Proximal spinal muscular atrophy

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  • Proximal spinal muscular atrophy is a heterogeneous group of inherited conditions with several subtypes.
  • Most involve SMA1 dysfunction. The most severe forms involve SMA2 dysfunction as well, but overexpression of SMA2 is protective.
    • 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 expression
    • 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
    • Spinal muscular atrophy - facioscapulohumeral type has not been well defined apart from phenotype

Treatment

Before 2017 most treatment was symptomatic but clinical trials of nusinersen show considerable promise and an increasing number of patients can access this gene therapy drug that seems most effective if given early. However gene replacement therapy with scAAV9.CB.hSMN has potentially cured two patients with pre-clinically detected Werdnig-Hoffman disease and achieved good benefit in most treated before 6 months of age, with poorer results after this[1]. Steroids may briefly modulate the inevitable course of the disease. The hope that valproate would modulate favourably SMN2 gene expression in a clinically meaningful way was disproved in three randomised controlled trials[2][3]. Other RCTs in SMA2 and SMA3 have failed to show efficacy for creatine, phenylbutyrate, gabapentin, thyrotropin releasing hormone, hydroxyurea, or the combination therapy with valproate and acetyl-L-carnitine[4].

References

  1. Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L'Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. The New England journal of medicine. 2017 Nov; 377(18):1713-1722.(Print)
  2. Kissel JT, Elsheikh B, King WM, Freimer M, Scott CB, Kolb SJ, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, Acsadi G, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson S, Maczulski JA, Swoboda KJ. SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle & nerve. 2014 Feb; 49(2):187-92.(Link to article – subscription may be required.)
  3. Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson S, Maczulski JA, Bromberg MB, Chan GM, Swoboda KJ. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PloS one. 2011; 6(7):e21296.(Link to article – subscription may be required.)
  4. Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST, Vrancken AF. Drug treatment for spinal muscular atrophy types II and III. The Cochrane database of systematic reviews. 2012; 4:CD006282.(Epub) (Link to article – subscription may be required.)