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DISTAL WEAKNESS IN MYOPATHIES


Distal Myopathies: Hereditary 7

DISTAL WEAKNESS: Differential Dx

General
  Features
  Pathology

Myopathies
ACTN2: 1q43
Congenital myopathies
  ACTA1
  Centronuclear, Type 2: DNM2; 19p13
  RYR1
Cystinosis, Nephropathic: CTNS; 17p13
Cytoplasmic body
Distal dystrophy: PLIN4; 19p13
Emery-Dreifuss
FSH dystrophy
Glycogenoses
  Acid maltase
  Debranching Enzyme
  Phosphorylase b Kinase
Gowers-Laing (MPD1): MYH7; 14q11
Hereditary IBM
  Dominant
  Recessive
  Respiratory failure
LGMD variants
  1A: Myotilin; 5q31
  1C: Caveolin-3; 3p25
  1D: DNAJB6; 7q36
  2B: Dysferlin; 2p13
  2G: Telethonin; 17q12
  2L: ANO5; 11p14
Mitochondrial: POLG1; 15q26
Miyoshi (MMD)
  MMD1: Dysferlin; 2p13
  MMD2: ? 10p
  MMD3: ANO5; 11p14
MPD
  1 (Gowers-Laing): MYH7; 14q11
  2 (Vocal cord): MATR3; 5q31
  3
  4 (Williams): FLNC; 7q32
  5 (Adolescent): ADSSL1; 14q32
  6: ACTN2
Myasthenia: Agrin; 1p36
Myofibrillar
  αB-crystallin: 11q22
  BAG3
  CCDC78: 16p13
  Desmin: 2q35
  Filamin C (MPD4): 7q32
  Scapuloperoneal: 12q13
  ZASP (LDB3): 10q23
Myofibrillary (Cytoplasmic body)
Myopathy + Paget's disease of bone
  with Dementia: VCP/p97; 9p13
  Type 2: HNRNPA2B1; 7p15
Myopathy + PEO: MYH2; 17p13
Myotonic Dystrophy 1: DMPK; 19q13
Nebulin: 2q23
Nemaline (Rod) myopathies
Neutral lipid storage: PNPLA2; 11p15
Nonaka-HIBMR: GNE; 9p13
Oculopharyngodistal
Scapuloperoneal syndromes
Ring fiber myopathy
SQSTM1: 5q35; Dominant
Titin; 2q31
  Finnish: Dominant
  Serbian: Recessive
Welander: TIA1; 2p13

Other
  Myopathy or Motor Neuropathy
    Distal weakness: KLHL9; 9p22
    Distal weakness: HSPB8; 12q24
    Distal, Hoarse, Deaf: MYH14; 19q13
    Distal atrophy: DNAJB5; 9p13
  Neuropathies
  Uncertain
    NSUN2

Acquired (Sporadic) disorders
  Myasthenia gravis
  Myopathy + Neuropathy
  Hyperthyroid
  IIM + VAMP (IBM-like) syndromes
    Inclusion Body Myositis
  Type Inheritance
Pattern
Gene &
Locus
Early
Weakness
CK Muscle
Welander Dominant TIA1
2p13
> 40 years
Hands: Extensor
Normal, or
  Slight
Myopathic
± Vacuoles
Finnish (Tibial;. Udd)
Dominant Titin
2q31
40 to 50 years
Legs: Anterior
Normal, or
  Slight
Myopathic
Vacuoles
HMERF
Dominant Titin
2q31
12 to 75 years
Distal anterior legs
Respiratory
Normal or
  Slight
Myopathic
Eosin inclusions
Cytoplasmic body
Vacuoles
Gowers-Laing (MPD1) Dominant MYH7
14q11
1.5 to 25 years
Dorsiflex: Ankle; Toe
up to 3x Myopathic: Mild
Vacuoles: Few
Distal dystrophy +
  Rimmed vacuoles
Dominant DNAJB6
7q36
10 to 50 years
Legs: Distal
Normal, or
  Slight
Myopathic
Vacuoles
HIBM1 Dominant Desmin
2q35
25 to 40 years
Legs: Distal;
  Quadriceps
Normal, or
  Slight
Myopathic
Vacuoles
Oculopharyngodistal Dominant Autosomal 40 years
Extraocular
3x Myopathic
Vacuoles
Vocal cord &
  Pharyngeal (MPD2)
Dominant Matrin 3
5q31
35 to 57 years
Legs, Hands
 or Vocal cord
Normal to
  8x
Myopathic
Vacuoles
Myopathy +
  Paget's & Dementia
Dominant VCP
9p13
20 to 40 years
Legs
Proximal & Distal
Normal or
  Slight
Myopathic
Vacuoles
Myopathy + Paget's Dominant HNRNPA2B1
7p15
35 to 42 years
Legs: Distal
Scapular
Normal
  or High
Myopathic
Cytoplasmic body Dominant Autosomal 40 to 50 years
Hands
Normal or
  Slight
Myofibrillary
  inclusions
MPD3 Dominant 8p22-q11 &
12q13-q22
32 to 45 years
Distal
Legs & Hands
Normal or
  Slight
Myopathic
Vacuoles
Myopathy with
  Anterior leg sparing
  (MPD4)
Dominant Filamin C
7q32
0 to 30 years
Distal
Legs & Hands
Normal or
  Slight
Varied
  fiber size
No vacuoles
Nonaka-HIBMR
    (HIBM2)
Recessive,
  or Sporadic
GNE
9p13
20 to 40 years
Legs: Anterior
up to 5x Myopathic
Vacuoles
Miyoshi ± LGMD 2B Recessive,
  or Sporadic
Dysferlin
2p13
20 to 50 years
Legs: Posterior
10x to
  150x
Myopathic
No vacuoles
LGMD 2G Recessive Telethonin
17q12
12 years
Legs: Proximal
  & Anterior distal
3x to 17x Myopathic
Vacuoles
Miyoshi-like 3 (MMD3) Recessive Anoctamin 5
11p14.3
11 to 50 years
Legs: Posterior
3x to
  100x
Myopathic
Sarcolemmal lesions
Nebulin Recessive Nebulin
2q23
Child or Adult
Toe & finger extensor
Normal Myopathic
Rods, Small
Adolescent Recessive ADSSL1
14q32
Adolescent
Posterior legs; Face
Mildly high Myopathic
Vacuoles, Few
Myofibrillar myopathies
Desmin Dominant or
  Recessive
2q35 20 to 40 years
Legs
Mild Myopathic
Desmin
αB-crystallin Dominant 11q22 Adult
Distal
Mild Myopathic
Desmin
Scapuloperoneal Dominant FHL1
Xq26
20 to 58 years
Distal; Legs
1.5x to
  10x
Myopathic, Focal
Desmin inclusions
ZASP,
    Markesbery
Dominant ZASP
10q23.2
Child to 73 years
Distal in 9%
Normal to
  6x
Myopathic
Desmin inclusions
Vacuoles: Small



