Distal Myopathy and Dysferlinopathy

Distal Myopathy and Dysferlinopathy/Dysferlinopathy include a spectrum of muscle disease characterized by two main phenotypes: Miyoshi myopathy with primarily distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B) with primarily proximal weakness. Miyoshi myopathy (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with a decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes are scapuloperoneal syndrome, distal myopathy with anterior tibial onset, elevated serum CK concentration only, and congenital muscular dystrophy.

Types of Dysferlinopathy or Distal Myopathy

Welander (Late-onset type I) Distal Myopathy

TIA1 cytotoxic granule-associated RNA-binding protein (TIA1); Chromosome 2p13.3; Dominant

• Epidemiology
  • Especially common: Mid-Sweden & Finland gene frequency 1/4000
  • Penetrance: Relatively low due to late age of onset
• Genetics ^[rx]
  • Mutation: E384K
  • Finnish & Swedish patients have shared haplotype
  • Homozygotes: Weakness is more severe & proximal
  • Allelic disorder: ALS-FTD (ALS 26)
  • TIA1 mutations also found in patients with SQSTM1 & MYH7 related distal myopathies
• TIA1 protein (Nucleolysin TIA-1 isoform p40)
  • Nucleic acid-binding protein: Preferentially recognizes poly(A) homopolymers
  • Induces DNA fragmentation in permeabilized thymocytes
  • Component of cytoplasmic stress granules
    • Other components: eIF3, G3BP & TIAL1
  • May be involved in the induction of apoptosis in CTL targets
  • Expressed in many tissues including muscle: Nuclear + some cytoplasmic
  • Accumulates in stress granules: Prion-like aggregation
  • RNA metabolism
• Clinical: Typical disease
  • Onset
    • Age: Usually > 40 years; Median 5th decade; Range 20 to 77
    • Location
      • Arms; Wrist & Finger extensors: Most common
      • Legs (Foot drop): 25%
  • Weakness
    • Hands > Legs in most
    • Muscles involved: Long finger extensors; Intrinsic hand; Thumb & index-finger
    • Progression to legs: Toe & ankle extensors
    • Only rarely proximal weakness
  • Tendon reflexes: Reduced at ankles
  • Slow progression with a normal life span
  • Sensory loss: Some patients; Subclinical neuropathy common
  • Autonomic: Altered peripheral vasomotor response after vasoconstriction
• Homozygotes: Subset with more severe disease
  • Earlier onset
  • Rapid progression
  • Early: Leg & Proximal weakness
  • Wheelchair < 50 years
• • CK: Normal or mildly elevated
  • EMG: Myopathic; Some irritability
  • Muscle Pathology
    • Chronic myopathic: Varied fiber size; Splitting
    • Rimmed vacuoles: Variably present; contain increased p62, Ubiquitin & TIA1
    • Tubulo-Filamentous inclusions (15 to 18 nm): Sarcoplasm & muscle fiber nuclei
    • Neurogenic changes
    • TIA1: Increase in the cytoplasm with occasional aggregates in atrophic & vacuolated muscle fibers
  • Sural nerve: Aδ fiber lossLaboratory
• TIA1 variant: ALS 26 (ALS-FTD)  ^[rx]
  • Epidemiology: 1 family, 5 patients; 5 other ALS mutation carriers
  • Genetics
    • Inheritance: Dominant or Sporadic
    • Mutations
      • Missense: P362L, V294M, M334I, G355R, V360M, A381Y
      • Low-complexity domain
    • Other ALS: Increased burden of TIA1 low-complexity domain mutations in ALS patients vs controls
    • ~ 2% of Familial ALS
    • Allelic disorder: Welander distal myopathy
  • TIA1 protein
  • Clinical
    • Onset ages: 28 to 73 years; Mean 59 years
    • Weakness
      • Bulbar
      • Limb
    • Aphasia
    • Fronto-Temporal dementia
    • Disease course: Death in 2 to 6 years
  • Laboratory
    • Brain pathology
      • Inclusions: Round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive; Lewy body like
      • Locations: Extra-motor neocortex, Motor cortex, Substantia nigra, Spinal cord corticospinal tracts & ventral horn

Finnish (Tibial) (Late-onset type IIa; Udd) Distal Myopathy

Titin  Chromosome 2q31.2; Dominant

• Epidemiology
  • Finland
    • Large population with the same mutation
    • Most common muscle disease
  • Other regions
    • French, Belgian & Spain families
    • Iberian mutation: c.107889delA
• Genetics
  • Finnish population
    • Probably arose from a single ancestor
    • 20 per 100,000 population
    • Mutations
      • Common: 11 bp insertion-deletion of nucleotides 293,269 to 293,279 (In terminal exon)
      • Other: Missense or Truncating; Last 2 TTN exons
  • Allelic Disorders
  • Genotype-Phenotype
    • Same (11 bp) mutation may produce different patterns of weakness
      • Most common: Tibial MD
      • Other: Proximal; Posterior leg
    • Severe or variant phenotype
      • Often have 2nd titin mutation (Recessive LGMD 2J)
• Clinical
  • Onset age
    • Heterozygotes
      • 4th to 8th decade; Most in 40’s
      • Many remain asymptomatic
    • Homozygotes: Childhood; LGMD 2J
  • Distribution of weakness
    • Legs: Anterior tibial selectively involved
    • Arms
      • Never hand weakness in Finnish patients
      • Some Non-Scandinavian families with hand weakness
    • Proximal weakness: 15%; Mild
  • Progression
    • Slow: Foot drop 10 to 15 years after onset when long toe extensors become weak
    • Proximal legs may become weak late in disease
    • Quadriceps weak in rare male
    • Many remain ambulatory
      • Earlier onset (2nd decade) may lose ambulation in 3rd to 6th decade
    • Homozygotes: Loss of ambulation by 3rd decade
  • Cardiomyopathy
• Laboratory
  • CK: Mild elevation or normal
  • MRI: Selective fatty replacement of muscles
    • Early: Anterior tibial; Gluteus minimus
    • Later: Gastrocnemius
• Pathology: Dystrophic (100%)
  • Muscle fibers: Size variation; Splitting; Internal nuclei
  • Basophilia
  • No inflammation
  • Rimmed vacuoles (30%): Contain degenerative cytoplasmic debris & organelles
  • Calpain 3: Reduced
  • Apoptosis in muscle nuclei
  • Anti-titin antibodies
    • Normal binding for most
    • Binding to C-terminal epitope reduced

Markesbery (Late adult-onset type IIb) Distal myopathy

ZASP; Chromosome 10q23.2; Dominant ^[rx]

• Epidemiology: English, French & Finnish families
• Genetics
  • Mutation: A165V; Common in European families
  • Allelic disorders
• Clinical
  • Onset age: > 40 years
  • Weakness
    • Early: Distal legs
    • Hands: Distal finger & wrist extensors
    • Late: Proximal arms & legs
  • Progression
    • Slow: Slower in Finnish tibial type
    • Disability common
  • Cardiomyopathy: Occasional patient
• Laboratory
  • Serum CK: Normal or Slightly elevated
  • Muscle pathology: Rimmed vacuoles
  • MRI

Hereditary Inclusion Body Myopathy 2 (HIBM2; Nonaka): Recessive

A UDP-N-Acetylglucosamine 2-Epimerase/N-Acetylmannosamine kinase (GNE) ; Chromosome 9p13.3; Recessive

