Genetic background of the hereditary spastic paraplegia phenotypes in Hungary - An analysis of 58 probands

J Neurol Sci. 2016 May 15;364:116-21. doi: 10.1016/j.jns.2016.03.018. Epub 2016 Mar 12.

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.

Conclusion: 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.

Keywords: Ethnic distribution; Hereditary spastic paraplegia; SPAST; SPG4; SPG7; Spastic paraplegia; Spastin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters / genetics
  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics*
  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Child
  • Child, Preschool
  • Cohort Studies
  • Computational Biology
  • Female
  • GTP-Binding Proteins / genetics
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Hungary
  • Infant
  • Male
  • Membrane Proteins / genetics
  • Metalloendopeptidases / genetics*
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Proteins / genetics
  • Spastic Paraplegia, Hereditary / epidemiology
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / physiopathology
  • Spastin
  • Young Adult

Substances

  • ABCD1 protein, human
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters
  • Membrane Proteins
  • NIPA1 protein, human
  • Proteins
  • SPG11 protein, human
  • Metalloendopeptidases
  • SPG7 protein, human
  • ATL1 protein, human
  • Adenosine Triphosphatases
  • GTP-Binding Proteins
  • ATPases Associated with Diverse Cellular Activities
  • Spastin
  • SPAST protein, human