Distal Myopathies: Weakness & Muscle involvement
Clinical Muscle Pathology
General Features
  • Common weakness pattern
    • Muscles around wrist & ankle
  • Very distal muscles
    • Hand & Foot intrinsics
      • Often relatively spared
  • Childhood onset
  • Neuropathy-associated

Myopathy: MRI Patterns
Weakness Patterns
Upper Extremity
Ophthalmoparesis
Vocal cord
Lower Extremity
Muscle Fibers Amyloid


Welander (Late onset type I) Distal Myopathy

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

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

  Titin ; Chromosome 2q31.2; Dominant

Markesbery (Late adult onset type IIb) Distal myopathy

  ZASP ; Chromosome 10q23.2; Dominant 17

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

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

Nosology
Epidemiology
Genetics
GNE protein
Clinical
Laboratory
Muscle Pathology
Variant

from M Sadeh
HIBM2: Quadriceps sparing
CT of thigh

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

From: C Angelini

 

 
Miyoshi distal myopathy: Straight legs & Small calves

Miyoshi Myopathy 2 (MMD2) 6

  Chromosome 8q22.3; Recessive

Gowers (Laing; Early Adult Onset Distal Myopathy Type III; MPD1) 3, 4

  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, 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 21
      • Severe phenotype: L1591P
    • Allelic disorders
    • May have additional TIA1 mutations
  • MYH7 protein
    • Present in type I (Slow) muscle fibers
    • Predicted mutation effect: Disrupts
      • Ability of myosin tail to form normal coiled coil structure
      • Myosin dimerization: Altered structure of 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 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 tubulo-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 19
    • 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

From: Wikipedia
William Gowers



"Hanging" Big Toes
Patient is attempting to dorsiflex toes

Distal Dystrophy with Rimmed Vacuoles 14

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

Hereditary Inclusion Body Myopathy (IBM1; HIBM1) : Dominant

  Desmin ; Chromosome 2q35; Dominant

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2; VCPDM) 37

  Matrin 3 (MATR3) ; Chromosome 5q31.2; Dominant
  • Epidemiology: North American, German & Bulgarian families
  • Genetics 22
    • Mutation: Ser85Cys
    • Allelic disorders
      • Familial ALS 21, Dominant
      • Fronto-Temporal Dementia
        • Mutation: Retrotransposed Full-Length Transcript of Matrin-3 Variant 5
  • Matrin 3 protein 46
    • Cell location
      • Nuclear matrix
      • Inner face of nuclear envelope
      • May move to 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
  • Laboratory
    • 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 pedrinuclear sarcomeres
        • Nuclei: Abnormal invaginations
  • MATR3 variant syndrome: Amyotrophic Lateral Sclerosis (ALS), Familial 21 (ALS21) 36
    • Epidemiology: Sardinian & British families
    • Genetics
    • 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