• Nosology: Same disorder as
  • GNE myopathy
  • Nonaka distal myopathy
  • IBM2
• Epidemiology
  • Iranian-Jewish families: Prevalence in Jews of Persian ancestry = 1:500
  • Other families: Mexico; India; Bahamas; Georgia
  • Prevalence range: 1 to 21 per 1,000,000
• Genetics: GNE gene mutations
  • Type
    • Missense >> Stop
    • Heterozygous > Heterozygous
  • Mutation locations
    • Across entire gene
    • Domains: Epimerase or Kinase
  • Geographic
    • Iranian-Jewish & Sangesar (Mahdishahr) in Northern Iran: Homozygous for Met712Thr
    • Japanese (Nonaka) & Korean: V572L (60%; Founder effect); Homozygous or Heterozygous
    • Japanese, Other: Asp207Val (Late-onset; Asymptomatic if homozygous); Val603Leu (Often homozygous)
    • Korean: C13S
    • Northern Britain: Ala662Val; Asp409Tyr
    • Roma Gypsy & Indian (Rajasthan): Ile618Thr (Homozygous)
    • Indian: Val727Met
    • Middle Eastern (Persian Jews): Met743Thr
  • Earlier onset: L539S
  • Milder or atypical phenotype: H333R; Y361X
  • Allelic disorder: Sialuria
• GNE protein: Bifunctional
  • Catalyzes 1st 2 steps in the synthesis of N-acetylneuraminic (sialic) acid: Rate-limiting step
  • Epimerase activity: N-terminal
  • Kinase activity: C-terminal
  • Tissue expression
    • Full-length protein: Liver; Salivary glands; Intestinal mucosa
    • Shorter form (exon 4 missing)
      • Predominantly expressed in skeletal muscle
      • Present in similar levels in control & myopathy patients
  • GNE Mutants: No correlation between Disease pattern & Changed enzyme activity
  • Sialic acid disorders
  • External link: GeneTests
• Clinical
  • Onset
    • Age: 2nd or 3rd decade; Range 12 to 78
    • Weakness: Foot drop
  • Weakness
    • Early: Peroneal & Anterior tibial
    • Distal & Proximal
    • Asymmetry: Some muscles
    • Lower extremity
      • Onset: Peroneal weakness (Anterior distal legs), Ankles & Toes
      • Then: Hips, Hamstrings & Gastrocnemius
    • Upper extremity
      • Wrist: Extension & Flexion
      • Hands: Intrinsic muscles; Grip
      • Shoulder girdle
        • Scapular winging: Some patients
    • Neck: Flexors or Extensors may be weak
    • Respiratory
      • Frequency: 30%
      • Especially with earlier onset
      • Rarely severe
    • Sparing
      • Quadriceps
        • Spared in most patients
        • Weak in few patients (4%): Disease progression
      • Arms: Deltoids
      • Legs
        • Hip muscles
        • Ankle: Plantar flexors
      • Cranial nerves
        • Ptosis: Rare
        • Facial weakness: Occasional patient
    • Progression: Slow
      • Usual: Weakness progresses to proximal & trucnal muscles
      • Disability within 10 to 20 years of onset
      • Often become wheelchair dependent
      • Few patients: Weakness remains distal
      • Lifespan: Not substantially reduced
    • Variants
      • Upper extremity early: Distal arm weakness
      • Proximal leg: Hamstring weakness, No foot drop
      • Axial early
      • Late-onset
• Laboratory
  • CK: Mild elevation, 2x to 5x
  • Urine sialic acid: Not elevated
  • EMG: Spontaneous activity; Myopathic potentials
  • MRI: Quadriceps sparing
• Muscle Pathology
  • Myopathic
    • Varied muscle fiber size
    • Necrosis & Regeneration: Some patients
  • Vacuoles: Red-rimmed
    • Contain paired helical filaments
    • ? Autophagic
    • Many, but not all, patients
  • Aggregates
    • Constituents: βAPP; Ubiquitin; SMI-31 binding; ApoE; LC3; α-synuclein; Tau; TDP-43.
    • 15 to 18 nm filamentous inclusions in cytoplasm & nucleus
  • Sialylation: Abnormal on muscle proteins
    • Mainly affects O-glycan sialylation
    • Peanut (PNA) lectin staining of Gal(β1-3)GalNAc disaccharide: Increased on the sarcolemma
    • NCAM pathology: Migrates as single, smaller 130 kD band on Western blot in some patients
  • Myopathic groups: Vacuolar & small fibers clustered in regions
  • Inflammation uncommon, but occasionally present
  • α-Dystroglycan staining: Reduced
  • LAMP2: Increased granular staining
• GNE variant: Sialuria
  • Epidemiology: 10 patients
  • Genetics
    • Inheritance: Dominant
    • GNE Mutations
      • Epimerase domain
      • Binding site of cytidine monophosphate-sialic acid of GNE/MNK
  • Functional defect: Loss of feedback inhibition
  • Clinical
    • Developmental delay
    • Hepatosplenomegaly
  • Laboratory
    • Urine: Free sialic acid high

Miyoshi Myopathies

• Miyoshi 1 (MMD1): Dysferlin; 2p13.2
• Miyoshi 2 (MMD2): ? 10p
• Miyoshi 3 (MMD3): ANO5; 11p14

Miyoshi (Early adult-onset distal myopathy type II; MMD1)

Dysferlin ; Chromosome 2p13.2; Recessive

• Genetic associations
  • Allelic with: Limb-girdle muscular dystrophy 2B
  • Genetic heterogeneity
    • ? Some families linked to chromosome 10 & other loci
• Protein: Dysferlin
  • Skeletal muscle > Heart
  • Attached to the cell membrane
• Clinical features
  • Presymptomatic: Mild gastrocnemius wasting
  • Early Adult-Onset: Teens to 38 years
  • Weakness & Wasting
    • Posterior Legs: Gastrocnemius; Soleus
    • Symmetric
    • Arms & Proximal muscles involved late
    • Calf wasting
    • Progression: Related to disease duration
    • Asymmetry in families not linked to 2p
• Laboratory
  • CK: Very high up to 20,000
  • MRI
    • Selective involvement of hamstring, gastrocnemius & soleus
    • Early muscle edema
  • Pathology: Dystrophic Muscle
    • Necrosis & degeneration of muscle fibers
    • Endomysial connective tissue: Increased in more involved muscles
    • Muscle fibers: Size variation; Splitting
    • No vacuoles
    • Inflammation
      • Perimysial & perivascular cell infiltrates
      • Variable: May occur in some muscles but not others
• Variant: Anterior tibial onset
  • Epidemiology: Spanish family
  • Dysferlin mutation: 5966delG
  • Onset: 14 to 28 years
  • Weakness: Rapidly progressive
  • Serum CK: Very high
  • Muscle: No vacuoles; Absent dysferlin
• Differential diagnosis: Calpain-3 mutation
  • Muscle CT scan: Abnormal medial head of the gastrocnemius
  • Muscle: Absent calpain-3; Normal dysferlin

Miyoshi Myopathy 2 (MMD2)

Chromosome 8q22.3; Recessive

• Epidemiology: 3 Dutch families

Gowers (Laing; Early Adult-Onset Distal Myopathy Type III; MPD1)

