Alvarez, VictoriaSánchez-Ferrero, ElenaBeetz, ChristianDíaz, MartaAlonso, BelénCorao, Ana IGámez, JosepEsteban, JesúsGonzalo, Juan FPascual-Pascual, Samuel ILópez de Munain, AdolfoMoris, GermánRibacoba, RenneMárquez, CeledonioRosell, JordiMarín, RosarioGarcía-Barcina, Maria JCastillo, Emilia DelBenito, CarmenCoto, Eliecer2013-10-072013-10-072010-10-08Alvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, et al. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol. 2010; 10:89http://hdl.handle.net/10668/1315Journal Article; Research Support, Non-U.S. Gov't;BACKGROUND Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.enAnálisis de mutaciones del ADNGTP fosfohidrolasasProteínas de unión al GTPGenotipoParaplejía espástica hereditariaAdenosina trifosfatasasMedical Subject Headings::Named Groups::Persons::Age Groups::AdolescentMedical Subject Headings::Named Groups::Persons::Age Groups::AdultMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Named Groups::Persons::Age Groups::ChildMedical Subject Headings::Named Groups::Persons::Age Groups::Child::Child, PreschoolMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational AnalysisMedical Subject Headings::Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry GroupMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::GTP PhosphohydrolasesMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::GTP Phosphohydrolases::GTP-Binding ProteinsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::GenotypeMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Named Groups::Persons::Age Groups::InfantMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane ProteinsMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::PedigreeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain ReactionMedical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Nervous System Malformations::Hereditary Sensory and Motor Neuropathy::Spastic Paraplegia, HereditaryMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Young AdultMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::Adenosine Triphosphatasesresearch article20932283open access1471-2377PMC2964648