title: ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.
abstract: Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Montecchiani
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pedace
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy 2 Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy.
authors.forename: Temistocle
authors.initials: T
authors.lastname: Lo Giudice
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Casella
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Mearini
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gaudiello
authors.affiliation: 3 Department of Neurology, Universidade Federal de São Paulo, Brazil.
authors.forename: José L
authors.initials: JL
authors.lastname: Pedroso
authors.affiliation: 2 Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Terracciano
authors.affiliation: 2 Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy 4 Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.affiliation: 2 Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Massa
authors.affiliation: 5 Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada 6 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 7 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.affiliation: 3 Department of Neurology, Universidade Federal de São Paulo, Brazil.
authors.forename: Orlando G P
authors.initials: OG
authors.lastname: Barsottini
authors.affiliation: 8 Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.affiliation: 1 Laboratorio di Neurogenetica, CERC - IRCCS Santa Lucia, Rome, Italy 2 Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy a.orlacchio@hsantalucia.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Orlacchio
mesh_terms: D016022:Case-Control Studies; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
keywords: ALS5/SPG11/KIAA1840 mutations; Charcot–Marie–Tooth disease; axonal degeneration; spatacsin