Neuropediatrics 2006; 37 - TP119
DOI: 10.1055/s-2006-945713

SACS MUTATIONS IN AUTOSOMAL RECESSIVE SPASTIC ATAXIAS

S Di Giandomenico 1, FM Santorelli 1, C Criscuolo 2, C Mariotti 3, A Simonati 4, GS Greco 5, A Brice 6, A Durr 6, A Filla 2, G Stevanin 6, E Bertini 1
  • 1Molecular Medicine, IRCCS Bambino Gesù Hospital, Rome, Italy
  • 2Department of Neurosciences, Federico II University, Napoli, Italy
  • 3IRCCS Besta Neurological Institute, Milan, Italy
  • 4Department of Vision and Neurosciences, University of Verona, Verona, Italy
  • 5IRCCS Mondino Neurological Istitute, Pavia, Rome, Italy
  • 6INSERM U679, Neurology and Experimental Therapeutics, Departement de Genetique, Cytogenetique, et Embryologie, Hopital de la Pitie-Salpetriere, Universite Pierre et Marie Curie, Faculte de Medecine, Paris, France

Objectives: To screen for SACS mutations in autosomal recessive spastic ataxias.

Background: A form of early onset autosomal recessive spastic ataxia has been originally described in the Charlevoix-Saguenay area in Quebec (ARSACS). Features include early onset, ataxia, spasticity, nystagmus, retinal striation, and peripheral neuropathy. The responsible gene, SACS, maps to chromosome 13q11. In the recent versions of Genome Project gene predictions, eight exons upstream the original ORF are indicated. The new ORF is 13.74 kb and encodes for a protein of 4579.

Methods: Thirteen patients from different families originating from North Africa, France and Italy with an ARSACS-like phenotype were studied. Nerve conduction study was recorded in nine. MRI was performed in all but one case. Seven patients have been tested for linkage to 13q11 locus. Direct sequencing of the nine exons and the intron-exon boundaries of SACS was performed.

Results: Spastic ataxia was a constant finding in our cases. The initial symptom was gait ataxia in eleven and spasticity in two. Mean age at onset was around age 5 years. Retinal striation at fundus oculi was present in one case. Cerebellar atrophy was present in all, the vermis being more involved then the hemispheres in three. Neurophysiological studies revealed axonal sensorimotor neuropathy in all, and signs of demyelination in two. Positive lod scores suggesting linkage to the ARSACS locus were found in six of seven families. In three of them a homozygous SACS mutation was detected. Two are new and one has been already reported in a Tunisian patient. In addition, one Italian patient carried a new heterozygous missense SACS mutation.

Conclusion: We confirm the ARSACS presence in the Mediterranean basin and report three new mutations in the SACS gene. The presence of a family with an ARSACS-like phenotype not linked to ARSACS locus suggests genetic heterogeneity.