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SPG11 compound mutations in spastic paraparesis with thin corpus callosum

From the Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (L.S., E.L., J.M.V.-T., J.I., P.P.), and Department of Neurology, Clínica Universitaria de Navarra (M.R., J.C.M., J.I., M.A.P., P.d.C., P.P.), University of Navarra, Pamplona, Spain.

Address correspondence and reprint requests to Dr. Pau Pastor, Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), Pío XII 55, 31008-Pamplona (Navarra), Spain ppastor{at}unav.es.

Background: Autosomal recessive hereditary spastic paraparesis with thin corpus callosum (ARHSP-TCC) is being increasingly recognized as a variety of spastic paraplegia with mental retardation. SPG11 gene mutations have been reported to be associated with ARHSP-TCC.

Methods: As an independent group, we investigated SPG11 gene involvement in four individuals not previously described with either recessive or sporadic HSP-TCC presentation.

Results: Chromosome 15q13-15 segregating autosomal disease haplotypes were different across the kindreds and sequencing of SPG11 identified four novel frameshift/nonsense segregating mutations and the R2034X mutation, which were in heterozygous compound status. The affected examined had decreased thalamic and bilateral paracentral frontal lobe metabolism on ¹⁸F-flurodeoxyglucose PET.

Conclusions: Loss-of-function SPG11 mutations are the major cause of autosomal recessive hereditary spastic paraparesis with thin corpus callosum in Southern Europe, even in apparently sporadic cases. Decreased thalamic metabolism was consistently a phenotypical SPG11 mutation hallmark.

Abbreviations: ARHSP-TCC = autosomal recessive hereditary spastic paraparesis with thin corpus callosum; NCVs = nerve conduction velocities; TMS = transcranial magnetic stimulation.

Supplemental data at www.neurology.org

L.S. holds a Torres Quevedo fellowship from the Spanish Ministry of Science and Technology.

Disclosure: The authors report no disclosures.

Received September 27, 2007. Accepted in final form April 24, 2008.