Myosin heavy chain 7 (MYH7); Chromosome 14q11.2; Dominant or Sporadic

• Epidemiology
  • Australian, German, Italian & Austrian families
• Genetics: MYH7 mutations
  • Types: Missense; Charge reversing
  • General location
    • LMM region
    • α-Helicoidal rod domain
    • Exons 32, 34, 35, and 36
  • Specific mutations: Arg1500Pro, Glu1508del, Lys1617del,
    Ala1663Pro, Leu1706Pro, Lys1729del, Leu1793Pro
  • Leu1793Pro: May also produce neonatal hypotonia & Cardiomyopathy
  • De novo mutations: 20% to 35%
  • Clinical correlations
    • Individual mutations may produce widely varied phenotypes
    • Severe phenotype: L1591P
  • Allelic disorders
  • May have additional TIA1 mutations
• MYH7 protein
  • Present in type I (Slow) muscle fibers
  • Predicted mutation effect: Disrupts
    • The ability of myosin tail to form normal coiled-coil structure
    • Myosin dimerization: Altered structure of the thick filament
• Clinical Features
  • Onset
    • Age
      • Common: < 5 years
      • Range: Childhood or Young adult, 1.5 to 26 years
      • Occasional: Neonatal or 6th decade
      • Interfamilial variation
    • Distal leg weakness: Steppage gait; Foot drop
    • Hypotonia
  • Weakness: Intrafamilial variation
    • Legs
      • Ankle dorsiflexion: Often severe with foot drop
      • Hanging big toe
      • Proximal muscles: Later in disease course
    • Neck: Sternocleidomastoids & Neck flexors
    • Arms
      • Extensors: Finger (esp 5th) & Wrist
      • Onset age: 3rd to 5th decade; 5 to 10 years after legs
      • Later: Infraspinatus & Supraspinatus
      • Intrinsic hand muscles: Normal
    • Later in the course: Some families
      • Hip & Shoulder abductors & external rotators
      • Face: Mild
    • Usually symmetric: Asymmetry reported
  • Muscle discomfort: Some patients
  • Muscle size: Anterior tibial usually atrophic
  • Tendon reflexes: Reduced at ankles; Present elsewhere
  • Scoliosis (50%)
  • Tremor: Hands, then postural
  • ? Peripheral neuropathy with hypomyelination: Some patients
  • Cardiomyopathy (50%)
    • Dilated, Hypertrophic or Non-compacted left ventricle
  • Course
    • Slow progression
    • Proximal weakness with disease progression
      • Legs, Abdominal muscles
    • Later ages: Mild disability
    • Life expectancy: Normal
• Laboratory
  • CK: Normal or Mild elevation to 8x high
  • EMG: Myopathic; Some spontaneous activity
  • NCV: Normal
  • Muscle Pathology
    • Myopathic: Varied fiber size; Internal nuclei
    • Type I muscle fibers: Small; Grouped; Predominance in some patients
    • Myosin heavy chain expression: Abnormal; Double positive fibers
    • Hyaline inclusions: Light green-stain on Gomori trichrome
    • Vacuoles: None in most patients; Autophagic rimmed reported
    • Cytoplasmic bodies
      • Severe, early-onset patient
      • Contents: Myotilin & Actin; Desmin+ rim
    • Intranuclear tubule-filamentous inclusions: 15 to 20 nm
    • Some muscle fibers (3%) express both fast & slow myosin
    • Distal muscles may be more abnormal
  • MRI
    • Leg: Atrophy & later Increased signal in tibialis anterior & EHL
    • Thigh: Abnormal Biceps & Semimembranosus
• MYH7 Variant: Distal myopathy with Hypertrophic cardiomyopathy ^[rx]
  • Genetics
    • Inheritance: Dominant
    • Mutation: Val606Met; Homozygous
  • Clinical
    • Later onset: 6th decade
    • Muscle hypertrophy: Anterior tibial
    • Cardiomyopathy: Hypertrophic
• MYH7 Variant: Proximal weakness & Cardiomyopathy
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous Glu1883Lys
  • Clinical
    • Weakness: Proximal
    • Cardiomyopathy: Hypertrophic
    • Pathology: Hyaline bodies in skeletal & cardiac muscle fibers

Distal Dystrophy with Rimmed Vacuoles 

Perilipin-4 (PLIN4) ; Chromosome 19p13.3; Dominant

• Epidemiology: 1 Italian family; 22 patients
• Genetics
  • Mutation
    • Large repeat insertion: 9 Extra 99-mer nucleotide repeats; In-frame
    • Coding
    • Exon 3
    • Amphipathic domain repeat expansion
• PLIN4 protein
  • Highest expression: Skeletal muscle
  • Coats: Phospholipid monolayer surrounding lipid droplets
  • Regulates: Lipid droplets
  • Absent perilipin-4: No phenotype
  • Amphipathic domain: Normal protein
    • 11-mer: Repeated 3 times; Forms a 33-mer
    • 33-mer: Repeated 29 or 31 times
  • Amphipathic domain: Mutated protein
    • 33-mer: Repeated 40 times
    • Size: Increased by 297 amino acids
  • Perilipin disorder: Other
    • Lipodystrophy, familial partial, type 4
• Clinical
  • Onset age
    • Adult; 4th to 50 years
  • Weakness
    • Early: Distal legs
    • Distribution
      • Most involved: Distal legs (Foot dorsiflexion)
      • Also: Neck flexion; Wrist & Finger extensors; Scapular
    • Progression
      • Variable: Asymptomatic to Severely disabled
      • Respiratory failure: Rare
• Laboratory
  • Serum CK: Normal, or Mildly elevated (Up to 4x)
  • EMG: Myopathic; High-frequency discharges
  • NCV: Normal
  • Cardiac: Normal
• Muscle pathology ^[rx]
  • Fiber size: Varied, atrophy & hypertrophy
  • Internal nuclei
  • Necrosis
  • Focal phagocytosis of muscle fibers
  • Rimmed vacuoles
    • Mainly in hypertrophic muscle fibers
    • Located near fiber surface
    • Contents: Basophilic granular material
    • Lysosomal features
      • Acid phosphatase positive: Around vacuoles
      • LAMP-1 & LAMP-2 negative
      • LIMP-I on the surface of vacuoles & fibers
  • Inclusions
    • Sarcoplasmic: p62; FK2; Perilipin-4
  • Muscle Western blot: 2 PLIN4 bands, Normal & Increased sizes

Hereditary Inclusion Body Myopathy (IBM1; HIBM1) Dominant

Desmin; Chromosome 2q35; Dominant

• Nosology
  • Originally identified as HIBM1
  • Desmin mutations found: Myofibrillar myopathy
• Clinical
  • Onset: Adult; 25 to 40 years
  • Weakness
    • Quadriceps early
    • Distal: Foot Dorsiflexion
    • Proximal: After disease progression
  • CNS involvement: Some families
  • Progression: Slow
• Laboratory
  • Serum CK: Normal or Mildly increased
  • Pathology
    • Red rimmed vacuoles: Prominent on GT stain
    • Multifocal myopathic changes
      • Myopathic fascicles: Variation in fiber size; Endomysial fibrosis
      • Vacuoles more common in myopathic fascicles
    • ± Inflammation
• Also see: Other IBM
  • Inclusion body myositis, Sporadic: Wrist & Finger flexors & Quadriceps weakness
  • IBM2: Sporadic or Recessive; GNE; Chromosome 9p12; Distal weakness
  • IBM3: Joint contractures & ophthalmoplegia: Myosin heavy chain IIa; Chromosome 17p13; Dominant; Proximal weakness
  • IBM + Paget’s & Dementia: VCP; Chromosome 9p13; Dominant; Proximal & Distal weakness
  • SQSTM1: 5q35; Dominant or Sporadic
  • Differential diagnosis of rimmed vacuoles

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2; VCPDM)

• Matrin 3 (MATR3); Chromosome 5q31.2; Dominant
• Epidemiology: North American, German & Bulgarian families
• Genetics ^[rx]
  • Mutation: Ser85Cys
  • Allelic disorders
    • Familial ALS 21, Dominant
    • Fronto-Temporal Dementia
      • Mutation: Retrotransposed Full-Length Transcript of Martin-3 Variant 5
• Martin 3 protein ^[rx]
  • Cell location
    • Nuclear matrix
    • The inner face of the nuclear envelope
    • May move to the cytoplasm in diseased cells
  • Tissue expression: Muscle & Other tissues
  • Contains RNA-DNA binding motif
  • Interacts with
    • Proteins: TDP-43; DHX9
    • DNA sequences: Repetitive; Adenine/Thymine-rich
    • RNA: RNA stabilized by MATR3 binding
    • Self-association
  • Functions
    • Transcriptional control
    • DNA repair
    • Stabilizes mRNA encoding Rad51
• Clinical
  • Onset
    • Age: 30 to 57 years; Average 46 years
    • Weakness: Legs (Anterior & Distal); Occasionally Hands or Voice
  • Weakness
    • Initially asymmetric; May become symmetric
    • Legs > Arms
      • Peroneal distribution
      • May also involve inversion
      • Gastrocnemius: Relatively spared
    • Hands
      • Different finger extensors: Variable weakness
      • Abductor policis brevis: Early
    • Proximal
      • Shoulder weakness: Especially deltoid
      • Asymmetric
    • Respiratory: < 86% of expected in 60%
  • Bulbar dysfunction
    • Voice (65%)
      • Onset usually after limb weakness
      • Initially: Hypophonic & Breathy
      • Later: Wet, gurgling, hoarse; Hypernasal resonance
    • Pharyngeal: Dysphagia & Aspiration
  • Tendon reflexes: Brisk; Absent at ankle
  • Course
    • Slowly progressive
    • Respiratory failure: After 1 to 2 decades
  • Serum CK: Normal to 8x High
  • EMG
    • Myopathic (especially pharynx & vocal cords)
    • Neuropathic: Spontaneous activity; Complex repetitive discharges
  • Nerve conductions: Normal or Mildly slowed
  • MRI: Fat replacement
    • Leg: Soleus & Medial gastroc
    • Thigh: Posterior, Semimembranosus
    • Paraspinal (50%)
    • Asymmetric in some
  • Muscle pathology
    • Myopathic: Gastrocnemius > Quadriceps
    • Fiber size: Varied
    • Internal nuclei
    • Rimmed vacuoles: Subsarcolemmal; Often elongated
    • Myonuclei
      • ? Variable staining
      • Aggregates: Perinuclear, Cytoplasmic
    • Ultrastructure
      • Absent perinuclear sarcomeres
      • Nuclei: Abnormal invaginationsLaboratory
• MATR3 variant syndrome: Amyotrophic Lateral Sclerosis (ALS), Familial 21 (ALS21) ^[rx]
  • Epidemiology: Sardinian & British families
  • Genetics
    • Inheritance: Dominant
    • Mutations: Missense; Phe115Cys, Thr622Ala, Pro154Ser; Ser85Cys; Ser707Leu
    • Allelic with: Distal myopathy with Vocal Cord & Pharyngeal Weakness (MPD2)
  • MATR3 protein
  • Clinical: Amyotrophic Lateral Sclerosis
    • Onset age: 4th to 8th decade
    • Weakness: Asymmetric; Arms & Legs; Dysarthria; Respiratory
    • Muscle atrophy: Distal > Proximal
    • Fasciculations
    • Tendon reflexes: Brisk
    • Cognitive disorders: Some patients (Phe115Cys, Ser707Leu)
    • Course
      • Death < 6 years
      • Common: Rapidly progressive
      • Ser85Cys: More slowly progressive
  • Pathology
    • Normal neurons: Nuclear, granular
    • Disease: c9orf72 ALS = Cytoplasmic

