics
    • Mutations: c.82541_82544dup; c.31846 + 1G>A
  • Clinical
    • Onset: Congenital
    • Hypotonia
    • Ophthalmoplegia: Complete; Ptosis
    • Weakness: Face; Proximal > Distal; Sleep apnea
    • Skeletal: Pectus excavatum; Scoliosis
  • Laboratory
    • Muscle MRI
      • Involved: Glutei; Anterior thigh & Leg
      • Spared: Thigh adductors
    • Muscle pathology
      • Fiber sizes: Varied
      • Central nuclei
      • Multiminicores
      • Caps
• Titin variant syndrome: Digenic Myopathy with SRPK3 mutations ¹⁶⁵
  • Epidemiology: 40 male patients, 23 families
  • Genetics
    • SRPK3: Serine/Argenine Protein Kinase 3
    • Inheritance: Digenic with Titin mutations
    • SRPK3 mutations: Stop, Frameshift, Splice, Missense in kinase domain; Heterozygous
    • Titin mutations: Truncating; Heterozygous
    • Manifesting female carriers: Skewed X-inactivation
  • SRPK3 protein
    • Protein kinase
    • Member of SRPK family
    • Expressed mostly in skeletal muscle
    • Phosphorylates proteins containing serine-arginine dipeptide motifs (SR proteins)
    • Regulate mRNA splicing through: Phosphorylation of SR-splicing factors & spliceosomal components
    • Disorders: Deficiency & Overexpression may produce myopathies with central nuclei in mice
  • Clinical
    • Onset age: Childhood
    • Weakness
      • Proximal & Axial
      • Legs > Arms
      • Respiratory (50%)
    • Course: Slow progression
  • Laboratory
    • Serum CK: Usually normal or mildly high; Up to 2,400
    • Muscle Pathology
      • Myopathic
      • Internal nuclei
      • Core-like structures
      • Type I fiber predominance (19/23).
      • Ultrastructure: Core-like areas; Myofibrillar disorganization; Z-line streaming; Myofibril branching
    • Muscle MRI involvement
      • Upper: Subscapularis
      • Lower trunk: Gluteus maximus
      • Thigh: Adductor longus, Vasti, Hamstrings
      • Leg: Medial gastrocnemius & Soleus
• Mouse model: Homozygous Titin knockout
  • Severe: Lethal
  • Weakness: Distal > Proximal

LGMD R11 (MDDGC1) : with Mental retardation and Reduced α-dystroglycan

• Nosology
  • LGMD 2K
  • MDDGC1: Muscular dystrophy-Dystroglycanopathy
• Epidemiology: 15 patients
• Genetics
  • Mutations: Missense mutations most common; Turkish Ala200Pro
  • Allelic disorders
    • Walker-Warburg syndrome: MDDGA1
    • Disease related mutations: > 76
• POMT1 protein
  • Clinical phenotype severity: Inversely correlated with POMT1 activity
• Clinical
  • Onset
    • Ages: 1 to 33 years
    • Motor: Fatigue; Difficulty climbing stairs & running; Early milestones normal
  • Muscle
    • Size: Mild pseudohypertrophy
    • Weakness: Proximal
    • Course: Slow progression
  • Skeletal
    • Joint contractures (50%): Ankles
    • Scoliosis
  • CNS (60%)
    • Mental retardation, IQ 50 to 76
    • Microcephaly
  • Cardiomyopathy (30%): LV dilatation
• Laboratory
  • Serum CK: Very high (9x to 40x elevated)
  • Muscle
    • Fiber size: Varied
    • Fibeer types: 1 predominance
    • Cores: Some patients
    • α-Dystroglycan: Reduced glycosylation
  • MRI: Normal CNS

• Nosology: LGMD 2L
• Epidemiology
  • May be 10% to 20% of LGMD families
  • Females: Less commonly, or less severely, affected
• Genetics
  • Mutations: > 20 identified
    • Splice site (C1295G; Aberrant splicing of Exon 13)
    • Duplication (c.191dupA (p.Asn64Lysfs*15) in exon 5): Common in Northern Europe
    • Arg758Cys in exon 20: Common mutation
    • Missense: G231V in exon 8
    • Locations: Distributed all along gene
  • Allelic disorders
    • Gnathodiaphyseal dysplasia ± Myopathy : Dominant ¹⁴⁷
    • Distal myopathy (MMD3): Recessive
    • LGMD R12
    • Exercise intolerance, Myalgia & High CK
  • Genotype-Phenotype correlations
    • Variable phenotypes, mild & severe, with most mutations
• Anoctamin 5 protein
  • Member of family of proteins with 8 transmembrane domains
    • Anoctamins 1, 2 &3 are calcium-activated chloride channels (CaCC)
    • ANO1 mutations: Intestinal dysmotility syndrome (IDMTS)
    • ANO3 mutations: Dominant Craniocervical Dystonia (DYT24)
  • Integral membrane glycoprotein
  • Intracellular
  • Functions: Myogenesis; Osteogenesis
  • Mutations may cause: Defective membrane repair
• Clinical
  • Variability
    • Intrafamilial
      • Prominent
      • Females less affected
    • Variant myopathy syndromes
      • Distal myopathy
      • Normal strength with high CK
  • Onset
    • Age: Mean = 33 to 43 years; Range 11 to 70 years
    • Weakness: Quadriceps, Asymmetric
  • Muscle
    • Atrophy: Quadriceps; Biceps brachii; Lower leg
    • Asymmetric
    • Weakness
      • Legs > Arms
      • Scapular
      • Biceps
      • Pelvic: Psoas; Quadriceps
      • Posterior leg: See MMD3
      • Distal arms: Normal strength
      • Face: Few patients
      • Progression: Slow
    • Muscle discomfort
      • Frequency: 86%; 50% with, or after, exercise
      • Common: Calf; Myalgia or Burning
    • Fatigue: May occur before weakness
    • Calf hypertrophy or atrophy: Some patients
    • Rhabdomyolysis: Few patients
    • Course
      • Slowly Progressive
      • Walking retained in most
    • Respiratory: Normal or Mild changes
  • Contractures: Unusual
  • Cardiac
    • Atrial: Arrhythmias; Bradycardia; Some patients
    • Cardiomyopathy: Dilated or Hypertrophic
• Laboratory
  • Muscle MRI
    • Early involvement: Medial quadriceps, Hamstrings, Adductor magnus
    • Asymmetric involvement
    • STIR+ lesions: Most common in Medial gasrocnemius, Vasti
  • Serum CK: Normal to 35,000
  • Cardiac Imaging: Abnormalities may be asymptomatic ¹³⁴
    • Aortic root dilation
    • Ventricular dilation
    • Cardiac fibrosis on late enhancement
• Pathology: Muscle
  • Muscle fibers
    • Size: Varied
    • Necrosis & Regeneration
    • Internal nuclei
    • Splitting
    • Internal architecture: Irregular; Whorled
    • Vacuoles: 2 patients
    • Ultrastructure: Multifocal sarcolemmal lesions
  • Endomysial connective tissue: Increased
  • Inflammation: In severe cases; Endomysial
  • Amyloid
    • Frequency: 50%
    • Location: Peri-Vascular & Muscle fiber
    • No relation to mutation location or clinical features
  • Dystrophy proteins
    • Dystrophin reduced: 40%
    • Calpain-3 reduced: 45%
    • Dysferlin: Normal
• ANO5 Variant syndrome: Distal Miyoshi-like myopathy 3 (MMD3)
  • Epidemiology: Dutch & Finnish families
  • Genetics
    • Inheritance: Recessive
    • ANO5 Mutations
      • Missense: Arg758Cys in exon 20
      • Duplication (c.191 dupA in exon 5)
    • Allelic with: LGMD 2L
  • Clinical
    • Onset
      • Age: 2nd & 3rd decade
      • Difficulty running & standing on toes
    • Weakness
      • Calf: Early; Difficulty running & walking on toes
      • Proximal: Ileopsoas; Hamstrings, Gluteus maximum, Hip adductors
    • Hypertrophy: Calf; Extensor digitorum brevis
    • Muscle discomfort: Calves
    • Asymmetry
  • Laboratory
    • Serum CK: 1,500 to 16,000
    • Muscle pathology
      • Cell membrane repair defect
    • Imaging: Medial gastrocnemius & soleus involvement
• ANO5 Variant syndrome: Exercise intolerance, Normal strength + Serum CK high ¹⁰⁶
  • Epidemiology: Males & Females
  • Clinical
    • Myalgias
    • Exercise intolerance
    • Calf: Hypertrophy or Atrophy
    • Some patients: Asymptomatic
    • Rhabdomyolysis: Some patients
    • Course: May remain with few, or mild, symptoms for long periods
  • Laboratory
    • Serum CK: High; 200 to 40,000 U/L; Vary over time
    • EMG: May be normal or myopathic
    • Muscle imaging: Medial gastrocnemius involved (55%)
    • Muscle biopsy: Non-specific or Normal

