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SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis

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Antonio Orlacchio, Carla Babalini, Antonella Borreca, Clarice Patrono, Roberto Massa, Sarenur Basaran, Renato P. Munhoz, Ekaterina A. Rogaeva, Peter H. St George-Hyslop, Giorgio Bernardi, Toshitaka Kawarai
DOI: http://dx.doi.org/10.1093/brain/awp325 591-598 First published online: 29 January 2010

Summary

The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria. The exclusion criterion was a diagnosis of hereditary spastic paraplegia with thin corpus callosum in line with an established protocol. Additional pathological and genetic evaluations were also performed. Surprisingly, 12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival. The countries of origin of these families were Italy, Brazil, Canada, Japan and Turkey. The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees, were absent in controls and were associated with amyotrophic lateral sclerosis neuropathology in one member of one of these families for whom central nervous system tissue was available. Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis.

  • amyotrophic lateral sclerosis
  • hereditary spastic paraplegia
  • mutations
  • spatacsin
  • Abbreviations:
    Abbreviations
    ALS
    amyotrophic lateral sclerosis
    ARJALS
    autosomal recessive juvenile amyotrophic lateral sclerosis
    SPG
    spastic paraplegia gene

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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