title: Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands.
abstract: BACKGROUND
  Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases with progressive lower limb spasticity and weakness. The aim of this study is to determine the frequency of different SPG mutations in Hungarian patients, and to provide further genotype-phenotype correlations for the known HSP causing genes.
  
  
  METHODS
  We carried out genetic testing for 58 probands with clinical characteristics of HSP. For historical reasons, three different approaches were followed in different patients: 1) Sanger sequencing of ATL1 and SPAST genes, 2) whole exome, and 3) targeted panel sequencing by next generation sequencing.
  
  
  RESULTS
  Genetic diagnosis was established for 20 probands (34.5%). We detected nine previously unreported mutations with high confidence for pathogenicity. The most frequently affected gene was SPAST with pathogenic or likely pathogenic mutations in 10 probands. The most frequently detected variant in our cohort was the SPG7 p.Leu78*, observed in four probands. Altogether five probands were diagnosed with SPG7. Additional mutations were detected in SPG11, ATL1, NIPA1, and ABCD1.
  
  
  CONCLUSIONS
  This is the first comprehensive genetic epidemiological study of patients with HSP in Hungary. Next generation sequencing improved the yield of genetic diagnostics in this disease group even when the phenotype was atypical. However, considering the frequency of the HSP-causing gene defects, SPG4, the most common form of the disease, should be tested first to be cost effective in this economic region.
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Balicza
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Grosz
authors.affiliation: Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33136, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Renata
authors.initials: R
authors.lastname: Bencsik
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Klara
authors.initials: K
authors.lastname: Pentelenyi
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Aniko
authors.initials: A
authors.lastname: Gal
authors.affiliation: Department of Neurology, University of Szeged, Semmelweis street 6, 6720 Szeged, Hungary.
authors.forename: Edina
authors.initials: E
authors.lastname: Varga
authors.affiliation: Department of Neurology, University of Szeged, Semmelweis street 6, 6720 Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Klivenyi
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary.
authors.forename: Julia
authors.initials: J
authors.lastname: Koller
authors.affiliation: Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömő Street 25-29, 1083 Budapest, Hungary. Electronic address: molnar.mariajudit@med.semmelweis-univ.hu.
authors.forename: Judit Maria
authors.initials: JM
authors.lastname: Molnar
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019295:Computational Biology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006814:Hungary; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D000074181:Spastin; D055815:Young Adult
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins; C478824:NIPA1 protein, human; D011506:Proteins; C520412:SPG11 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; C440006:ATL1 protein, human; D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; D000074183:ATPases Associated with Diverse Cellular Activities; D000074181:Spastin; C400283:SPAST protein, human
keywords: Ethnic distribution; Hereditary spastic paraplegia; SPAST; SPG4; SPG7; Spastic paraplegia; Spastin