• Nosology
  • LGMD 2M
  • Muscular dystrophy-Dystroglycanopathy
• Epidemiology: 5 families; Portuguese, Turkish, French, Israeli Jewish & Indian
• Genetics
  • Mutations
    • Types: Stop & Missense
    • 1167dupA; 1363delG; Arg47X; Ala170Glu; Arg246Gly; Arg307Gln; Tyr371Cys
  • Allelic disorders
• Clinical
  • Onset
    • Age: Less than 6 months
    • Hypotonia
    • Motor delay
    • Deterioration with acute febrile illness
  • Weakness
    • General: Diffuse; Variable severity
    • Distribution: Axial & Proximal > Distal
    • Legs > Arms
    • Face: Mild to Moderate
    • Improves with corticosteroid treatment
    • Many patients ambulant
    • Course: Progressive
  • Muscle size
    • Wasting: Most muscles
    • Hypertrophy: Posterior leg ± Tongue & other
  • CNS
    • Normal in mildest patients
    • Reduced intelligence: Variable association with degree of weakness
  • Skeletal
    • Spinal rigidity
    • Joint contractures
  • Cardiomyopathy: Some patients
• Laboratory
  • Serum CK: Very high
  • Muscle biopsy
    • Morphology: Dystrophic; Muscle fiber necrosis
    • Endomysial connective tissue: Increased
    • Glycosylated α-dystroglycan: Nearly absent
    • Laminin-α2, β1 & γ1: Mildly reduced
  • MRI: May show cortical & posterior fossa pathology
    • Vermis hypoplasia
    • Polymicrogyria

• Epidemiology: 5 families from UK & Finland
• Genetics
  • Compound heterozygous
  • Mutation type: Truncating
  • Allelic disorders
• MYH2 protein
  • Myosin subtype
  • Location: Type 2A muscle fibers
• Clinical
  • Onset age: Early childhood
  • Weakness
    • Generalized
    • Mild
    • Proximal > Distal
    • Face & Neck
    • Extraocular muscles
      • Severe ophthalmoplegia
      • Ptosis 20%
    • Prognosis: Slow progression with age
  • Muscle wasting
  • Joints: Hypermobility
• Laboratory
  • Muscle pathology
    • Type 2A fibers: Absent
    • Fiber size: Varied
    • Internal nuclei
    • Endomysial connective tissue: Increased
  • EMG: Myopathic
  • Serum CK: Normal
  • Muscle imaging: Selective nvolvement of
    • Leg: Medial gastrocnemius
    • Thigh: Semitendinosus, Gracilis & Vastus lateralis
• Also see: Myopathies with Ophthalmoplegia

• Nosology: Same as MYH2 mutations
• Epidemiology: Israeli-Arab inbred families
• Genetics
  • MYH2 mutation: c.2400delG in exon 19
  • Allelic disorders
  • Variant syndrome: Juvenile-onset myopathy with PEO
• Clinical
  • Onset age: Early childhood
  • Ocular: External ophthalmoplegia (100%)
    • Conjugate
    • Non-restrictive
    • Impairment greatest in upgaze
    • No ptosis or aberrant eye movements
  • Weakness
    • Symmetric
    • Severity: 4/5
    • Face: Mild; Eyes > Mouth
    • Voice: Nasal
    • Neck: Flexors (100%)
    • Limbs
      • Proximal arms: Most common (75%)
      • Distal arms (50%)
      • Proximal legs (30%)
      • Distal legs: Normal
    • Associated with wasting
    • Progression: Slow
  • Skeletal
    • Face: Dysmorphism
    • Scoliosis (73%)
• Laboratory
  • Orbital MRI: Fatty replacement of oculorotatory muscles
  • EMG: Myopathic (50%)
  • Serum CK: Usually normal; Occasional <2x normal in younger patients
• Muscle biopsy
  • Muscle fiber types
    • Type 1 muscle predominance
    • Type 2A absent
  • Core-like changes
• MYH2 variant syndrome: Juvenile-onset myopathy with PEO ⁹⁷
  • Epidemiology: Australian patient
  • Genetics
    • Mutation: c.5630T>C, p.(Leu1877Pro)
    • Inheritance: Sporadic
  • Clinical
    • Onset age: 16 years
    • Weakness
      • Distal: Hands most severe; Feet
      • Proximal: Hip & knee flexion
      • Scapular winging
      • Bulbar: Hypophonia; Palatal movements reduced; Dysphagia
      • Face
      • Respiratory
    • Eyes
      • Ophthalmoplegia: Progressive to severe with some preserved downgaze
      • Ptosis
    • Atrophy: Upper extremities
    • Tendon reflexes: Absent proximally
    • Contractures: Ankles
  • Laboratory
    • EMG: Myopathic
    • Serum CK: 153 to 806
    • Muscle MRI
      • Extensive fat replacement
      • Relative sparing: Deltoid & Anterior legs
    • Muscle
      • Fiber size: Varied; Small to Hypertrophy
      • Internal nuclei
      • Endomysial fibrosis. Dystrophic features were present, being
      • Lobulated fibers & Core-like structures
      • Fiber types: Most type 1, Few small type 2
      • Dystrophy related protein staining: Normal
      • No vacuoles

• Epidemiology: 1 family
• Genetics
  • Mutation: Q819X; Homozygous
  • Allelic disorders
• Clinical
  • Onset
    • Age: Childhood; 2 to 4 years
    • Contractures
  • Weakness
    • Distribution: Proximal + Distal
    • Severity: Mild to Moderate
    • Vital capacity: Reduced
  • Contractures
    • All joints: Limbs; Jaws; Spine
    • Progressive
    • No hypermobility
• Laboratory
  • Serum CK: Mildly high (1.5x)
  • Muscle biopsy
    • Endomysial connective dissue: Diffusely increased
    • Muscle fibers
      • Size: Varied
      • Internal nuclei
      • Laminin β1: Reduced on extrajunctional basal lamina
      • Collagen VI
        • Discontinuous on muscle basal lamina
        • Absent from capillaries
        • Reduced on Western blot
    • Ultrastructure
      • Basement membrane defects: Thickening & Duplication
      • Pericytes: Increased numbers