HEREDITARY INCLUSION BODY MYOPATHY (HIBM) + PAGET DISEASE (IBMPFD)

Inclusion Body Myopathy with Paget disease of Bone & Dementia 1 (IBMPFD1)

Valosin-containing protein (VCP, p97); Chromosome 9p13.3; Dominant

• Nosology: Multisystem proteinopathy 1 (MSP1)
• Epidemiology
  • Worldwide: > 70 families
  • Male = Female
• Genetics ^[rx]
  • Mutations
    • Missense
    • > 60 different
    • Several involve same amino acid residue
  • Locations
    • N-terminal: Exons 1 to 6; N-, L1, or D1-ATPase domains
    • Arg95G; Ile126Phe; P137L; Arg155C; Arg155H; Arg155Leu; Arg155P; Arg155S;
      G156S; G157Arg; R159H; Leu198Trp; Arg191Gln; A232E; A439S
  • Clinical genetic correlations
    • R155C: Frontotemporal dementia with intraneuronal inclusions
    • Arg159His: Interfamily variability
      • Onset age: Later for myopathy
      • Bone disease: Uncommon
      • Some families: No dementia, Milder disease ^[rx]
      • Other families: Patients may present with frontotemporal dementia ^[rx]
      • Pathology
        • Ubiquitin+ intranuclear inclusions & Dystrophic TDP-43+ neurites
    • A232E: Fractures & Paget disease at earlier age
  • Homozygous mutation: Arg159His
  • Allelic with
    • ALS, Familial 14 ± FTD (9%)
    • Familial Spastic Paraparesis
    • Distal myopathy + Dementia
    • CMT 2Y
    • Demyelinating neuropathy
    • Parkinson disease (4%)
    • Cardiomyopathy
• VCP protein
  • Locations: Ubiquitous
  • Functions
    • Protein degradation pathways (Autophagy): Regulatory role
    • Cell cycle & Membrane fusion
    • Segregates ubiquitinated protein complexes
  • Binds ubiquitin
  • AAA ATPase
  • Chaperone
  • Expression: Most tissues
  • Aggregate-related
    • Associates with aggregate prone polyglutamine containing proteins
    • Present in inclusions from ALS, Parkinson’s disease & Huntington disease
  • Mutated protein ^[rx]
    • Causes increased levels of ubiquitinated cell proteins
    • Sensitization to proteasome stress
    • Impairs endoplasmic reticulum-associated degradation (ERAD) of proteins
    • Promotes formation of aggregates
      • Contain p97/ VCP, ubiquitin conjugates & ER-resident proteins
      • Impaired protein aggregate clearance
    • Upregulation of autophagy-related proteins
    • Normal: Polymerization into hexamers; ATPase activity
• Clinical ^[rx]
  • Intrafamilial variability: Prominent
  • Onset
    • 3rd & 4th decade
    • Variable: Back pain; Weakness; Dementia
  • Myopathy: Weakness (90%)
    • Onset
      • Ages: Mean 43 years; Range 3 to 66 years
      • Presenting symptom in > 50%
    • General: Marked variability in severity & pattern within families
    • Legs: Distal & Proximal
    • Arms: Proximal & Distal
    • Respiratory
      • Often involved: Vital capacity 29% to 70%
      • Failure: With disease progression
    • Scapular winging: Supraspinatus & Infraspinatus weakness
    • Other regions: Some patients
      • Cranial nerves: Face (50%); Tongue
      • Posterior neck: Head ptosis
      • Back: Camptocormia
      • Dysphagia (22%)
      • Finger flexion
      • Ophthalmoplegia: 1 family (R155S)
    • Asymmetric: Often
    • Progression
      • Slow: Over 1 to 2 decades
      • To severe disability
        • Severe weakness: Common
        • Loss of independent walking in 13 years
      • Death in 5th to 7th decade
  • Bone disease (42%)
    • Paget disease  (43% to 49%)
      • Spine: Most common lesion location
      • Other lesion locations: Hip; Skull; Pelvis
      • Pain
      • Onset: Mean 42 years; Range 29 to 61 years
      • External link: Paget disease
    • Skeletal: Lumbar lordosis
  • Dementia (30% to 37%)
    • Onset
      • Mean 52 to 55 years; Range 30 to 86 years
      • Usually after Paget’s or Myopathy
    • Frontotemporal (Behavioral variant)
      • Language: Anomia; Aphasia; Mutism
      • Personality change: Apathy; Agitation
      • Hallucinations: Visual; Auditory
      • Relatively preserved memory
  • Cardiomyopathy: Occasional
    • Heart failure late in disease course
    • Dilated
    • Amyloid may be present
  • Sensation: Normal
  • Other: Occasional
    • Hepatic disorders
    • Cataracts
    • Polyneuropathy: Sensory-Motor
    • Motor neuron loss
    • Parkinsonism
• Laboratory
  • Serum CK: Normal (80%), or Mildly increased (400 to 1165)
  • Serum Alkaline phosphatase: High with Paget disease
  • EMG: Variable
    • Myopathy: Small amplitude, Polyphasic Brief motor unit potentials
    • Spontaneous activity: Fibrillations; Positive sharp waves
    • Chronic denervation: Some patients
  • NCV: Normal
  • Muscle biopsy
    • Fiber sizes
      • Varied
      • Atrophy: Regional or Grouped; Some angular fibers, scattered
      • Hypertrophy: Scattered muscle fibers
    • Endomysial connective tissue: Patchy Increased
    • Vacuoles: Rimmed
    • Aggregates
      • VCP staining inclusions: Sarcoplasmic & Myonuclear
      • Other aggregates: TDP43; p62
    • MHC-I on muscle fibers: Varied
    • Ultrastructure: Tubulofilamentous inclusions
  • Muscle MRI: Widespread changes including axial muscles
  • Echocardiogram: Cardiomyopathy (Late)
  • Radiology: Paget disease of bone
  • Brain pathology
    • Cortical atrophy
    • Inclusions: Intranuclear; Ubiquitin & TDP-43 positive
• VCP Variant syndrome: ALS, Familial 14 ± FTD (FTDALS6; ALS 14 ) ^[rx]
  • Epidemiology: 1% to 2% of Familial ALS
  • Genetics
    • Dominant or Sporadic
    • VCP Mutations: Ile151Val; R155H; R159G; R191Q; D592N
  • Clinical
    • Onset
      • Age: 4th to 6th decade
      • Weakness: More commonly in legs
    • Upper motor neuron
      • Spasticity: Arms & Legs
      • Bulbar: Dysarthria; Dysphagia
      • Tendon reflexes: Brisk, including jaw jerk
    • Lower motor neuron signs
      • Atrophy
      • Weakness: Patterns not well described
      • Respiratory failure
    • Progression: Variable
      • Respiratory failure
      • Death: 1 to 12 years
    • May also have VCP multisystem disease
      • Dementia
      • Paget
      • Myopathy
  • Laboratory
    • EMG: Denervation & Reinnervation
      • Fibrillations
      • Fasciculations
    • Serum CK: Normal to 900
    • Brain pathology
      • Corticospinal tract pallor
      • Ubiquitin-positive inclusions in surviving neurons
      • TDP43 or p62 (SQSTM1) aggregates
      • tau (MAPT ) aggregates: D395G mutation (601023.0014)
• VCP Variant syndrome: Distal myopathy + Dementia ^[rx]
  • Epidemiology: Finnish family
  • VCP mutation: P137L
  • Clinical
    • Onset
      • Age: > 35 years
      • Leg weakness
    • Weakness: Distal, anterior legs
    • Dementia: Onset > 50 years
    • Paget disease: 1 patient
  • Muscle pathology (Anterior tibial)
    • Myopathic
      • Endomysial fibrosis
      • Atrophy
      • Hypertrophy
      • Ring fibers
    • Vacuoles, rimmed: Some staining for TDP-43 or p62
• VCP Varant syndrome: Progressive spastic paraplegia + Paget’s disease of bone ^[rx]
  • Epidemiology: Dutch family
  • VCP mutation: Arg159Cys
  • Clinical
    • Onset
      • Age: 5th to 6th decade
      • Gait disorder
    • Spastic paraparesis
      • Tendon reflexes: Increased in legs
      • Spasticity: Legs
    • Weakness: Distal legs (Anterior tibial)
    • Tongue fasciculations: 1 patient
    • Paget’s disease of bone
    • Cognition: Normal
    • Course
      • Progressive to wheelchair over 10 years
      • Survival: > 2 decades
  • Laboratory
    • Alkaline phosphatase: High
    • EMG: Denervation
• VCP Variant syndrome: CMT 2Y Sensory-Motor neuropathy
  • Epidemiology: 1 family
  • VCP genetics
    • Mutation: Gly185Lys
    • Inheritance: Dominant
  • Clinical
    • Onset age: 1st to 6th decade
    • Weakness: Distal; Legs > Arms
    • Sensory loss: Distal; Legs > Arms; Panmodal
  • Laboratory
    • NCV
      • CMAP & SNAP amplitudes: Reduced
      • Velocities: Normal
• VCP Variant syndrome: Demyelinating Neuropathy ^[rx]
  • Epidemiology: 1 patient, others in family with ALS or IBM
  • Genetics
    • Mutation: Arg191Gln in family, patient not studied
  • Clinical
    • Onset age: 6th decade
    • Weakness: Diffuse, Arms & Legs
    • Sensory loss: Vibration
    • Tendon reflexes: Absent
    • Cardiomyopathy
  • Laboratory
    • NCV: DL prolonged; CV 25 to 39 M/s; F-waves absent
    • Nerve biopsy: Schwann cells with intranuclear ubiquitin; No demyelination
    • CSF: Normal
    • Serum CK: Normal
• VCP allelic disorder: VCP homozygous mutation ^[rx]
  • Epidemiology: Belgian male
  • Genetics
    • Mutation: Homozygous; Arg159His
    • Families (Heterozygous): Myopathy; Parkinsonism; Dementia
  • Clinical
    • General: May be similar severity to heterozygotes
    • Onset age: 29 years
    • Weakness
      • Limb-Girdle
      • Distal legs
      • Legs > Arms
      • Periscapular
      • Paraspinal
    • Muscle wasting: Legs
    • Paget disease of bone
  • Laboratory
    • Serum CK: 1100
    • Muscle
      • Rimmed vacuoles
      • Endomysial macrophages
      • Necrosis & Regeneration
      • MHC1: Patchy increase
    • EMG: Mixed myopathy & Neuropathy
    • MRI: Asymmetric, patchy involvement; Paraspinal & Legs
    • Bone: Paget lesions

