Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 71, Issue 3, 518-527, 1 September 2002
doi:10.1086/342359
Infantile-Onset Ascending Hereditary Spastic Paralysis Is Associated with Mutations in the Alsin Gene
Eleonore Eymard-Pierre1, Gaetan Lesca2, Sandra Dollet1, Filippo Maria Santorelli3, Matteo di Capua4, Enrico Bertini3, 4 and Odile Boespflug-Tanguy1, 
, 
1 INSERM UMR384 et Fédération de Génétique Humaine Auvergne, Faculté de médecine, Clermont-Ferrand, France
2 Service de Génétique, Université de Lyon, Lyon
3 Unit of Molecular Medicine, Bambino Gesu Children’s Hospital, Rome
4 Division of Pediatric Neurology, Bambino Gesu Children’s Hospital, Rome
Address for correspondence and reprints: Prof. Odile Boespflug-Tanguy, INSERM UMR384, Faculté de Médecine, 28, place Henri Dunant, BP 38, 63001 Clermont-Ferrand Cedex, FranceAbstract
We studied 15 patients, from 10 families, who presented with severe spastic paralysis with an infantile onset and an ascending progression. Spastic paraplegia began during the first 2 years of life and extended to upper limbs within the next few years. During the first decade of life, the disease progressed to tetraplegia, anarthria, dysphagia, and slow eye movements. Overall, the disease was compatible with long survival. Signs of lower motor-neuron involvement were never observed, whereas motor-evoked potentials and magnetic resonance imaging demonstrated a primitive, pure degeneration of the upper motor neurons. Genotyping and linkage analyses demonstrated that this infantile-onset ascending hereditary spastic paralysis (IAHSP) is allelic to the condition previously reported as juvenile amyotrophic lateral sclerosis at the ALS2 locus on chromosome 2q33-35 (LOD score 6.66 at recombination fraction 0). We analyzed ALS2, recently found mutated in consanguineous Arabic families presenting either an ALS2 phenotype or juvenile-onset primary lateral sclerosis (JPLS), as a candidate gene. In 4 of the 10 families, we found abnormalities: three deletions and one splice-site mutation. All the mutations lead to a truncated alsin protein. In one case, the mutation affected both the short and the long alsin transcript. In the six remaining families, absence of cDNA ALS2 mutations suggests either mutations in regulatory ALS2 regions or genetic heterogeneity, as already reported in JPLS. Alsin mutations are responsible for a primitive, retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to a clinical continuum from infantile (IAHSP) to juvenile forms with (ALS2) or without (JPLS) lower motor-neuron involvement. Further analyses will determine whether other hereditary disorders with primitive involvement of the central motor pathways, as pure forms of spastic paraplegia, could be due to alsin dysfunction.
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