• Nosology: LGMD 2P
• Epidemiology: Turkish, British, Chinese families
• Genetics
  • Mutations
    • Missense: Thr192Met, R776C; Homozygous
    • In 1 patient of original MDDGC series
  • Allelic disorders
    • Asymptomatic high CK, Recessive or Dominant
    • Congenital muscular dystrophy MDDGA9
• DAG 1 protein
  • Mutation: Alters DAG1 glycosylation & interaction with LARGE
• Clinical
  • Onset
    • Age: 1st decade
    • Fatigue
    • Weakness: Stairs; Running
  • Muscle
    • Weakness: Proximal > Distal
    • Size: Normal or Mild increase in thigh or calves
    • Progression: Slow: Patients remain ambulant
  • Contractures: Ankles (50%)
  • CNS
    • Mental retardation: Mild to severe
    • Head size: Small
• Laboratory
  • Serum CK: Very High
  • Muscle
    • Fiber size: Varied
    • Regeneration & Occasional necrosis
    • Endomysial connective tissue: Increased
    • α-Dystroglycan: Reduced
  • Brain MRI: Normal
• DAG1 variant syndrome: High CK, Asymptomatic or Pauci-symptomatic ⁹⁶
  • Epidemiology: 13 patients
  • Genetics
    • Inheritance: Recessive or Dominant
    • Mutations
      • Recessive (Compound Heterozygous): Val74Ile & Asp111Asn
      • Dominant (Heterozygous): Loss of function, Stop
  • Clinical
    • Strength: Normal
    • Symptoms: Some patients
      • Myalgia
      • Cramps
    • Pseudohypertrophy: Calf
  • Laboratory
    • Serum CK
      • Recessive: 1,855 to 6,512
      • Dominant: 195 to 2,800
    • Muscle
      • Fiber size: Varied
      • Regenerating fibers: Few
      • Internal nuclei
      • Endomysial fibrosis: Mild
      • α-Dystroglycan: Reduced glycosylation
    • Muscle CT
      • Low intensity: Rectus femoris, Semimembranosus, Gastrocnemius
• DAG1 variant syndrome: Congenital muscular dystrophy MDDGA9
  • Epidemiology: 2 families, Israeli-Arab & Libyan
  • Genetics
    • Inheritance: Recessive
    • Mutations: Homozygous; Cys669Phe, 1-BP del, 743C
  • Clinical
    • Onset: Congenital
    • CNS: Developmental delay; Mental retardation
    • Eye: Cataract, Retinal dystrophy, Myopia, Buphthalmos
    • Motor: Hypotonia; Reduced movements; Respiratory failure
    • Death: Infancy; Respiratory failure
  • Laboratory
    • Serum CK: High, 800 to 2,000
    • Muscle: Fiber size varied; α- & β-dystroglycan absent
    • Brain MRI: Brainstem kinking; Cerebellar vermis atrophy; White matter cysts;
        Hydrocephalus; Polymicrogyria; Corpus callosum thin; Calcifications

• Nosology: LGMD 2S
• Epidemiology: > 10 families
• Genetics
  • Mutations
    • Missense, Deletion or Splice site
    • Gly980Arg (Syrian); Ala372_Ser429del (Hutterite); c.661-1G>T, splice site
• TRAPPC11 protein
  • TRAPP multisubunit tethering complex
  • Function: ER to Golgi vesicle trafficking (ERGIC)
  • Expression: Ubiquitous
  • Mutations
    • Disrupt Golgi apparatus architecture
    • Slow exit of proteins from Golgi to cell surface
    • LAMP1 & LAMP2: Abnormal; Increased glycosylation
• Clinical
  • Myopathy (60%)
    • Onset: Infant or Childhood
    • Proximal
    • Legs > Arms
    • Face: Mildly myopathic
    • Scapular winging: Mild
    • Discomfort: Myalgia; Cramps
    • Fatigue
    • Progressive: Reduced ambulation
  • CNS
    • Intellectual disability: Moderate; Global or Motor delay
    • Variable features
      • Seizures
      • Ataxia: Truncal
      • Leg spasticity
      • Hyperkinetic movements
        • Infantile onset
        • Choreiform, Athetoid or Dystonia
      • Tendon reflexes: Reduced
  • PNS: Variable
    • Tendon reflexes: Reduced
    • Autonomic
      • Alacrima
      • Achalasia
  • Skeletal
    • Hip dysplasia
    • Scoliosis
  • Systemic: Variable among families
    • Cardiac: Usually normal
    • Eye: Cataracts, infantile-onset; Strabismus
    • Hepatomegaly with steatosis
• Laboratory
  • Serum CK: High in 100%; 300 to 9000
  • Brain MRI: Normal or Mild cerebral or cerebellar atrophy
  • Muscle
    • Myopathic
      • Fiber size: Varied
      • Necrosis & Regeneration
      • Internal nuclei
      • Endomysial connective tissue: Increased
      • Lipid increased: 1 family
      • α-Dystroglycan: Normal or Reduced
    • Neuropathic: Fiber type grouping in 1 family
  • Muscle MRI: Gluteal & Posterior leg muscle involvement
  • Cerebellum pathology: Atrophy; Granmule cell hypoplasia; Purkinje cell loss