Myopathy with Paget disease of Bone ± Cognitive change or Motor Neuron Disease (IBMPFD2) ^{[rx], [rx]}

Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) ; Chromosome 7p15.2; Dominant

• Nosology: Multisystem proteinopathy 2 (MSP2)
• Epidemiology: 1 US family, 5 patients
• Genetics
  • Mutation: Missense; D290V/D302V; Located in prion-like domain
  • Allelic disorder: Paget disease of Bone, P310L mutation
• HNRNPA2 protein
  • Most abundant isoform of hnRNPA2B1
  • Localization: Nucleus > Cytoplasm (mRNP granules containing untranslated mRNAs)
  • RNA binding
  • Contains: Prion-like domain
  • Essential for assembly of ribonucleoprotein granules
  • Tends to assemble into self-seeding fibrils: Exacerbated by disease mutations
  • Recruited to stress granules
• Clinical
  • Onset age: 3rd to 5th decade
  • Myopathy (100%)
    • Weakness
      • Legs: Distal, Ankles & Toes
      • Upper extremity: Proximal; Scapular winging
    • Muscle atrophy
    • Slowly progressive
  • Paget disease of bone (100%)
    • May be severe & widespread
    • Location: Long bones
  • Cognitive disorders (40%)
  • Motor neuron disease (40%)
    • Weakness
    • Rapidly progressive
• Muscle pathology
  • Fiber size: Varied; Atrophic groups
  • Internal nuclei
  • Increased endomysial connective tissue
  • Vacuoles: Rimmed
  • TDP-43 inclusions
  • Muscle fiber degeneration & Regeneration: Occasional
• Laboratory
  • Radiology: Paget disease of bone
  • EMG: Myopathic
  • Serum CK: High or Normal; May become normal with progressive disease
  • Serum Alkaline phosphatase: High
  • Serum Osteocalcin: High in some patients

Myopathy (IBM) with Paget disease of Bone without Dementia (IBMPFD3)  ^[rx]

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1); Chromosome 12q13.13; Dominant

• Nosology: Multisystem proteinopathy 3 (MSP3)
• Epidemiology: German family
• Genetics
  • Mutations: Missense; D262V/D314V; Located in prion-like domain
  • Allelic disorders
    • ALS20 & Motor syndromes
    • IBM + Paget without Dementia 3
• HNRNPA1 protein
  • Localization: Nucleus & Cytoplasm
  • Ribonuclear proteins & Disorders
  • Contains: Prion-like domain (PrLD)
    • Enriched in uncharged polar amino acids & glycine
    • Other proteins with PrLD
      • TDP-43: ALS 10
      • FUS: ALS 6
      • EWSR1: ALS, Sporadic
      • TAF15: ALS, Sporadic
      • HNRNPA2B1: Myopathy + Pagets ± Motor neuron disease or Cognitive disorders
      • TIA1: Welander distal myopathy
      • HNRNPA1: IBMPFD3
  • Involved in
    • RNA binding
    • Packaging of pre-mRNA into hnRNP particles
    • Transport of poly(A) mRNA from nucleus to cytoplasm
  • Essential for assembly of ribonucleoprotein granules
  • Tends to assemble into self-seeding fibrils: Exacerbated by disease mutations
  • Recruited to stress granules
• Clinical ^[rx]
  • Onset
    • Childhood: Clumsy
    • Weakness: 35 to 43 years
  • Myopathy (100%)
    • Early: Proximal legs; Iliopsoas
    • Foot dorsiflexors
    • Abdominal wall
    • Arms: Usually spared
    • Scapular winging: Slight
    • Progressive: Wheelchair in 5th or 6th decade
  • Paget disease (50%)
  • Cognition: Normal
• Muscle pathology
  • Fiber size: Varied
  • Internal nuclei
  • Vacuoles: Rimmed
  • TDP-43 inclusions
• Laboratory
  • Serum CK: 225 to 1250
  • Alkaline phosphatase: Normal to 8x high
• HNRNPA1 Variant syndrome: Motor neuron disease only (ALS20)
  • Nosology: ALS19 or ALS20
  • Epidemiology: 2 Families & 1 Simplex patient
  • Genetics
    • Inheritance: Dominant
    • Mutations
      • Family: Same as myopathy (D262V/D314V)
      • Single ALS patient: N267S/N319S
      • Flail arm: c.862/1018C>T (p.P288S/P340S)
  • Clinical
    • Onset age: Adult
    • Motor neuron syndromes
      • ALS-like
      • Flail-arm syndrome
        • Muscle wasting & weakness: Distal or Proximal; Arms > Legs
        • Also: Bulbar features, Dysphagia, Dysarthria
        • Tendon reflexes: May be brisk
        • Course: Slow progression (3 decades)
      • Scapuloperoneal SMA
    • Other CNS: Normal
  • Electrodiagnostic
    • EMG: Ongoing & Chronic denervation
    • NCV: Normal

