370 tested for SPG4 & SPG3A
Less than 20% of the 370-strong HSP test population have mutations in SPG4 or SPG3A. Also surprising, over half of all the mutations found were new mutations.
Editor’s Note: Principal Author, Dr. Victoria Alvarez commented that with the discovery of many more HSP genes in recent years, the approx. 50% figure normally quoted (for prevalence of SPG4, SPG3A, SPG6 & SPG31) is now appearing too high. Other recent studies in the Research Highlights section of this website have also reported much lower prevalence of the main HSP genes than 50%.
BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases.
METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).
RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.
CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.
SOURCE: BMC Neurol. 2010 Oct 8;10:89. PMID: 20932283 [PubMed – in process] PMCID: PMC2964648
Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.
Alvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, Gámez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, López de Munain A, Moris G, Ribacoba R, Márquez C, Rosell J, Marín R, García-Barcina MJ, Del Castillo E, Benito C, Coto E; Group for the Study of the Genetics of Spastic Paraplegia.
Laboratory of Molecular Genetics -Genetic Unit, Hospital Universitario Central de Asturias, Oviedo, Spain. [email protected]