Other Dominant Myopathies

• Nosology: LGMD D5
• Gene mutations: >50 identified
  • Most mutations located between Exons 3 and 14
  • Most are amino acid substitutions: Glycine most common (Gly-X-Y)
    • Usually in triple helix region
    • Some mutations in globular region
    • Disease pathogenesis: ? Dominant negative effect
  • Inframe deletion in exon 14 of Collagen α1 (IVS14DS, G-A, +1): Common mutation
  • Can also cause disease by stop codon : Produces haploinsufficiency
    • Lower incidence of contractures
  • Other disease correlations
    • Most severe disease: COL6A1 multi-exon out-of-frame deletion; Mutations inside triple helix
    • Milder: Exon-skipping mutations; N-terminal globular region
    • Recessive COL6A2 mutations: Stop & Splicing (c.1770delG & R784H in cis) + Missense (R830W)
  • Allelic disorders
    • Bethlem myopathy: Dominant
    • Ullrich Scleroatonic muscular dystrophy
      • Same 3 COL6A subunit genes mutated
      • Recessive
    • Myosclerosis: COL6A2 mutations
    • Ossification of posterior longitudinal ligament: Mutations in different part of COL6A1 gene
    • Early-Onset Isolated Dystonia 27 (DYT27) : COL6A3, Recessive
    • Landseer Dogs, Early-onset MD: COL6A1 mutations; Recessive ¹⁰⁰
  • Also see: Bethlem myopathy, Collagen XII
• Protein: Collagen VI
  • Collagen
  • Location
    • Extracellular matrix: In most connective tissues
    • Basement membrane
      • Abundant around fat cells, nerves & muscle
      • Normal: Co-localizes with perlecan & collagen IV
      • Mutant: Variable co-localization with perlecan & collagen IV
    • Synthesized by: Interstitial fibroblasts
    • Sources of other collagens
      • Collagens I, III & V: Skeletal muscle
      • Collagen IV & Laminin: Fibroblasts & Mononucleated myoblasts
  • Collagen VI synthesis in muscle: By Interstitial fibroblasts
  • Monomer: Contains 3 subunits α1 (140kD), α2 (140 kD) & α3 (260kD)
  • Subunit domains
    • Short collagenous triple helix of repeating Gly-X-Y sequence
    • Large N- & C-terminal globular regions: Homology to von Willibrand factor type A
  • Assembly of monomers: Intracellular
    • First, into antiparallel overlapping dimers
    • Then dimers align in parallel to form tetramers
    • Assembly stabilized by disulfide bridges
    • Forms microfibrillar network
  • Possible functions of Collagen VI
    • Anchor basement membranes in extracellular matrix: Interacts with
      • Proteoglycans: Perlican; Decorin; Biglycan; Fibromodulin
      • Other extracellular matrix components: Fibrillar collagens I & II; Fibronectin
    • Bridges cells with the extracellular matrix: Mediated by
      • Integrins: α1β1, α2β1 & α3β1
      • Cell surface proteoglycan: NG2
    • Cell differentiation
    • Apoptosis: Suppression
  • Disease mechanisms ¹⁵
    • Glycine mutations: May impair assembly pathway
      • Mildly affected patients (Bethlem): Normal amounts of collagen VI in fibroblast matrix
      • Severely affected patients (Ullrich): Reduced amounts of collagen VI in fibroblast matrix
    • Collagen VI point mutations (G1679E and G1679Q in α3): May produce
      • Lower protein levels
      • Misfolded protein
• Clinical features
  • Onset
    • Age: Variable within families
      • Prenatal: Fetal movements reduced
      • Neonatal: Hypotonia
      • Early childhood (< 2 years): Common with Weakness or Contractures
      • Adult: As late as 6th decade
    • Motor: Hypotonia
    • Joints: Laxity or Contractures
  • Clinical
    • Weakness
      • Diffuse; Proximal > Distal
      • Progressive
        • Usually mild in childhood
        • May become severe & disabling in adulthood
      • Occasional respiratory muscle weakness: Severe cases
      • Falling common in children
      • Face: Spared
    • Muscle cramps or pain: Some patients
    • Muscle size
      • Wasting: Proximal muscles; Distal in legs
      • No muscle hypertrophy
    • Contractures
      • Distribution
        • Flexion: IP joints medial 4 fingers, wrists, elbows, ankles
        • Proximal: Pectorals, Knees, Shoulders, Hips
        • Truncal
          • Congenital: Torticollis
          • Disease progression: Restrictive lung disease correlates with weakness & contractures
          • Spine
        • Dorsiflexion contractures at ankles in COL6A2 (G250S) mutation
      • Course
        • After birth: Often spontaneously improve
        • Joints: Some are initially hypermobile May develop contractures over time
        • Childhood & Adult: May progress independent of weakness
        • Some patients in families may never have contractures
      • No functional impairment
    • Skin
      • Follicular hyperkeratosis (Hyperkeratosis pilaris)
      • Keloid formation
      • 'Cigarette paper' scarring over knees
    • Course
      • Early: Benign
      • Improvement in function around puberty
      • Adult
        • Progression in weakness common between 25 & 40 years
        • Many wheelchair-bound in adulthood: Usually 6th or 7th decade
        • Others work into old age
        • Cramps in some patients
    • Cardiac disease
      • Conduction abnormalities described in 10% ³²
    • Differential diagnosis: Emery Dreifuss MD
• Laboratory
  • CK: Normal or Elevated to 1,750
  • EMG: Myopathic; Sparse fibrillatons
  • Cardiac: Normal
  • MRI: T1W sequences ³¹
    • Vastus lateralis & hamstrings: Peripheral involvement, Central sparing ³⁷
    • Paravertebral involvement
  • Muscle ultrasound: "Central cloud"
  • Muscle biopsy
    • Non-specific myopathy
      • Fiber size variation
      • Fiber Splitting
      • Internal nuclei
      • Connective tissue increased
    • Lobulated type I muscle fibers
    • Collagen VI
      • Levels: Usually normal; May be reduced
      • Localization: Reduced co-localization with basal lamina (Collagen IV & Perlecan)
    • Laminin β1
      • Reduced in muscle fiber basal lamina but not vessels
      • May also be reduced in Lamin A/C mutations

• Epidemiology: 4 families
• Genetics
  • Mutations: Gly2786Asp; Arg1965Cys; Gly2777Arg
  • Allelic disorder: Ullrich CMD2
  • Also see: Bethlem myopathy 1, Collagen 6
• COL 12A1 protein
  • FACIT collagen
  • Interacts with: Collagen I; Decorin; Tenascin X
  • Regulates fibrillar scaffolds
  • Location: Perimysium
  • Mutation: Collagen XII
    • Less abundant
    • Disorganized
    • Intracellular retention
• Clinical
  • Onset
    • Age: Congenital
    • Hypotonia
    • Distal laxity
  • Weakness
    • Motor milestones: Delayed
    • Generalized: Proximal > Distal; Neck
    • Improves: During childhood & teenage years
    • May progress in later decades
  • Scapular winging
  • Skeletal
    • Joint hypermobility
    • Contractures: Long finger flexors; Proximal
    • Spine: Kyphosis or Scoliosis
    • Facial dysmorphism: Long face, Micrognathia, High-arched palate
  • Skin: Atrophic scarring
  • Progression: Mild or Improvement
  • Heart: Normal
• Laboratory
  • Serum CK: Normal to 1300
  • EMG: Normal or Myopathic
  • MRI
    • Common: Rectus femoris atrophy
    • More severe disease: Quadriceps, Adductors & Medial gastrocnemius
    • Asymmetry: Some muscles
  • Muscle
    • Collagen: XII reduced in muscle membranes; VI normal
    • Myopathic
    • Endomysial connective tisssue: Increased
    • Laminin B1 reduced
  • EM skin fibroblast
    • Col XII retained intracellulary
    • Endoplasmic reticulum: Distorted
• Collagen 12A1 variant syndrome: Ullrich congenital muscular dystrophy 2 (UCMD2) ¹⁵⁹
  • Epidemiology: 2 families
  • Genetics
    • Inheritance: Recessive
    • Mutations: Homozygous; Frameshift or Misense (Pro2943Leu)
    • Allelic with: Bethlem myopathy 2
    • Also see: Ullrich 1
  • Clinical
    • Onset age: Congenital
    • Motor
      • Hypotonia
      • Development: Delayed
    • Face: Weak; Dysmorphic
    • Skeletal
      • Distal joints: Laxity
      • Palate: High arched
    • Skin: Normal in childhood
    • CNS
      • Seizures
      • Spasticity
  • Laboratory
    • Muscle & Fibroblasts: Collagen 12 absent

• Genetics
  • COL9A3
    • Mutation: Splice acceptor mutation in intron 2
    • Mutant collagen IX is poorly cross-linked
    • Allelic with: Intervertebral disk disease, tendency
  • COL9A2 mutations
    • Splice donor site of exon 3: c.186G>A; c.186+2T>C
    • Cause skipping of exon 3 from COL9A2 mRNA
    • Allelic with: Intervertebral disk disease, tendency
  • COMP mutations
    • C-terminal domain
    • Allelic disorders: Carpal Tunnel syndrome, Familial
  • Myopathy present with some, but not all, mutations
• Type IX collagen proteins
  • Collagen
  • Fibril-associated collagen with interrupted triple helices
  • Chain structure: 4 Noncollagenous domains (NC1-4) separated by 3 triple helical collagenous domains (COL1-3)
  • Location (Tissue-specific isoforms): Cartilage; Eye vitreous; Myotendinous junction
  • Function: Organization & spacing of type II collagen fibrils
  • Modifications: NC3 domain of 2(IX) chain can be modified by a single glycosaminoglycan
• COMP protein
• Clinical
  • General
    • Onset: Childhood; Knee pain
    • ? Males worse than females
  • Weakness: Mild; Symmetric
    • Neck flexion
    • Arms
      • Shoulder abduction
      • Elbow extension
    • Legs
      • Proximal
      • Hamstrings weaker than Quadriceps
      • Waddling gait
  • Joints
    • Early onset degenerative disease
    • Especially knees: Pain
    • Sparing: Hips; Distinguishes conditions from Ribbing & Fairbank types of MED
    • Osteoarthritis
      • Joint space narrowing; Femoral condylar bony flattening; Osteophytes & subchondral cysts
      • Onset: Mid-adulthood
  • Skeletal: No short stature or brachydactyly
• Laboratory
  • Serum CK: Mildly elevated
  • X-rays: Epiphyses
    • Delayed ossification
    • Small & Irregular
  • Muscle biopsy
    • Mild myopathic changes: Varied muscle fiber size
    • Perimysial collagen: Normal
    • Immunostaining: Normal dystrophin, merosin & sarcoglycans
  • Epiphyseal chondrocytes: Intracytoplasmic inclusions

