Phenotype and Genotype of Children with ALS2 gene-Related Disorder

Abstract

Introduction The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor. The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract. The phenotypes resulting from variants in ALS2 gene are infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225), juvenile primary lateral sclerosis (JPLS, OMIM # 606353), and juvenile amyotrophic lateral sclerosis (JALS, OMIM # 205100). Our study objectives were to describe the clinical phenotype and genotype of children with an established diagnosis of ALS2 gene-related disorder.

Methods The clinical details, laboratory data, and genotype findings of children with an established diagnosis of ALS2 gene-related disorder were collected from the hospital electronic database after obtaining institutional review board approval.

Results One family with three affected siblings, a second family with a proband and an affected fetus, and a third family with two affected siblings with ALS2 gene variants were identified. IAHSP was diagnosed in all of our patients with variants in ALS2 gene. The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria. Nonsense variants were observed in four patients while frameshift variant was observed in one family. Novel variants in ALS2 gene were identified in two unrelated families.

Conclusion ALS2 mutation results in rare neurodegenerative disorders with the clinical spectrum encompassing IAHSP, JPLS, and JALS disorders. In view of allelic heterogeneity described in the literature, more research studies are needed for establishing genotype–phenotype correlation in patients with ALS2 gene-related disorder.

Keywords

Alsin Rho Guanine Nucleotide Exchange Factor - ALS2 gene - Infantile-onset ascending hereditary spastic paralysis (IAHSP) - Corticospinal tract - Neurodegenerative disorder

Author's Contribution

S.Y. and M.K. prepared the manuscript. R.A., S.R.R., B.S.U., S.P.O., S.D., and M.T. revised the manuscript. All authors approved the final manuscript.

Publication History

Received: 24 April 2024

Accepted: 30 August 2024

Article published online:
18 October 2024

• References

• 1 Ben Hamida M, Hentati F, Ben Hamida C. Hereditary motor system diseases (chronic juvenile amyotrophic lateral sclerosis). Conditions combining a bilateral pyramidal syndrome with limb and bulbar amyotrophy. Brain 1990; 113 (Pt 2): 347-363
• 2 Lerman-Sagie T, Filiano J, Smith DW, Korson M. Infantile onset of hereditary ascending spastic paralysis with bulbar involvement. J Child Neurol 1996; 11 (01) 54-57
• 3 Hentati A, Bejaoui K, Pericak-Vance MA. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet 1994; 7 (03) 425-428
• 4 Eymard-Pierre E, Yamanaka K, Haeussler M. et al. Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis. Ann Neurol 2006; 59 (06) 976-980
• 5 Gros-Louis F, Meijer IA, Hand CK. et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol 2003; 53 (01) 144-145
• 6 Daud S, Kakar N, Goebel I. et al. Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia. Amyotroph Lateral Scler Frontotemporal Degener 2016; 17 (3-4): 260-265
• 7 Sztriha L, Panzeri C, Kálmánchey R. et al. First case of compound heterozygosity in ALS2 gene in infantile-onset ascending spastic paralysis with bulbar involvement. Clin Genet 2008; 73 (06) 591-593
• 8 Gros-Louis F, Gaspar C, Rouleau GA. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 2006; 1762 (11–12): 956-972
• 9 Eymard-Pierre E, Lesca G, Dollet S. et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 2002; 71 (03) 518-527
• 10 Wakil SM, Ramzan K, Abuthuraya R. et al. Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T. Gene 2014; 536 (01) 217-220
• 11 Panzeri C, De Palma C, Martinuzzi A. et al. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain 2006; 129 (Pt 7): 1710-1719
• 12 Verschuuren-Bemelmans CC, Winter P, Sival DA, Elting JW, Brouwer OF, Müller U. Novel homozygous ALS2 nonsense mutation (p.Gln715X) in sibs with infantile-onset ascending spastic paralysis: the first cases from northwestern Europe. Eur J Hum Genet 2008; 16 (11) 1407-1411
• 13 Helal M, Mazaheri N, Shalbafan B. et al. Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant. Neurol Sci 2018; 39 (11) 1917-1925
• 14 Lesca G, Eymard-Pierre E, Santorelli FM. et al. Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Neurology 2003; 60 (04) 674-682
• 15 Racis L, Tessa A, Pugliatti M, Storti E, Agnetti V, Santorelli FM. Infantile-onset ascending hereditary spastic paralysis: a case report and brief literature review. Eur J Paediatr Neurol 2014; 18 (02) 235-239
• 16 Sheerin UM, Schneider SA, Carr L. et al. ALS2 mutations: juvenile amyotrophic lateral sclerosis and generalized dystonia. Neurology 2014; 82 (12) 1065-1067
• 17 Hadano S, Hand CK, Osuga H. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 2001; 29 (02) 166-173
• 18 Yang Y, Hentati A, Deng H-X. 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. Nat Genet 2001; 29 (02) 160-165
• 19 Devon RS, Helm JR, Rouleau GA. et al. The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. Clin Genet 2003; 64 (03) 210-215
• 20 Kress JA, Kühnlein P, Winter P. et al. Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol 2005; 58 (05) 800-803
• 21 Herzfeld T, Wolf N, Winter P, Hackstein H, Vater D, Müller U. Maternal uniparental heterodisomy with partial isodisomy of a chromosome 2 carrying a splice acceptor site mutation (IVS9-2A>T) in ALS2 causes infantile-onset ascending spastic paralysis (IAHSP). Neurogenetics 2009; 10 (01) 59-64
• 22 Mintchev N, Zamba-Papanicolaou E, Kleopa KA, Christodoulou K. A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family. Neurology 2009; 72 (01) 28-32
• 23 Shirakawa K, Suzuki H, Ito M. et al. Novel compound heterozygous ALS2 mutations cause juvenile amyotrophic lateral sclerosis in Japan. Neurology 2009; 73 (24) 2124-2126
• 24 Srivastava S, Cohen JS, Vernon H. et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol 2014; 76 (04) 473-483
• 25 Flor-de-Lima F, Sampaio M, Nahavandi N, Fernandes S, Leão M. Alsin related disorders: literature review and case study with novel mutations. Case Rep Genet 2014; 2014: 691515
• 26 Xie F, Cen ZD, Xiao JF, Luo W. Novel compound heterozygous ALS2 mutations in two Chinese siblings with infantile ascending hereditary spastic paralysis. Neurol Sci 2015; 36 (07) 1279-1280
• 27 Vanderver A, Simons C, Helman G. et al. Leukodystrophy Study Group. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79 (06) 1031-1037
• 28 Lin JZ, Zheng HH, Ma QL. et al. Cortical damage associated with cognitive and motor impairment in hereditary spastic paraplegia: evidence of a novel SPAST mutation. Front Neurol 2020; 11: 399
• 29 Nogueira E, Alarcón J, Garma C, Paredes C. ALS2-related disorders in Spanish children. Neurol Sci 2021; 42 (05) 2091-2094
• 30 Sprute R, Jergas H, Ölmez A. et al. Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations. Am J Med Genet A 2021; 185 (02) 344-354
• 31 Farrugia Wismayer M, Farrugia Wismayer A, Borg R. et al. Genetic landscape of ALS in Malta based on a quinquennial analysis. Neurobiol Aging 2023; 123: 200-207