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Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene
Eleonore Eymard-Pierre1, Gaetan Lesca, Sandra Dollet
1INSERM UMR384 et Fédération de Génétique Humaine Auvergne, Faculté de médecine, Clermont-Ferrand, France.
Insights
Mutations in the ALS2 gene cause infantile-onset ascending hereditary spastic paralysis (IAHSP), a pure upper motor neuron degeneration. This research identifies alsin gene mutations in IAHSP, linking it to juvenile forms of motor neuron disease.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare neurological disorder characterized by progressive spasticity.
- Previous research suggested a link between IAHSP and the ALS2 locus on chromosome 2q33-35.
Purpose of the Study:
- To investigate the genetic basis of IAHSP.
- To identify mutations in the ALS2 gene as a cause of IAHSP.
Main Methods:
- Studied 15 patients from 10 families with IAHSP.
- Performed genotyping, linkage analyses, and ALS2 gene analysis (including cDNA mutation screening).
- Utilized motor-evoked potentials and MRI to assess upper motor neuron degeneration.
Main Results:
- Identified ALS2 gene mutations (deletions and splice-site mutation) in 4 of 10 families, all leading to a truncated alsin protein.
- Confirmed allelism between IAHSP and juvenile amyotrophic lateral sclerosis (ALS2) at the ALS2 locus.
- Demonstrated pure upper motor neuron degeneration without lower motor neuron involvement.
Conclusions:
- Mutations in the ALS2 gene are responsible for IAHSP.
- Alsin dysfunction causes a spectrum of motor neuron diseases, from infantile to juvenile forms.
- Further research is needed to explore alsin's role in other hereditary spastic paraplegias.
Abstract:
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.