• Nosology: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH)
• Clinical
  • Weakness
    • Proximal
    • Onset: Mean 29 years
    • Progressive
  • Skeletal
    • Fractures, easy
    • Poor healing of long bones
    • Onst: Mean 18 years
  • Other
    • Skin: Thin
    • Hair: Premature gray
    • Hernias
• Laboratory
  • Clotting disorders
  • EMG: Myopathic
  • Bones: Coarse trabeculation, Patchy sclerosis, Cortical thickening, Narrowing of medullary cavities

• Epidemiology: Chinese Han family, 15 patients
• Clinical
  • Onset age
    • 4th to 6th decade
    • Earlier in males
  • Weakness
    • Early: Proximal legs; Neck flexion; Axial
    • Proximal arms: With disease progression
    • Distal extremities: Occasional; Usually mild
    • ? More severe in males
  • Course: Slowly progressive; Walking preserved
• Laboratory
  • Muscle
    • Necrosis & Regeneration
    • Fiber size: Varied; Some angular fibers
    • Rimmed vacuoles: In atrophic fibers
    • No inflammation
    • Congophilic inclusions: Few
    • Myofibfillar stains: Rare desmin & αB-crystallin aggregates
    • Ultrastructure: Cytoplasmic inclusions, 15–21 nm filaments
  • Serum CK: Mildly high; 300 to 400
  • EMG: Myopathic; Irritable
  • NCV: Normal
  • MRI: Medial & Lateral thigh atrophy

• Nosology: ? LGMD 1B
• Clinical
  • Onset: 4 to 38 years
  • Weakness
    • Proximal; Symmetric
    • Lower > upper extremity
    • Biceps involved @ 40 years
  • Contractures: Mild or absent
  • Cardiac
    • Dysrhythmias & conduction disturbances
    • Sudden death
• Laboratory
  • Serum CK: Median 3x normal; Range - normal to 25x
  • EMG & biopsy: Myopathic

• Clinical
  • Male predominance
  • Onset: 2nd or 3rd decade
  • Weakness: Proximal; Symmetric
  • Joint contractures: Ankles
  • Progression: Often disabled by 6th decade
  • Cardiac: Normal
• Laboratory
  • Serum CK: Very high; 12x to 55x normal
  • Muscle biopsy
    • Variation in muscle fiber size
    • Occasional necrotic muscle fibers

• Dominant; ? LGMD 1

Other Recessive Myopathies

• Nosology
  • Congenital disorder of glycosylation, Type 1o (CDG1O)
• Epidemiology: 6 patients
• Genetics
  • Mutation: Leu14Pro, Leu44Pro, Leu85Ser, Deletion
  • Allelic disorder: MDDGB15
• DPM3 protein
  • Binds DPM1
  • Accessory protein DPM3 of Dol-P-Man transferase (synthase)
    • Dol-P-Man: Glycosyl donor for all mannosylation reactions on luminal side of ER
• Clinical
  • Onset
    • Age: 11 to 42 years
    • Weakness: Proximal
    • Waddling gait
  • Weakness
    • Proximal ± Distal
    • Progression: Slow
    • Scapular winging, mild
  • Pseudohypertrophy: Gastrocnemius
  • Tendon reflexes: Reduced or Normal
  • Contractures: Ankle
  • Cardiomyopathy (80%)
    • Dilated
    • Stroke-like episodes
  • Short stature
  • CNS & Eye: Normal
• Laboratory
  • Serum CK: 1,500 to 4,300
  • CDG type I: Defective N-glycosylation in Endoplasmic reticulum
    • Increased ratio of mono- versus diglycosylated transferrin
    • Partial absence of complete biantennary N-glycans
  • EMG: Myopathic
  • Muscle MRI, Thigh: Hamstring; Adductors; Rectus femoris
  • Muscle: Myopathic
    • Fiber-size variation
    • Internal nuclei
    • Necrotic fibers
    • Rimmed vacuoles
    • Fiber splitting
    • Endomysial fibrosis
    • α-Dystroglycan: Reduced
    • Abnormal O- & N-glycosylation
• DPM3 variant disorder: MDDGB15 ¹⁵⁰
  • Epidemiology: 5 families
  • Genetics
    • Inheritance: Recessive
    • Mutations: Missense; P42A, Tyr74Cys, L85X
    • Allelic disorders
  • Clinical
    • Onset age: 30 months
    • Walking: Delayed
    • Intellectual development & Learning: Mildly impaired
    • Seizures: Absence; Onset age 6
    • Cardiac: Normal
  • Laboratory
    • Serum CK: Very high
    • Brain MRI: Periventricular WM changes
    • Muscle biopsy
      • Fiber sizes: Varied
      • Internal nuclei
      • α-Dystroglycan: Reduced

• Epidemiology: 1 Canadian family
• Genetics
  • Mutations: Missense; L345P, P119L, N114K
• LIMS2 protein
  • Z-disk
  • Functions: Adhesion; Integrin signalling
• Clinical
  • Onset age: Childhood
  • Weakness
    • Severe
    • Arms & Legs
    • Face spared
  • Tongue
    • Triangular
    • Macroglossia
  • Muscle size: General atrophy; Calf hypertrophy
  • Cardiomyopathy: LV dysfunction; Onset in 3rd decade
• Laboratory
  • Serum CK: Very high; Up to 5,000
  • MRI: Muscle atrophy
  • Muscle
    • Fiber size: Varied
    • Internal nucle
    • Endomysial connective tissue: Increased
    • PINCH2 staining: May be reduced

• Nosology: LGMD 2X
• Epidemiology: 10 families; 12 patients
• Genetics
  • Mutations
    • Often: Loss of function; Homozygous
    • Missense: c.602C>T, p.Ser201Phe; Pseudo-dominant
    • Splice site: c.1A>G; c.816 + 2T>C
    • Stop: c.262C>T
• POPDC1 protein ¹⁵³
  • Nosology: Blood vessel epicardial substance (BVES)
  • Localization: Plasma membrane; T-tubule; Nuclear envelope
  • cAMP-binding & effector protein
  • Expressed in cardiac & skeletal muscle
  • Cell adhesion molecule
  • Formation & regulation of tight junction paracellular permeability barrier in epithelial cells
  • VAMP3-mediated vesicular transport
  • Interactions: Caveolin-3; TREK-1 (KCNK2)
• Clinical
  • Onset age: 2nd to 5th decade
  • Weakness (60%)
    • Proximal
    • Legs
    • Symmetric
    • Respiratory: Some patients
  • Exercise intolerance
  • Myalgia
  • Cardiac: Syncope; A-V block; Palpitations
  • Scoliosis: Mild
• Laboratory
  • Serum CK: 700 to 8000
  • EMG: Myopathic, Fibrillations or Normal
  • Muscle biopsy
    • Fiber size: Varied
    • Internal nuclei
    • Necrosis & Regeneration: Scattered
    • Sarcolemma: Reduced POPDC1 & POPDC2
  • Muscle MRI
    • Thigh
      • Posterior
      • Biceps femoris, long head; Adductor magnus
    • Asymmetric
    • Distal leg spared
    • Often normal
  • Holter monitor: A-V block

