Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.

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.

[1]  A. Dürr,et al.  Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. , 2002, American journal of human genetics.

[2]  Robert H. Brown,et al.  A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. , 2002, American journal of human genetics.

[3]  P. Hedera,et al.  Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia , 2001, Nature Genetics.

[4]  M. Pericak-Vance,et al.  The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis , 2001, Nature Genetics.

[5]  S. Scherer,et al.  Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2, and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2) critical region at chromosome 2q33-q34: candidate genes for ALS2. , 2001, Genomics.

[6]  S. Hadano,et al.  A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 , 2001, Nature Genetics.

[7]  F. Boaretto,et al.  A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27-q28. , 2000, American journal of human genetics.

[8]  C. McDermott,et al.  Hereditary spastic paraparesis: a review of new developments , 2000, Journal of neurology, neurosurgery, and psychiatry.

[9]  D. Rubinsztein,et al.  A locus for autosomal dominant "pure" hereditary spastic paraplegia maps to chromosome 19q13. , 2000, American journal of human genetics.

[10]  Bertrand Fontaine,et al.  Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia , 1999, Nature Genetics.

[11]  T. Bird,et al.  “Pure” hereditary spastic paraplegias , 1999, Neurology.

[12]  M. Devoto,et al.  Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. , 1999, American journal of human genetics.

[13]  S. Scherer,et al.  A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33-q34. , 1999, Genomics.

[14]  M. Pericak-Vance,et al.  Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers , 1998, Neurogenetics.

[15]  Sergio Cocozza,et al.  Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease , 1998, Cell.

[16]  B. Crain,et al.  Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. , 1998, American journal of human genetics.

[17]  J. Haines,et al.  Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33–q35 , 1994, Nature Genetics.

[18]  R. Stevenson,et al.  X–linked spastic paraplegia (SPG1), MASA syndrome and X–linked hydrocephalus result from mutations in the L1 gene , 1994, Nature Genetics.

[19]  A. Munnich,et al.  X–linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus , 1994, Nature Genetics.

[20]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[21]  W. Brown,et al.  Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. , 1992, Brain : a journal of neurology.

[22]  J. Haines,et al.  Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. , 1991, The New England journal of medicine.

[23]  M. Hamida,et al.  Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. , 1990, Brain : a journal of neurology.

[24]  L. Kurland,et al.  Familial adult motor neuron disease: amyotrophic lateral sclerosis , 1986, Neurology.

[25]  J. Ott,et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. , 1985, American journal of human genetics.

[26]  I. Choi,et al.  Hereditary spastic paraplegia. , 1983, Yonsei medical journal.

[27]  A. Harding.  Hereditary "pure" spastic paraplegia: a clinical and genetic study of 22 families. , 1981, Journal of neurology, neurosurgery, and psychiatry.