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DISTAL WEAKNESS IN MYOPATHIES

Congenital myopathies
Cytoplasmic body myopathies
Desmin
Emery-Dreifuss
FSH dystrophy
Glycogenoses
  Acid maltase
  Debranching Enzyme
  Phosphorylase b Kinase
Myopathy + Neuropathy
Myopathy with ringed fibers
Myotonic Dystrophy
Nemaline (rod) myopathies
Oculopharyngodistal myopathy 
Scapuloperoneal syndromes
Distal myopathies: Hereditary

Other: Distal or Proximal weakness
  Inclusion body myopathies
    Autosomal Dominant IBM (IBM1)
    Nonaka (IBM2)
    Joint contractures &
        Ophthalmoplegia (IBM3)
    Distal myopathy + Respiratory
    Dominant IBM + Pagets
    Myositis (Acquired)
  Myasthenia gravis
  Hyperthyroid
Weakness in distal myopathies
  often involves muscles
  around the wrist and ankle.

The most distal muscles,
  such as intrinsics in hands & feet,
  are frequently relatively spared.




Distal Myopathies: Hereditary7

Differential Diagnosis

Centronuclear myopathy 2: Dynamin 2; 19p13
Cytoplasmic body
Distal dystrophy: 19p13
Finnish: Titin; 2q31
Glycogenoses
Gowers-Laing (MPD1): MYH7; 14q11
Hereditary IBM
  Dominant
  Recessive
  Respiratory failure: 6q27
LGMD 1A: Myotilin; 5q31
LGMD 1C: Caveolin-3; 3p25
LGMD 2G: Telethonin; 17q11
Miyoshi
  ± LGMD 2B
: Dysferlin; 2p13.1
MPD3
Myofibrillar
  αB-crystallin: 11q22
  Desmin: 2q35
  + Cardiomyopathy: 10q22
  Scapuloperoneal: 12q13
  ZASP: 10q22
Myofibrillary
  (Cytoplasmic body)

Myopathy + Paget's disease of bone
  with Dementia: VCP/p97; 9p13
  Type 2
Myotonic Dystrophy: DMPK; 19q13
Nebulin: 2q21
Nonaka-HIBMR: GNE; 9p12
Oculopharyngodistal
Other
Vocal cord & Pharyngeal (MPD2): 5q31
Welander: 2p13

Pathology
  Type Inheritance
Pattern
Gene &
Locus
Early
Weakness
CK Muscle
Welander Dominant 2p13 > 40 years
Hands: Extensor
Normal, or
  Slight é
Myopathic
± Vacuoles
Miyoshi ± LGMD 2B Recessive,
  or Sporadic
Dysferlin
2p13.1
20 to 50 years
Legs: Posterior
10x to
  150x é
Myopathic
No vacuoles
Finnish (Tibial)
Dominant Titin
2q31
40 to 50 years
Legs: Anterior
Normal, or
  Slight é
Myopathic
Vacuoles
Nonaka-HIBMR
    (HIBM2)
Recessive,
  or Sporadic
GNE
9p12-p11
20 to 40 years
Legs: Anterior
é up to 5x Myopathic
Vacuoles
Gowers-Laing (MPD1) Dominant MYH7
14q11
1.5 to 25 years
Legs: Anterior
é up to 3x Myopathic: Mild
Vacuoles: Some
Distal dystrophy +
  Rimmed vacuoles
Dominant 19p13.3 10 to 50 years
Legs: Distal
Normal, or
  Slight é
Myopathic
Vacuoles
HIBM Dominant Autosomal 25 to 40 years
Legs: Distal;
  Quadriceps
Normal, or
  Slight é
Myopathic
Vacuoles
Oculopharyngodistal Dominant Autosomal 40 years
Extraocular
3x é Myopathic
Vacuoles
LGMD 2G Recessive Telethonin
17q11-12
12 years
Legs: Proximal
  & Anterior distal
3x to 17x é Myopathic
Vacuoles
Vocal cord &
  Pharyngeal (MPD2)
Dominant 5q31 35 to 57 years
Legs, Hands
 or Vocal cord
Normal to
  é 8x
Myopathic
Vacuoles
Myopathy +
  Paget's & Dementia
Dominant 9p13 20 to 40 years
Legs
Proximal & Distal
Normal or
  Slight é
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 é
Myofibrillary
  inclusions
HIBM +
  Respiratory failure
Dominant 6q27 32 to 75 years
Distal legs
Respiratory
Normal or
  Slight é
Myopathic
Eosinophilic
  inclusions
Vacuoles
MPD3 Dominant Autosomal 32 to 45 years
Distal
Legs & Hands
Normal or
  Slight é
Myopathic
Vacuoles
Myopathy with
  Anterior leg sparing
Dominant Autosomal 0 to 30 years
Distal
Legs & Hands
Normal or
  Slight é
Varied
  fiber size
No vacuoles
Myofibrillar myopathies
Desmin Dominant or
  Recessive
2q35 20 to 40 years
Legs
Mild é Myopathic
Desmin é
αB-crystallin Dominant 11q22 Adult
Distal
Mild é Myopathic
Desmin é
Myofibrillar
  + Cardiomyopathy

