Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations

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