Spinal muscular atrophy

From Ganfyd

The spinal muscular atrophies are a group of conditions that neurologists regard as pathologically and clinically distinct from motor neuron disease although for historic reasons they are classified with it as the pathology also destroys anterior horn cells. Most, if not all, forms are genetic by convention. See also familial amyotrophic lateral sclerosis.

Classification Systems

There have been attempts to rationalise the duplication of names. For example

• Distal hereditary motor neuronopathy (dHMN or HMN)
  • Heterogeneous group of autosomal dominant inherited conditions (in past recessive conditions also classified by this name):
    • HMN type I - mutations in the IGHMBP2 gene at 11q13.2-q13.4 that codes for cardiac transcription factor-1.
    • HMN type II
      • HMN2A - juvenile onset
      • HMN2B - adult onset
    • HMN types III and IV now classified as DSMA3 (below)
    • HMN type V (HMN5) - upper limb involvement
    • HMN type VII - with vocal cord paralysis
    • HMN type VI (dHMN6 or HMN6) - mutations in the IGHMBP2 gene at 11q13.2-q13.4 that codes for cardiac transcription factor-1.
      • HMN7A
      • HMN7B
  • Anterior horn cell degeneration
  • Patients have:
    • Progressive distal motor weakness
    • Muscular atrophy
    • No sensory impairment
• Distal spinal muscular atrophy
  • Heterogeneous group of autosomal recessive inherited conditions with at least 4 subtypes.
    • DSMA1 (SMARD1)
    • DSMA2
    • DSMA3 (includes HMN types III and IV)
    • DSMA4
• SMAX3- X-linked recessive spinal muscular atrophy at Xq13.1-q21
• Nonprogressive spinal muscular atrophy at 12q23-q24 (benign congenital with contractures spinal muscular atrophy).
• Proximal spinal muscular atrophy
  • Heterogeneous group of inherited conditions with several subtypes.
    • SMA1 - spinal muscular atrophy type I (Werdnig-Hoffman disease)
      • Caused by mutation or deletion in SMN1 gene at 5q12.2-q13.3
      • Commonest type
      • Onset before 6 months and death by 2 years
      • Hypotonia-profound
      • Symmetrical flaccid paralysis
      • No head movement control
    • SMA2
      • Caused by defect in the SMN1 gene but this is complicated by there being multiple SMN2 copies in human genome and some very complex interactions.
      • Age onset 7-18 months
      • Patient may sit but not stand and dies by late adolescence usually
      • Usually kyphoscoliosis
      • Usually fine hand tremor
    • Finkel type of late-onset autosomal dominant spinal muscular atrophy caused by mutations in the gene at 20q13.3 encoding vesicle-associated membrane protein-associated protein B (VAPB) which also has polymorphisms which seem relevant to motor neuron disease
    • SMA3 - autosomal dominant childhood-onset proximal SMA (Kugelberg-Welander syndrome, spinal muscular atrophy type III)
      • Caused by defect in the SMN1 gene but this is complicated by there being multiple SMN2 copies in human genome and some very complex interactions.
      • Onset after 18 months
      • Patient is able to walk and death is usually in adult life
      • Clinical presentation very variable, essentially up to range of SMA2
    • SMA4 (autosomal recessive adult-onset proximal spinal muscular atrophy)
      • Caused by defect in the SMN1 gene
      • Onset 2nd or third decade
    • Spinal muscular atrophy - facioscapulohumeral type