Dominant 10q22.3 20 to 60 years
Distal
Normal to
  Mild é
Myopathic
Myofibrillar
Scapuloperoneal Dominant 12q13.3-q15 20 to 58 years
Distal; Legs
1.5x to
  10x é
Myopathic, Focal
Desmin inclusions
ZASP,
    Markesbery
Dominant 10q22.3-q23.2 44 to 73 years
Distal in 9%
Normal to
  6x é
Myopathic
Desmin inclusions
Vacuoles: Small


Welander (Late onset type I) distal myopathy

  l Chromosome 2p13; Dominant

Finnish (Tibial) (Late onset type IIa; Udd) distal myopathy

  l Titin ; Chromosome 2q31; Dominant

Markesbery (Late adult onset type IIb) distal myopathy

  l ZASP ; Chromosome 10q22.3-q23.2; Dominant17

Hereditary Inclusion Body Myopathy (IBM2; Nonaka) : Recessive

  l GNE ; Chromosome 9p12-p11; Recessive

Miyoshi (Early adult onset distal myopathy type II)

  l Dysferlin; Chromosome 2p13.3-p13.1; Recessive
  l ? Some families linked to Chromosome 106; Recessive

From: C Angelini

 

 
Miyoshi distal myopathy: Straight legs & Small calves

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

  l Myosin heavy chain 7 (MYH7) ; Chromosome 14q12; Dominant or Sporadic

Distal dystrophy with rimmed vacuoles

  l Chromosome 19p13.3; Dominant


Hereditary Inclusion Body Myopathy (IBM1): Dominant

  l Autosomal Dominant

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2)

  l Chromosome 5q31; Dominant

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

  l Valosin-containing protein (VCP, p97) ; Chromosome 9p13.3-p12; Dominant

Myopathy with Paget disease of Bone, type 28

  l Autosomal Dominant

Distal Myopathy with early Respiratory failure (HIBM-ERF; ADMERF) 5

  l Chromosome 6q27; Dominant


Myopathy with ringed muscle fibers1


Distal Myopathy: MPD3 9

  l Autosomal Dominant

Distal myopathy with spared anterior leg muscles15

  l Autosomal Dominant

Distal nebulin myopathy20

  l Nebulin ; Chromosome 2q21.2-q22; Recessive


Syndromes with Neuropathy & Myopathy




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References
1. Neuromuscular Disorders 1991;1:205-9
2. Genetics in Medicine 2000;2:232-241, Mol Genet Metab 2001; December On-Line
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
6. Neuromuscular Disorders 1998;8:317-320
7. Muscle Nerve 2001;24:1440-1450
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
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
15. Neurology 2005;64:1245–1254
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

1/16/2008