title: SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Centro Europeo di Ricerca sul Cervello -Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia, 64 Via del Fosso di Fiorano, Rome 00143, Italy. a.orlacchio@hsantalucia.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Orlacchio
authors.forename: Carla
authors.initials: C
authors.lastname: Babalini
authors.forename: Antonella
authors.initials: A
authors.lastname: Borreca
authors.forename: Clarice
authors.initials: C
authors.lastname: Patrono
authors.forename: Roberto
authors.initials: R
authors.lastname: Massa
authors.forename: Sarenur
authors.initials: S
authors.lastname: Basaran
authors.forename: Renato P
authors.initials: RP
authors.lastname: Munhoz
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Rogaeva
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
mesh_terms: D000328:Adult; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; C520412:SPG11 protein, human