Congo red stain
MPD2: Large vacuoles

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

IBMPFD (Dominant)
  1: VCP; 9p13
  2: HNRNPA2B1; 7p15
  3: HNRNPA1; 12q13


Inclusion Body Myopathy with Paget disease of Bone & Dementia 1 (IBMPFD1) 2

  Valosin-containing protein (VCP, p97) ; Chromosome 9p13.3; Dominant
  • Nosology: Multisystem proteinopathy 1 (MSP1)
  • Epidemiology
    • Worldwide: > 70 families
    • Male = Female
  • Genetics 12
    • 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 16
        • Other families: Patients may present with frontotemporal dementia 24
        • Pathology
          • Ubiquitin+ intranuclear inclusions & Dystrophic TDP-43+ neurites
      • A232E: Fractures & Paget disease at earlier age
    • Homozygous mutation: Arg159His
    • Allelic with
  • 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 18
      • 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 23
    • 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 ) 27
    • 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 29
    • 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 33
    • 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 45
    • 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 43
    • 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





IBM + Paget's: Scapular winging




IBM + Paget's: Paget's disease of bone


Myopathy with Paget disease of Bone ± Cognitive change or Motor Neuron Disease (IBMPFD2) 8, 34

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

Myopathy (IBM) with Paget disease of Bone without Dementia (IBMPFD3) 34

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

Myofibrillar Myopathy with Early Respiratory Failure (MFM9; HIBM-ERF; HMERF; ADMERF) 5

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

Myopathy with Ringed muscle fibers 1


Distal Myopathy: MPD3 9

  Autosomal Dominant

Distal myopathy with spared anterior leg muscles (William's myopathy) (MPD4) 15

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

Distal nebulin myopathy 20

  Nebulin ; Chromosome 2q23.3; Recessive

Distal Myopathy 5 (MPD5; Rod Myopathy) 40

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

Cystinosis, Nephropathic

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

Distal weakness, Early onset 25

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

dHMN: Distal Weakness, Hoarseness, Hearing loss (PNMHH) 28

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

Intellectual Disability 31

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

Myopathy/Neuropathy 129

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

Syndromes with Neuropathy & Myopathy


Return to Myopathy & NMJ Index
Return to Neuromuscular home page

References
1. Neuromuscular Disorders 1991;1:205-9
2. Genetics in Medicine 2000;2:232-241, Mol Genet Metab 2001; December On-Line, Neuromuscul Disord 2009;19:308-315, Muscle Nerve 2020 Nov 3
3. Muscle Nerve 2000;23:1876-1879; Neuromuscular Disord 2002;12:350-357, Arch Neurol 2003;60:1321-1325
4. Neuromuscular Disorders 2001;11:11-19; Am J Hum Genet 2004;75:703-708
5. Ann Neurol 2001;49:443-452, Neuromuscul Disord. 2005;15:595-600, Brain 2012 May 9, Brain 2012 May 9
6. Neuromuscular Disorders 1998;8:317-320
7. Muscle Nerve 2001;24:1440-1450, Neuromuscular Disorders 2012;22:5–12, Muscle Nerve 2018; Online August
8. Am J Med Genet 2002;108:187-191
9. Current Opinion in Neurology 2001;14:561-566, Neuromusc Disord 2004;14 March
10. Neuromuscular Disorders 2002;12:897-904, Ann Neurol 2012; Online December
11. Neurology 2003;61:384-386
12. Nature Genet 2004; On line March 21
13. Mol Genet Metab 2004;81:196-202
14. Ann Neurol 2004;56:133–138, Acta Neuropathol 2020 May 25
15. Neurology 2005;64:1245–1254, Am J Hum Genet 2011; Online May
16. Neurology 2005;65:1304-1305
17. Brain 2007 Mar 2
18. Hum Mol Genet 2006;15:189-199
19. Neuromuscul Disord 2007; Mar 22
20. Brain 2007;130:1465-1476
21. Neuromuscular Disord 2009 Jan 10
22. Am J Human Genet 2009 Online April 2
23. Neuromuscul Disord 2009 Apr 11, Orphanet J Rare Dis 2020 Sep 29;15(1):267
24. Neurology 2009;73:626–632
25. Brain 2010; Online June
26. Clin Neuropathol 2010;29:71-77
27. Neuron 2010;68;857–864
28. Hum Mutat 2011 Feb 24, Muscle Nerve 2016 Nov 22
29. Neuromuscular Disorders 2011; Online June
30. Neurology 2011; Online November
31. Am J Human Genet 2012; Online April A, B
32. J Neurol Sci 2012 Aug 7
33. Brain 2012; Online September
34. Nature 2013; Online March
35. Journal of the Neurological Sciences 2010;291:79–85
36. Nature Neuroscience 2014; Online March
37. Ann Neurol 2014; Online Aug
38. J Neurol Neurosurg Psychiatry 2014 Sep 24
39. Acta Neuropathologica Communications 2015;3:44
40. Ann Neurol 2015; Online October, Neuromuscular Disorders 2017; Online Feb
41. J Pediatr 2017;183S:S22-S23
42. Neuron 2017;95:808-816.e9
43. Neurology 2019 Dec 17
44. Neurology 2020 Jul 9
45. Neurobiol Aging 2020 Nov 14
46. JCI Insight 2021;6:143948

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