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DISTAL WEAKNESS IN MYOPATHIES


Distal Myopathies: Hereditary 7

DISTAL WEAKNESS: Differential Dx

General
  Features
  Pathology

Myopathies
Centronuclear, Type 2: Dynamin 2; 19p13
Congenital myopathies
Cystinosis, Nephropathic: CTNS; 17p13
Cytoplasmic body
Distal dystrophy: 19p13
Emery-Dreifuss
Finnish: Titin; 2q31
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
MPD3
Myasthenia: Agrin; 1p36
Myofibrillar
  αB-crystallin: 11q22
  CCDC78: 16p13
  Desmin: 2q35
  Filamin C (MPD4): 7q32
  Scapuloperoneal: 12q13
  ZASP: 10q23
Myofibrillary (Cytoplasmic body)
Myopathy + Paget's disease of bone
  with Dementia: VCP/p97; 9p13
  Type 2
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
Vocal cord (MPD2): MATR3; 5q31
Welander: TIA1; 2p13

Other
  Myopathy or Motor Neuropathy
    Distal weakness: KLHL9; 9p22
    Distal weak, Hoarse, Deaf: MYH14; 19q13
  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)
Dominant Titin
2q31
40 to 50 years
Legs: Anterior
Normal, or
  Slight
Myopathic
Vacuoles
HIBM +
  Respiratory failure
Dominant Titin
2q31
18 to 75 years
Distal legs
Respiratory
Normal or
  Slight
Myopathic
Eosin inclusions
Cytoplasmic body
Vacuoles
Gowers-Laing (MPD1) Dominant MYH7
14q11
1.5 to 25 years
Legs: Anterior
up to 3x Myopathic: Mild
Vacuoles: Some
Distal dystrophy +
  Rimmed vacuoles
Dominant 19p13.3 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 Autosomal 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
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
  • Common weakness pattern
    • Muscles around wrist & ankle
  • Very distal muscles (Hand & Foot intrinsics)
Lower leg: Patterns Muscle fiber pathology


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

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 10; Recessive


Gowers (Laing; Early adult onset distal myopathy type III; MPD1) 3, 4


From: Wikipedia
William Gowers
  Myosin heavy chain 7 (MYH7) ; Chromosome 14q11.2; Dominant or Sporadic

Distal dystrophy with rimmed vacuoles

  Chromosome 19p13.3; Dominant


Hereditary Inclusion Body Myopathy (IBM1; HIBM1) : Dominant

  Desmin ; Chromosome 2q35; Dominant

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2)

  Matrin 3 (MATR3) ; Chromosome 5q31.2; Dominant

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

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 with Paget disease of Bone (IBMPFD3) 34

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

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

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


Myopathy with ringed muscle fibers1


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

Cystinosis, Nephropathic

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

Distal weakness, Early onset 25

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

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


Syndromes with Neuropathy & Myopathy




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4/4/2014