RESUMO
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.