Myofibrillar Myopathy with Early Respiratory Failure (MFM9; HIBM-ERF; HMERF; ADMERF)

Titin (TTN)  Chromosome 2q31.2; Dominant or Sporadic

• Nosology
  • Hereditary IBM with Early Respiratory Failure
  • Distal myopathy with Early Respiratory Failure
  • Myofibrillar myopathy with Early Respiratory Failure
  • Edstrom myopathy
  • Myopathy with Proximal Weakness, Early Respiratory Failure & Cytoplasmic aggregates
  • Necklace body myopathy
• Epidemiology: > 30 families
• Genetics
  • TTN mutations
    • Missense
      • Common: Cys31712Arg; Cys30071Arg (British founder mutation)
      • Other: W30088 (Hotspot); P30091L; N30145K; G30150 (Hotspot); R32450W
    • Location: Myosin binding (Fibronectin; FN3 119 domain) A-band; Exons 343-344
    • Commonly private
    • May be de novo
• Titin protein
• Clinical
  • Onset: Variable
    • Age: 12 to 71 years; 4th & 5th decade most common; Mean 35 to 42 years
    • Weakness
      • Legs: Most common
      • Patterns: Symmetric; Foot dorsiflexion; Respiratory; Proximal
  • Weakness: Variable patterns
    • Patterns
      • Distal 30%
      • Proximal 40%
      • Other 30%: Distal + Proximal
      • Legs > Arms
    • Legs: Distal & Proximal; Anterior tibial
    • Arms: Wrist flexion & extension; Deltoid; May be diffuse
    • Trunk: Severe weakness common
    • Neck flexors
    • Ankle extension: Strong
    • Face: Mild in some patients
    • Symmetric (90%)
    • Progression
      • Slow
      • Cane & occasionally wheelchair needed after 5 to 15 years
      • Weakness: Proximal legs; Shoulders; ? Quadriceps sparing
      • Nocturnal non-invasive ventilatory support
  • Respiratory failure
    • VC & FEV1 < 75% of predicted in most patients at presentation
    • Course: Progressive
  • Muscle hypertrophy: Posterior leg (Calf)
  • Contractures: None
  • Cardiac
    • Conduction Δ (32%)
    • Mild cardiomyopathy (18%)
• Laboratory
  • Serum CK: 65 to 966
  • EMG: Myopathic; Irritable
  • Nerve conduction studies: Normal
  • MRI: Muscle
    • Proximal legs
      • Selective early involvement: Semitendinosus & Obturator externus
      • Proximal more than distal involvement in individual muscles
      • Adductor longus spared
    • Distal legs
      • Most involvement: Antero-Lateral; Tibialis anterior
      • Relative sparing: Gastrocnemius & Soleus
    • Shoulder girdle
      • Moderate involvement: Supraspinatus, Infraspinatus, Serratus anterior, Subscapularis & Trapezius
• Muscle pathology
  • Fiber size: Varied
  • Myofibrillar pathology: Cytoplasmic aggregates
    • Contain: Actin; Desmin
    • In type I muscle fibers
    • Myofibrillar pathology
    • Not typical Cytoplasmic bodies
  • Eosinophilic inclusions
    • Congophilic
    • Variably contain: β amyloid, desmin, SMI-31 binding
  • Cytoplasmic bodies (95%)
    • Stain for F-actin (Phalloidin)
    • “Necklace” pattern in muscle fibers ^[rx]
  • Muscle fiber splitting: With more severe weakness
  • Vacuoles (50%): Rimmed, blue; With more severe weakness
  • Fiber types: Type 1 predominance (50%)
  • Internal nuclei
  • No necrosis or inflammation
  • Calpain-3: Reduced on Western blot
  • Ultrastructure
    • Z-line streaming
    • Thin filaments & Dense material related to Z-discs

Myopathy with Ringed muscle fibers ^[rx]

• Inheritance: Sporadic
• Clinical features
  • Onset: 3rd decade
  • Weakness: Proximal (quadriceps) + Ankle dorsiflexion
  • Progression: Moderate 1 to 5 years
• Lab
  • Serum CK: Normal
  • EMG: Irritable myopathy
• Muscle Pathology
  • Myopathic: Fiber size variation; Increased connective tissue; Central nuclei
  • Rings in fibers: Outer sarcoplasmic pad; Middle annular myofibrils; Center normal

Distal Myopathy: MPD3  ^[rx]

Autosomal Dominant

• Genetics: Two possible loci 8p22-q11 & 12q13-q22
• Epidemiology: Single Finnish family
• Onset
  • Age: 32 to 45 years
  • The clumsiness of hands or legs
• Weakness
  • Legs
    • Distal
    • Anterior & Posterior
    • Muscles involved: TA, EDL, Gastrocnemius, Gluteus medius; TFL
  • Arms: Hands
    • Distal
    • Abductor pollicis; Opponens policis; 1st Dorsal interossei; Abductor digiti minimi
  • Asymmetric
  • Intrafamilial variability
  • Course: Progressive
    • Over years
    • To more proximal limbs: Forearm, Triceps, Infraspinatus, Proximal legs
    • Patients remain ambulatory
• Laboratory
  • EMG: Myopathic
  • Serum CK: Normal or Slightly elevated
• Muscle biopsy
  • Myopathy: Severe; Endomysial fibrosis; Fiber size variation
  • Rimmed vacuoles
  • Cytoplasmic inclusion bodies

Distal myopathy with spared anterior leg muscles (William’s myopathy) (MPD4)  ^[rx]

Filamin C (Filamin 2; FLNC) ; Chromosome 7q32.1; Dominant

• • Epidemiology: Australian & Italian families
  • Genetics
    • Missense mutations
      • In actin-binding domain
      • Met251Thr, Ala193Thr
    • Allelic with
      • Myofibrillar myopathy
      • Distal myopathy with upper limb predominance
  • Filamin C protein
  • Clinical
    • Variable within the family: Some affected members are asymptomatic
    • Onset
      • Age: 0 to 30 years
      • Weakness
      • Muscle discomfort
    • Weakness
      • Symmetric
      • Distal
      • Arms + Legs
        • Arms: Forearm pronators, Finger flexors, Intrinsic hand muscles
        • Legs: Ankle evertors, Plantar-flexors (Calf atrophy)
          • Differential diagnosis: LGMD 2B
      • Sparing: Anterior leg; Posterior arm
    • Muscle wasting: Distal
    • Discomfort
      • Type: Cramps; Deep pain
      • Worse after exercise
    • Tendon reflexes: Absent at ankles
    • Systemic
      • Cardiomyopathy: 2 patients
      • No respiratory involvement
    • Course
      • Slowly progressive
      • Patients remain ambulatory
  • Laboratory
    • Serum CK: Normal or Mildly elevated
    • EMG: Myopathic
    • MRI
      • Involvement of posterior & lateral leg muscles
      • Some asymmetry
    • Muscle
      • Varied fiber size: Small angular fibers
      • Internal architecture: Irregular in some biopsies
      • No myofibrillar aggregates, vacuoles or inflammation
      • Dysferlin normal

• FLNC variant syndrome: Distal myopathy with upper limb predominance ^[rx]
  • Epidemiology: Bulgarian families, 13 patients
  • FLNC mutations
    • Stop: c.5160delC frameshift deletion; p.Phe1720Leufs*63
    • Missense: Actin binding domain; p.Ala193Thr, p.Met251Thr
    • Mechanisms: Haploinsufficiency of filamin C
    • Inheritance: Dominant
    • Penetrance: Partial
  • Clinical
    • Onset
      • Age: 20 to 54 years
      • Weakness: Fingers
      • Walking difficulty: Steppage gait
    • Weakness
      • Distal > > Proximal
      • Arms before Legs in some
      • Finger extensors & Interossei
    • Atrophy: Distal arms & legs
    • Sensory: Loss in 40%
  • Other
    • Pes cavus (20%)
    • Hypertension (30%)
    • Cardiomyopathy (10%)
  • Laboratory
    • Serum CK: Normal to 6x high
    • NCV: CMAP amplitude reduced
    • EMG: Myopathic
    • Muscle
      • Varied fiber size
      • Necrosis
      • Pyknotic nuclear clumps
      • Type I predominance
      • No or Few myofibrillar aggregates
      • Ultrastructure: Myofibrillar disorganization