• Epidemiology; 4 families; 7 patients
• Genetics
  • Mutations: Homozygous; Lys154Glu; Leu155His, Leu217Phe, Arg261Gln
• POPDC3 protein
  • Expression: Heart; Skeletal muscle
  • Transmembrane
  • Bind: cAMP (Popeye domain); TREK-1 (KCNK2)
  • Modulate membrane trafficking of interacting proteins
  • POPDC proteins: Other
    • POPDC1: LGMD R25
    • POPDC2 : AV block
• Clinical
  • Onset age: Adult; 20 to 40 years
  • Weakness: Proximal; Legs > Arms; Poor running
  • Calf hypertrophy
  • Cardiac: Normal
• Laboratory
  • Serum CK: Mean 3500; Range 1050 to 9200
  • Muscle MRI
    • Involvement: Paraspinal; Proximal leg; Medial gastrocnemius
    • Spared: Gracilis; Sartorius; Rectus femoris
  • Muscle pathology
    • Muscle fibers: Varied size; Necrosis; Whorled; Internal nuclei
    • Endomysial connective tissue: Increased
    • POPDC3 protein: Reduced
  • EKG & Echocardiography: Normal

• Epidemiology: 2 families, 4 patients
• Genetics
  • Mutation: Frameshift; Homozygous c.186delG
  • Genotype vs Phenotype
    • LAP1B-specific mutations: Myopathy, Progressive
    • Loss of both LAP1B & LAP1C isoforms: Syndromic disorder; Muscle, Brain, Eyes, Ear, Skin & Bones ¹³⁹
  • Allelic disorders ¹²⁴
    • Dystonia, Cerebellar atrophy, Cardiomyopathy
    • Multisystem disorders, Progeroid appearance, Early death
    • Multisystem disorder: Developmental delay, Hearing Loss, Cataracts, Cardiac, Skeletal, Muscle atrophy
    • Congenital Myasthenic Syndrome
• LAP1B protein
  • Location: Inner nuclear membrane
  • Binds type A & B lamins
  • ? Regulates TorsinA ATPase
• Clinical
  • Onset age: 1st decade
  • Contractures
    • Rigid spine
    • Interphalangeal joints: Distal & Proximal
  • Weakness
    • Limb-Girdle: Legs > Arms
    • Dysphagia
    • Respiratory insufficiency
    • Progressive
  • Cardiomyopathy, dilated: 1 patient
• Laboratory
  • Serum CK: 80 to 10,000
  • EMG: Irritable myopathy
  • Muscle MRI
    • Trunk: Rectus abdominus, Glutei, Obturator internus, Obliques, Iliacus
    • Thigh: Medial (Adductors & Gracilis & Posterior (Bicceps fermoris & Semitendinosus)
  • Muscle pathology
    • Muscle fibers: Varied size; Internal nuclei; Necrosis & Regeneration
    • Endomysial connective tissue: Increased
    • C_5b-9 on sarcolemma
    • TOR1AIP1: Absent
    • Nuclei: Irregular
    • Ultrastructure: Abnormal nuclear envelope
• TOR1AIP1 variant syndrome: Myasthenic syndrome
  • Epidemiology: 2 families, 5 patients
  • Genetics
    • Inheritance: Recessive
  • Clinical
  • Onset age: Adult
  • Weakness: Limbs; Mild to Moderate
  • Course: Stable or Slow progression
  • Treatment: Cholinesterase inhibitors

• Epidemiology: 23 patients, 17 families
• Genetics
  • Mutations
    • Most in C-terminus
    • Missense or Stop
    • Missense in C-terminus: Milder disease
• SNUPN protein
  • Nuclear transport of small nuclear ribonucleoproteins (snRNPs)
  • Mutations: Splicing deregulation
  • Spliceosome
• Clinical
  • Onset: Childhood
  • Weakness
    • Proximal > Distal
    • Legs then Arms
    • Respiratory & Axial
  • Contractures: Ankles; Elbows; Generalized
  • Intrafamilial variability
  • Course: Ambulation often lost in teens
• Laboratory
  • Muscle
    • Muscle fiber necrosis
    • Endomysial connective tissue: Increased
    • Vacuoles: Rimmed; Few
    • Aggregates: Gomori trichrome; Myotilin, p62, LC3
    • Z-disc disorganization
    • Muscle fiber surface: Col IV, Dystroglycan & SGCA reduced
  • Muscle MRI involvement: Paravertebral, Vasti, Sartorius, Gracilis, Reroneal, Medial gastrocnemius
  • EMG: Myopathic
  • Serum CK: 290 to 2,500
  • Brain imaging: Cerebellar atrophy; Corpus callosum thin

• Nosology: LGMD 2Z
• Epidemiology: 9 families
• Genetics
  • Mutations: Homozygous; Missense; D233E, R98W, Y57C, I129T, Y156N, R183W
  • Allelic disorder: Galli-Galli/Dowling-Degos disease (DDD4)
• POGLUT1 protein
  • Notch posttranslational modification
    • Notch pathway: Maintains Satellite cell quiescence
  • O-Glucosyltransferase activity on Notch
  • Specifically adds O-glucose or O-xylose to properly folded EGF repeats containing CXSX(P/A)C consensus sequence
  • Glycosyltransferase: Directly add sugar molecules to an amino acid & not to other sugars
  • Mutation: Impairs muscle development
• Clinical
  • Onset age: Congenital to 5th decade
  • Weakness
    • Proximal
    • Legs > Arms
    • Scapular winging
    • Respiratory: 4th decade
  • Course: Slow progression; Some require wheelchair
• Laboratory
  • Brain MRI: Normal
  • Muscle MRI: Internal thigh muscle pathology
  • Muscle
    • Fiber size: Varied
    • Endomysial connective tissue: Increased
    • Nuclei: Internal in some muscle fibers
    • α-Dystroglycan: Hypoglycosylation
    • Satellite cells: Reduced numbers
  • Serum CK: Normal or Mildly high

• Nosology: MYOSCO; CMYP19; CMYO19
• Epidemiology: 5 patients, 4 families
• Genetics
  • Mutations: c.86-1G>A; Arg74*; Arg56Cys; Arg145*
• PAX7 protein
  • Satellite cells
  • Muscle development
• Clinical
  • Onset age: Birth to Few months of age
  • Hypotonia: Especially axial
  • Ptosis
  • Muscle
    • Atrophy
    • Weakness
      • Distal or Diffuse
      • Respiratory: More severe patient
      • Course: Progressive
    • Gait: Abnormal in most
  • Tendon reflexes: Normal or Reduced
  • Skeletal
    • Scoliosis
    • Short stature
  • Face: Mild dysmorphism
  • Systemic: Renal in patient with severe disease
• Laboratory
  • Muscle pathology
    • Fiber size variation: Atrophic fibers
    • Myonuclei: Number reduced
    • Replacement by fat
    • PAX 7 & MYF5 expression: Absent
  • Serum CK: Normal
  • EMG: Early normal; Teens myopathic
  • Brain MRI: Normal

