title: Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.
abstract: BACKGROUND
  In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form.
  
  
  OBJECTIVE
  To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4).
  
  
  METHODS
  SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed.
  
  
  RESULTS
  151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype.
  
  
  CONCLUSIONS
  Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.
authors.affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Centre for Brain Cognition and Behaviour, Nijmegen, The Netherlands. st.bot@neuro.umcn.nl
authors.forename: S T
authors.initials: ST
authors.lastname: de Bot
authors.forename: R T M
authors.initials: RT
authors.lastname: van den Elzen
authors.forename: A R
authors.initials: AR
authors.lastname: Mensenkamp
authors.forename: H J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: M A A P
authors.initials: MA
authors.lastname: Willemsen
authors.forename: N V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: H P H
authors.initials: HP
authors.lastname: Kremer
authors.forename: B P C
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010641:Phenotype; D012678:Sensation Disorders / Q000150:complications / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000235:genetics*; D000074181:Spastin; D014202:Tremor / Q000150:complications / Q000235:genetics
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human