Distal nebulin myopathy ^[rx]

Nebulin; Chromosome 2q23.3; Recessive

• Genetics
  • Mutations: Missense; Often homozygous
  • Different from Rod myopathy in which at least 1 mutation causes protein termination
  • Allelic with: Rod myopathy
• Clinical
  • Onset age: Child or Adult
  • Weakness: Similar to MPD1 (Gowers-Laing myopathy)
    • Distal
    • Hanging big toe sign
    • Extensor finger weakness: Index finger spared
    • Neck flexors
  • Slender stature
• Muscle
  • Rods: None or Small
  • Ultrastructure: Z-line streaming; Minor rod changes

Distal Myopathy 5 (MPD5; Rod Myopathy)

Adenylosuccinate synthase-like 1 (ADSSL1); Chromosome 14q32.33; Recessive

• Epidemiology
  • Korean & Japanese families
  • Japan: Most common nemaline rod myopathy ^[rx]
• Genetics
  • Mutations: Compound heterozygous; D304N (c.910G>A), I350fs (c.1048delA), L407P (c.1220T>C)
  • Common in Japan: c.781G>A; c.919delA
• ADSSL1 protein
  • Location: High in skeletal muscle
  • Muscle isozyme of adenylosuccinate synthase
  • Conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP): Catalyzes initial reaction
• Clinical
  • Onset age: 5 to 8 years
  • Weakness
    • Early: Diffuse
    • Distal > Diffuse
    • Legs > Arms
    • Quadriceps: 4th decade
    • Face: Common
    • Neck
    • Dysphagia (38%)
    • Respiratory
  • Muscle size: Mild atrophy
  • Sensory: Normal
  • Disease course: Slow progression; Remain ambulant
  • Cardiomyopathy, Hypertrophic
• Laboratory
  • Serum CK: 108 to 493
  • Muscle MRI
    • Lower extremity
      • General: Hyperintense signal in lower leg muscles
      • Posterior > Anterior
      • Thigh
        • Vastus lateralis (Periphery), Adductor, Biceps femoris
        • Quadriceps: Involved later
        • Spared: Rectus femoris; Sartorius; Semitendinous
      • Leg: Soleus; Gastrocnemius
    • Tongue & Masseter: Fat replacement
    • Trunk: Neck & Upper thoracic
  • Muscle pathology
    • Fiber size: Varied
    • Internal architecture: Internal nuclei; Splitting
    • Rimmed vacuoles (50%): Few fibers
    • Endomysial connective tissue: Increased
    • Type I fiber predominance:? Fiber type groups
    • ADSSL1 expression: Absent or Reduced
    • Nemaline rods [^rx]
    • Lipid droplets (Type 1 fibers)

Cystinosis, Nephropathic

Cystinosin (CTNS) ; Chromosome 17p13.2; Recessive

• Genetics: Mutations
  • General: Missense & Stop
  • French-Canadians: 57-kb deletion
• CTNS protein
  • Lysosomal membrane
• Clinical
  • Frequency ^[rx]
    • 30% to 40% of patients with cystinosis
    • Similar frequency in patients with & without cysteamine treatment
  • Onset
    • Age: 1st year to Adult
    • Failure to thrive: 1st year
  • Skeletal
    • Short stature
    • Frontal bossing
    • Hypophosphatemic rickets
    • Contractures (15%): Hands
  • Eyes: Retinopathy; Corneal cysteine crystals
  • GI: Not frequent
    • Hepatomegaly; Pancreatic insufficiency; Splenomegaly
    • GI complaints related to Cysteamine treatment: Treat with protein pump inhibitor
  • Renal
    • Fanconi syndrome
    • Renal failure: Transplant often necessary
  • Endocrine
    • Hypothyroidism, Primary
    • Diabetes mellitus: Insulin-dependent
    • Delayed puberty
  • Skin
    • Hypohidrosis
    • Light hair pigmentation
  • Cardiac: Coronary artery calcifications
  • Muscle
    • Weakness
      • Distal > Proximal
      • Hands (Thenar & Hypothenar; Grip) > Feet
      • Proximal muscles involved: Neck flexion; Arm abduction; Hip flexion
      • Dysphagia (30% to 60%)
      • Respiratory
      • Face (10%)
    • Wasting
  • CNS: Visuo-spatial processing defect
  • Treatment
    • Replacement of renal losses
    • Cystine-depleting agents: Cysteamine
• Laboratory
  • Diagnosis: Leukocyte cystine measurement
  • Urine: Proteinuria; Glucosuria; Microscopic hematuria
  • Blood: Hyponatremia; Hypokalemia; Hypophosphatemia; Hyperlipidemia
  • Carnitine deficiency
  • Aminoaciduria, Generalized
  • White blood cell cystine: Elevated
  • Brain: Cerebral atrophy
• Muscle pathology
  • Muscle fiber size: Varied
  • Vacuoles: Rimmed; Mildly acid phosphatase positive
  • Aggregates: AMPDA+

Distal weakness, Early-onset ^[rx]

Kelch-like homologue 9 (KLHL9) ; Chromosome 9p22; Dominant

• Nosology: Maybe distal myopathy or predominantly motor neuropathy
• Epidemiology: German family
• Genetics
  • Mutation: Missense; L95F
• KLHL9 protein
  • Complexes with Culllin 3
  • Ubiquitin-dependent protein degradation pathway
• Clinical
  • Onset age: 8 to 16 years
  • Weakness
    • Hands: Intrinsic muscles
    • Legs: Distal
    • Proximal: Normal
  • Atrophy: Anterior tibial
  • Contractures: Ankles
  • Sensory loss
    • Distal
    • Arms & Legs
    • Later in disease course
  • Course
    • Very slow progression
    • Remain ambulant
• Laboratory
  • Serum CK: 110 to 1400; Usual 150 to 260
  • NCV
    • Motor: Velocities normal; Distal latency occasionally long
    • Sensory: Normal
  • EMG: Distal fibrillations & Polyphasic large potentials
  • Muscle biopsy: Varied fiber size
  • MRI: Atrophy of distal leg muscles

dHMN: Distal Weakness, Hoarseness, Hearing loss (PNMHH)

Myosin heavy chain 14, non-muscle (MYH14) ; Chromosome 19q13.33; Dominant

• Epidemiology: Korean & North American families
• Genetics
  • Mutation: Missense; Arg941Leu (c.2822G>g;T); In tail domain
  • Allelic with: Deafness, autosomal dominant 4 (DFNA4)
  • Contains microRNA, miR-499
• MYH14 protein
  • Myosin: Non-muscle
  • Locations: Heart, Slow muscles, Extraocular (EO) muscles; GI tract; Renal
  • Myosin disorders
• Clinical
  • Onset age: 4 to 23 years
  • Weakness
    • Distal: Occasionally also proximal
    • Legs > Arms
    • Symmetric
    • Slow progression over decades
  • Hoarseness (50%)
  • Sensory loss: None
  • Tendon reflexes: Variable
  • Foot deformity (50%)
  • Hearing loss (30% to 100%): Onset after weakness
  • Cardiac: Normal
• Laboratory
  • Serum CK: Normal to mildly high (< 2.5-fold high)
  • EMG: Denervation, More distal
    • Fibrillations
    • Motor unit potentials: Large
    • Recruitment: Reduced
  • NCV
    • Velocities: Normal
    • CMAP amplitudes: Small
    • SNAPs: Normal
  • Muscle biopsy
    • Fiber type grouping
    • Grouped atrophy
    • Ultrastructure: Abnormal mitochondria; Paracrystalline inclusions