• Epidemiology: 2 patients
• Genetics
  • Mutation: p.Q247X, Homozygous
  • Variant: Digenic syndrome
• Trim63 protein
  • Regulator of muscle atrophy
  • E3 ligase
  • Expression: Skeletal & Cardiac muscle
• Clinical
  • Onset age: 6th decade
  • Strength: Normal
  • Cardiomyopathy
• Laboratory
  • Cardiac hypertrophy
  • Serum CK: 700
  • EMG: Myopathy, Mild
  • Muscle MRI
    • Patchy asymmetric changes
    • Muscles involved: Gluteus minimus„ Vastus lateralis, Semimembranosus, Medial gastrocnemius
  • Muscle biopsy
    • Necrotic fibers: Few
    • Muscle fiber size: Varied
    • Internal nuclei
    • Internal capillaries: 5–10% of muscle fibers
• TRIM63 variant syndrome: Cardiac & Skeletal Aggregate Myopathy with Combined MuRF1 & MuRF3 mutations ¹¹⁶
  • Epidemiology: 1 patient
  • Genetics: Digenic
    • Murf1 (TRIM63) mutations: p.Q247X, Homozygous
    • Murf3 (TRIM54) mutation: p.Asp106Asn, Heterozygous
  • Clinical
    • Onset age: 15 years
    • Weakness
      • Distribution: Arms & Legs; Proximal; Symmetric
      • Gait: Waddling
      • Respiratory: Moderate reduction
      • Course: Slow progression
    • Muscle hypertrophy: Deltoids, Biceps, Calf
    • Scapular winging
    • Rigid spine, hypertrophy
  • Laboratory
    • Echocardiogram: Hypertrophic cardiomyopathy
    • EKG: Atrial flutter & enlargement
    • Serum CK: 2x to 6x high
    • EMG: Myopathic
    • Muscle MRI
      • Subcutaneous tissue: Reduced
      • Fat replacement: Lumbar paraspinous; Glutei; Thigh, anterior & posterior
      • Hypertrophy: Rectus femoris, Sartorius, Gracilis
    • Muscle biopsy
      • Fiber sizes: Some small fibers
      • Fiber aggregates
        • Location: Sub-sarcolemmal
        • Type I fibers
        • Components: MyHC, MuRF3, M-protein, Myomesin
        • Ultrastructure: Aberrantly oriented sarcomere fragments
      • Nuclei: Large
      • Endomysial connective tissue: Mildly increased

• Epidemiology: 29 patients
• Genetics
  • Mutations
    • Loss of function
    • Missense, In-frame deletion, Nonsense & Frame shift
• JAG2 protein
  • Notch ligand
  • Notch signaling pathway: Cell & Tissue development
  • Expression: Skeletal muscle, Heart, Pancreas
  • Notch-related processes
    • Schwann cell development: Immature
    • Myogenesis
      • Notch pathway: Maintains Satellite cell quiescence
  • Notch-related disorders
    • JAG1: CMT2 + Vocal cord
    • JAG2: LGMD R27
    • POGLUT1: LGMD R21
    • MEGF10: EMARDD
    • OPDM3 & NIID: NOTCH2NLC
• Clinical
  • Onset age: Infant to Young adult
  • Weakness
    • Proximal > Distal
    • Axial & Neck
    • Face & Ptosis (25%)
    • Vital capacity: 41% to 100%
  • Tendon reflexes: Reduced or Absent
  • Skeletal
    • Scoliosis (60%)
    • Contractures (50%): Ankle
    • Rigid spine (50%)
  • Cardiac (30%)
  • Cognitive involvement (17%)
  • Course: Progressive; Loss of ambulation in more severe patients
• Laboratory
  • Serum CK: Normal or Mildly high
  • EMG: Myopathic
  • Muscle MRI
    • Vastus & Rectus femoris pathology worse at periphery
      • Similar to COL6
    • Most muscles somewhat involved
    • Asymmetry: Mild
  • Muscle biopsy
    • Fiber sizes: Varied
    • Internal nuclei
    • Fiber splitting
    • Internal architecture: Irregular; Core-like areas
    • Other muscle: PAX7 reduced
  • NCV: Normal

• Epidemiology: 6 families, 15 patients
• Genetics
  • Mutations: Missense + 1 deletion
  • Mutation effects: Hypomorphic
• HMGCR protein
  • Transmembrane glycoprotein
  • Endoplasmic reticulum, is the rate-limiting enzyme in
  • Cholesterol biosynthesis: Rate-limiting enzyme
  • Converts HMG-CoA to Mevalonate
  • Immune myopathies
    • HMGCR is target of serum autoantibodies in some patients
    • Anti-HMGCR antibodies: Associated with muscle fiber necrosis
  • Mutated protein: Reduced activity
• Clinical
  • Onset
    • Ages: Childhood to 39 years
    • Serum CK: May be high in early childhood
  • Pain: On exertion
  • Weakness
    • Proximal & Axial
    • Legs ≥ Arms
    • Respiratory: With disease progression
    • Gait: Waddling
  • Course: Progressive, often to wheelchair
  • Possible treatment: Mevalonolactone
  • No systemic features
• Laboratory
  • Serum CK: High; Normal with disease progression; Range 77 to 35,000
  • Muscle biopsy
    • Non-diagnostic in most: Varied fiber sizes
    • Vacuoles in some
    • Endomysial connective tissue: Increased in some
    • Ultrastructure: Myofibril dysruption
  • Fasting blood sugar: Midly high
  • Cholesterol & Triglycerides: Normal
  • MRI: Fatty replacement of most proximal & axial muscles
  • EMG: Myopathic

• Epidemiology: 2 Sicilian families
• Genetics
  • Mutations: c.4-1G>C (Disrupts acceptor splice site of exon 2; Y23C
• DPM2 protein
  • Dolichol-phosphate-mannose (Dol-P-Man; DPM) synthase complex component
  • Catalyzes synthesis of DPM at cytosolic face of ER membrane
• Clinical
  • Onset age: Congenital
  • Microcephaly, progressive
  • Visual defect, Severe
  • Epilepsy
  • Muscular dystrophy: Hypotonia
  • Liver involvement
  • Death: < 18 months
• Laboratory
  • Coagulation factors: Decreased
  • Serum CK: High; 1,200 to 1,400
  • EMG: Myopathic
  • Muscle
    • Fiber-size variation
    • Internal nuclei
    • Endomysial fibrosis
    • Reduced: α-Dystroglycan; Laminin-α2
  • Transferrin: Abnormal N-glycosylation
  • Brain MRI: Cerebellar vermis hypoplasia

• Epidemiology
  • > 23 patients
  • Commin in: Oman
• Genetics: Mutations
  • Homozygous or Heterozygous
  • c.525delG, c.696_697insC, c.160delG, c.362dupT
• PTRF protein
  • Termination of RNA polymerase I (Pol I)
  transcription
  • Release of both pre-rRNA & Pol I from template
  • Required for caveola formation & sequestration of mobile caveolin into immobile caveolae
• Clinical
  • Onset
    • Age: Congenital, Infancy or Early childhood
    • Lipodystrophy
  • Lipodystrophy
    • Generalized: Reduced subcutaneous fat
    • Loss of adipose tissue in several regions including face
  • Weakness
    • Mild
    • Distal dominant or Generalized
  • Muscle
    • Muscle hypertrophy
    • Muscle activity
      • Muscle mounding
      • Rippling
      • Electrically silent
    • Myalgias: Occasional
  • Cardiac
    • Tachycardias: Supraventricular & Ventricular
    • Bradycardia
    • Long-QT syndrome
    • Cardiomyopathy: Hypertrophic
    • Sudden cardiac death: Teens
  • GI
    • Smooth muscle hypertrophy
    • Hypertrophic pyloric stenosis
    • Impaired gastrointestinal motility: Constipation
    • Chalasia
    • Liver: Fatty changes; Large
  • Bone
    • Impaired bone formation
    • Osteopenia
    • Osteoporosis
    • Atlanto-axial instability
    • Skeletal: Lordosis or Scoliosis
  • Other systems
    • Acromegaloid features
    • Umbilical prominence
  • Immune: Some patients
    • Transient immunodeficiency (IgA)
    • Recurrent pneumonia
  • Not present
    • Intellectual deficit
    • Acanthosis nigricans
• Laboratory
  • Serum CK: High; 500 to 2600
  • Muscle
    • Chronic dystrophic changes
      • Variation in fiber size: Marked
      • Enlarged fibers
      • Internal nuclei
      • Endomysial fibrosis
      • Necrotic & Regenerating fibers: Few
    • Caveolin family members
      • Deficiency & Mislocalization of all 3
      • Caveolin-3: Reduced on sarcolemma: Increased in cytoplasm
      • Caveolin-1 & Caveolin-2: Reduced in blood vessels
      • Caveolae structure: Reduced
    • Dysferlin: Decreased in sarcolemma; Mislocalized into cytoplasm
    • PTRF: Absent from muscle by Western blot
    • Normal: Dystrophin, Sarcoglycans, Dystroglycans, Emerin, Merosin, Collagen VI
  • Hypertriglyceridemia
  • Insulin resistance
  • Duodenum: Absent submucosal adipose tissue

