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GENATLAS PHENOTYPE
last update : 12-10-2016
Symbol SMA
Location 5q13.2
Name spinal muscular atrophy, type 1
Other name(s) Werdnig-Hoffmann disease
Corresponding gene SMN1 , SMN2 , NAIP
Other symbol(s) SMA@, SMA1
Main clinical features
  • onset before 6 months of age, sits with support only, life expectancy <2 y
  • neuronal death enhancing and begining during fetal development, degeneration of the anterior horn cells leading to symmetrical muscle weakness and wasting of voluntary muscles, at muscle biopsies, large numbers of round atrophic fibers and clumps of hypertrophic fibers, and with early death
  • associated with congenital heart defects in any cases, including atrial septal defects, dilated right ventricle (RV) and ventricular septal defects
    • Genetic determination autosomal recessive
    Prevalence SMA types I, II, and III , 7.8 in 100,000 live births
    Related entries . type II intermediate (OMIM 253550 ) . type III juvenile (Kugelberg-Welander OMIM 253400) . also including some SMA with arthrogryposis multiplex congenita
    Function/system disorder neuromuscular
    neurology
    Type disease
    Gene product
    Name survival motor neuron
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense     compound heterozygoty in about 5 p.100 of patients with a subtle mutation (with the Y272C missense mutation being the most frequent), on one chromosome and a deletion/gene conversion on the other
    missense     in exon 3 inducing exon skipping
    deletion     homozygous deletion of exon 7, or exon 7 and 8, of SMN1 in about 95 p100 of patients
      deletion   large genomic deletions encompassing the SMN gene often extend to involve the NAIP gene
    Remark(s)
  • SMN1 is considered to be the primary disease causing gene ; deletion of SMN2 dos not cause the disease; SMN2 cannot fully compensate lack of SMN1 expression because most normal SMN2 transcripts lack exon 7
  • a single base substitution in SMN2, c.859G>C, was identified in exon 7 in the patients DNA, change creating a new exonic splicing enhancer element and increasing the amount of full-length transcripts, thus resulting in the less severe phenotypes (PMID: 19716110))
  • missense mutation S230L—a mutation causing SMA—disrupts SMN–profilin2a interaction (PMID: 21920940))
  • PLS3 is a modifier of SMA in motor-neurons (MN) (PMID: 27499521))
    • Genotype/Phenotype correlations
  • phenotypes in SMN1 mutations span a continuum without clear delineation of subtypes, which are classified by age of onset and maximum function achieved; the SMN2 copy number influences disease severity
  • patients with a single SMN2 copy had congenital SMA with haemodynamically relevant atrial or ventricular septal defects (Rudnik-Schöneborn 2008)
  • disease severity is mainly influenced by the number of SMN2 gene copies (PMID: 18971205))
  • most individuals with type I SMA carry two SMN2 copies, those with type II SMA three SMN2 copies, those with type III SMA four SMN2 copies, and those with type IV SMA four to six SMN2 copies (PMID: 27499561))