Intellectual Disability

NOL1/NOP2/SUN domain family, member 2 (NSUN2); Chromosome 5p15.31; Recessive

• Epidemiology: Pakistan & Iran families
• Mutation: Homozygous; Missense; Gly679Arg
• NSUN2 protein
  • RNA Methyltransferase
  • Catalyzes the formation of 5-methylcytosine at C34 of tRNA-leu(CAA)
  • Role in spindle assembly during mitosis & chromosome segregation
  • Localization: Nucleolus
• Clinical
  • CNS
    • Intellectual disability
    • IQ: 40 to 50
    • Developmental delay: Motor; Speech
  • Upper motor neuron
    • Muscle tone: Increased
    • Tendon reflexes: Brisk
  • Morphology
    • Face: Long; Pointed nose & chin
    • Microcephaly
    • Fingers: Tapering
    • Height & Weight: Low
    • Feet: Pes cavus; Abnormal toe separation
  • Strabismus
  • Distal myopathy: Not well documented
• Laboratory
  • Head CT: Normal
  • Serum CK: Mildly high in 2 patients

Myopathy/Neuropathy ^[rx]

DNAJ/HSP40 homolog, subfamily B, member 5 (DNAJB5); Chromosome 9p13.3; Dominant

• Epidemiology: 1 patient
• Genetics
  • Mutation: p.P15S
• DNAJB5 protein
  • DNAJ family
  • Other DNAJ disorders
• Clinical
  • Onset age: 20 years
  • Myoclonus
  • Muscle
    • Weakness
    • Atrophy: Distal
• Laboratory
  • NCV: Median motor 52 m/sec; Median CMAP 6 mV
  • EMG: Spontaneous activity; Motor units small or large

Syndromes with Neuropathy & Myopathy

• Systemic disorders
  • Paraneoplastic (with weight loss > 15%)
    • Neuropathy: Distal; Sensory > Motor
    • Myopathy: Proximal with type II muscle fiber atrophy
  • Metabolic
    • Uremia
    • Acromegaly
  • Immune
    • Collagen vascular disorders: Sjögren
    • Sarcoid
    • Graft vs Host disease
    • HIV Infection
      • Myopathy: Inflammatory
      • Neuropathy: Several types
• Inclusion Body Myositis
  • Debrancher deficiency
  • HMSN: BAG3
  • Lamin A/C mutations
  • Congenital muscular dystrophy: Merosin (Laminin-α2) deficiency
  • Dynamin-2
  • Marinesco-Sjögren
  • Mitochondrial: MNGIE; MERRF
  • Motor neuropathy + Myopathy: VWA1
  • Trifunctional protein deficiency
  • TyrosinemiaHereditary
• Drugs & Toxins
  • Amiodarone
  • Chloroquine
  • Chlorphenoxy
  • Clofibrate: Risk factor – renal failure
  • Colchicine: Risk factor – renal failure
  • Doxorubicin
  • Eosinophilia-myalgia syndrome
  • Ethanol: Risk factor – fasting
  • Hydroxychloroquine
  • Organophosphates
  • Perhexiline
  • Vincristine

Causes of Distal Myopathy and Dysferlinopathy

Symptoms of Distal Myopathy and Dysferlinopathy

• Ankle dorsiflexion and finger extension weakness, as well as neck flexion weakness were common in our patients
• Abnormal, sometimes waddling, walk
• Joints that are fixed in a contracted position (late in the disease)
• Large and muscular-looking calves (pseudohypertrophy), which are not actually strong
• Loss of muscle mass, thinning of certain body parts
• Shoulder weakness
• Weakness of the muscles in the face (later in the disease)
• Weakness in the muscles of the lower legs, feet, lower arms, and hands (later in the disease)
• Chronic respiratory infections precipitated by weakness in the smooth muscle of the bronchioles.[rx]
• Impotence caused by gonadal atrophy, which is characteristically associated with myotonic dystrophy.[rx]
• It is common to possess dysphagia, which is esophageal muscle involvement.[rx]
• Myotonia is a term that describes the inability to relax muscles, which classically indicating as an inability to loosen one’s grip or release a handshake.[rx]
• As a pediatric disease, parents will often complain that their child is clumsy or becomes extremely weak quickly.[rx]
• The Gower sign is when subjects try to stand from a supine position, they march their hands and feet to each other).[rx]
• Weakness and stiffness of distal muscles are usually the presenting symptoms in adolescents with myotonic dystrophy.[rx]
• Proximal muscle weakness (pelvic and/or shoulder girdle) with early-onset (age <12 years), adult-onset, or late-onset (age >30 years)
• Symmetric atrophy and wasting of proximal limb and trunk muscles; calf hypertrophy is rarely and sometimes only transiently present [Fardeau et al 1996].
• Scapular winging, scoliosis, Achilles tendon contracture, and other joint contractures (including hip, knee, elbow, finger, and spine)
• Waddling gait; tip-toe walking; difficulty in running, climbing stairs, lifting weights, and getting up from the floor or from a chair
• Sparing of facial, ocular, tongue, and neck muscles
• Elevated creatine kinase (CK) concentrations, especially in childhood or adolescence, with or without overt muscle symptoms
• Absence of cardiomyopathy and intellectual disability

Clinical findings

• Initial weakness of the great toe and ankle dorsiflexors – eventually leading to a high-stepping gait and secondary tightening of the Achilles tendon. Onset is usually before age five years, but maybe later (into the 6th decade).
• Subsequent weakness of the finger extensors – (onset from months to 3 decades after lower-limb weakness), with sparing of the thumb, and often accompanied by an action tremor of the hands
• Mild involvement of the facial musculature – particularly of the orbicularis oculi and oris muscles
• Early weakness of neck flexion in most families
• The very slow progression of weakness – with gradual involvement of the proximal leg and trunk muscles. With early-onset, a wheelchair may eventually be required for mobility.
• Lower leg weakness – follows a typical sequence: initially dorsiflexion of the ankle and the great toe is affected and leads to a high-stepping gait, dropped big toe, and secondary tightening of the Achilles tendon. Early development of anterior compartment weakness has led to the marked tightening of the Achilles tendon bilaterally, with the affected individual unable to place his heels on the ground.
• Weakness of finger extensors – develops between months and several decades after the onset of leg weakness [Lamont et al 2014]. The third and fourth fingers appear to be more severely affected than the other fingers, although any of the fingers can be affected. The thumb is spared. Weakness of the finger extensors is often accompanied by a postural and action tremor of the hands. Individual with Laing distal myopathy attempting to extend her second to fifth fingers. Note marked weakness of third- and fourth-finger extension.
• Mild facial weakness – is often present, leading to the inability to bury the eyelashes completely when closing the eyes tightly, and the inability to keep the lips pursed against resistance. One affected individual has a mild Bell phenomenon.
• Weakness of neck flexion – seen in all affected individuals, is usually early in onset, though the weakness of neck flexion did not manifest in one family until the sixth decade. In most affected individuals and sites, the weakness is symmetric.
• Proximal weakness – After distal weakness has been present for more than ten years, mild proximal weakness occurs, with a slight Trendelenburg gait and mild scapular winging. Axial musculature may be mildly weak as well (manifesting as, e.g., inability to do a sit-up).
• Progression – is usually extremely slow; however, in one person the weakness became generalized and a wheelchair was required for mobility by age 15 years [Lamont et al 2014].
• Spinal manifestations – which can include kyphoscoliosis, spinal rigidity, and spinal extensor muscle contractures, occur in one-third of individuals and can vary within a family [Feinstein-Linial et al 2016, Fiorillo et al 2016]. Severe axial involvement with scoliosis, cervical hyperextension, and bent spine has been described [Dabaj et al 2018].
• Cardiac problems – are common. In their review of 88 affected individuals from 22 families, Lamont et al [2014] reported cardiac involvement ranging from hypertrophic cardiomyopathy with onset from birth to the third decade of life to dilated cardiomyopathy with onset from birth to the second decade of life. In an earlier report, a father and son in one family developed a dilated cardiomyopathy for which no other cause was found [Hedera et al 2003].
• Respiratory issues – present in approximately 40% of individuals in the form of reduced forced vital capacity, are not usually life-threatening [Lamont et al 2014]. Sleep apnea or sleep-related respiratory insufficiency may develop [Yu et al 2020].
• CNS involvement – with white matter lesions and epilepsy has been described in a single-family including three of 14 family members over three generations [Lefter et al 2015].

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