• Epidemiology: 2 patients
• Genetics
  • Mutations
    • 30 kb deletion: Leads to fusion gene with pseudogene TNXA; Truncating
    • Arg4072Cys
  • Allelic with: Ehlers-Danlos syndrome, autosomal dominant, hypermobility type
• TNXB protein
  • Extracellular matrix of muscle & Blood vessels
  • Regulator of collagen deposition by dermal fibroblasts
• Clinical
  • Weakness
    • Onset age: 4th decade
    • Proximal & Axial
    • Symmetric
    • Weakest muscles: Abdominal; Knee extensors
    • Scapular winging
    • Functional: Difficulty running
    • Muscle bulk: Reduced
    • Course: Slowly progressive
  • Tendon reflexes: Reduced
  • Skin: Hyperextensible
  • Hematomas: After minimal trauma
  • Contractures: Fingers or None
• Laboratory
  • EMG: Myopathic; Pseudomyotonic discharge
  • NCV: Normal
  • Serum CK: High; Up to 5x normal
  • CT: Rectus femoris most preserved in Thigh; Distal legs normal
  • Cardiac echo: Systolic function mildly reduced
  • Platelet aggregation: Mildly abnormal
  • Muscle
    • Soft consistency
    • Fiber size: Varied
    • Internal nuclei
    • Fiber type groupisng
    • Myotendinous junctions: Increased
    • Endomysial connective tissue: Normal
    • Tenascin-X staining: Reduced in muscle & skin
    • Ultrastructure: Plasma membrane focally disrupted; Basal lamina abnormally folded

• Northern Indiana Amish
• Linked to LGMD 2E

• Lipid Storage
  • Carnitine Deficiency
  • Riboflavin Responsive (multiple enzyme deficiencies)
• Acid Maltase deficiency & other Glycogen storage syndromes

• Epidemiology: 1 family; 2 British females
• Clinical
  • Onset: 12 years
  • Early developpment: Normal
  • Weakness
    • Legs > Arms
    • Proximal > Distal
    • Neck flexor
  • Contractures: Knee
• Laboratory
  • Serum CK: High, 500 to 700
  • EMG: Myopathic
  • MRI: Wasting of thigh muscles sparing adductors
  • Muscle
    • Autophagic vacuoles
    • Endomysial connective tissue: Mildly increased
• Also see: XMEA

• Epidemiology: 1 Japanese male
• Clinical
  • Onset: Myopathy as adult
  • Ocular
    • Achromatopsia: From childhood
    • Retinal pigmentary degeneration: Blindness in 3rd decade
    • Optic atrophy
  • Weakness
    • Proximal > Distal
    • Scapular winging
  • Other muscle
    • Exertional pain
    • Dyspnea
  • Cardiomyopathy
    • EKG: Bradycardia with transient sinus arrest & prolonged PQ interval
    • Echocardiography: Hypertrophy & partial dilatation of left ventricular wall; Decreased ejection fraction
  • Lung: Fibrosis
• Laboratory
  • Serum CK: High, 500
  • IgG & IgE: High
  • ⁶⁷Ga uptake in skeletal muscles
  • Muscle
    • Autophagic vacuoles
    • Fiber size: Moderate variation
  • Liver: Vacuoles in hepatocytes
  • Renal: Proteinuria
• Also see: XMEA

• Nosology
  • Ceroid lipofuscinosis, neuronal, 3
  • Batten disease
• Epidemiology: > 100 patients
• Genetics
  • Mutations: Missense (Gly165Glu), Splice & Stop; Common 1 kb deletion
  • Allelic disorder: Neuronal ceroid lipofuscinosis, juvenile form
• CLN3 protein
  • Organs: Brain + other tissues
  • Subcellular
    • Membrane protein
    • Nucleus & Cytoplasm
    • Lysosomal (Endolysosomal)
  • Highly glycosylated
  • Cell types: Astrocytes & Endothelium
  • Regulates
    • Autophagic vacuoles: Maturation
    • Actin-dependent events at plasma membrane
    • Response to oxidative stress: Stress granule dynamics & translational activity
• Clinical
  • Onset age: Juvenile; 6 to 9 years
  • Eye
    • Early in disease course
    • Retinitis pigmentosa
    • Retinal atropny
    • Visual loss
  • CNS
    • Epilepsy: Tonic-clonic
    • Cognitive: Mild impairment of verbal fluency & executive functions
  • Cardiac
    • Hypertrophic cardiomyopathy
    • Sick sinus syndrome
    • Conduction defect
    • Onset: Later in disease course
  • Motor function: Normal
  • Course: Slow progression over decades
• Laboratory
  • Serum CK: Up to 600
  • Muscle
    • Acid phosphatase+
      • Cytoplasmic granules
      • Autophagic debris
    • AVSFs
    • Autofluorescent material
  • Nerve: Inclusions
    • Locations
      • Schwann cells
      • Vessels: Endothelial cells; Smooth muscle
      • Perineurium
      • Not axons
    • Types
      • Curvilinear profiles
      • Fingerprint bodies
      • Lipopigments, Granular, Osmiophilic
  • EMG: Myopathy, mild
  • EEG: Spikes & sharp waves
  • Blood lymphocytes: Cytoplasmic vacuolization
  • Brain MRI: Cerebral & Cerebellar atrophy
  • Ultrastructure
    • Lipopigment pattern: Fingerprint profile (Lymphocytes)

• Epidemiology: Many patients; Often Ashkenazi Jewish
• Genetics
  • Mutations: Deletion, large; Stop; Missense
• ML1 protein
• Clinical
  • Onset age: 1st decade
  • Psychomotor delay: Severe; Absent expressive language, Good comprehension
  • Cerebral palsy-like encephalopathy
  • Eye: Retinal dystrophy; Corneal clouding
  • Course: Slow progression; Maximum development achieved equivalent to age 1–2 years; No ambulation; Life expectancy reduced
• Laboratory
  • Brain MRI: White matter pathology; Corpus callosum thin
  • Serum CK: High
  • Serum Gastrin: High
  • Iron deficiency
  • Anemia, Microcytic
  • Renal impairment: Later in course
  • Muscle
    • Fiber sizes: Varied
    • Internal nuclei: Few
    • Cytoplasmic inclusions: Basophilic, Granular; Stain for acid phosphatase & LAMP2
    • Ultrastructure: Lamellar inclusions; Lipopigment