Abstract
ALS2 gene encoding for alsin protein is responsible for neurological disorders due to retrograde degeneration of the upper motor neurons of the pyramidal tracts, inherited in an autosomal recessive manner, and displaying a clinical continuum including the infantile ascending hereditary spastic paraplegiaidentified in three Spanish children presented here.
Avoid common mistakes on your manuscript.
Dear Editor-in-Chief,
We hereby report on three ALS-like cases in Spanish children linked to gene ALS2 (alsin Rho guanine nucleotide exchange factor ALS2) of 2q33.1 encoding alsin protein. ALS2-related disorders are considered a consequence of retrograde degeneration of upper motor neurons (UMN) of pyramidal tracts displaying a clinical continuum with infantile to juvenile onset and a recessive inheritance pattern, ranging from IAHSP (infantile ascending hereditary spastic paraplegia) and JPLS (juvenile primary lateral sclerosis), both primarily assigned to UMN, to JALS (juvenile amyotrophic lateral sclerosis), with additional lower motor neuron (LMN) involvement [1, 2].
The prevalence of ALS2 disorders is unknown, with only a few cases having been described in a variety of ethnic backgrounds including Caucasians. Among the latter, the first Spanish patients reported hereby were three children of non-consanguineous parents, from Castilla La Mancha (two sibs in family 1, F1) and the Basque Country (case in family 2, F2). ALS2 mutations were initially discovered in F1 index case and the F2 case submitted to a genome analysis for spastic paraplegia undertaken by next generation sequencing (NGS) with the use of the TruSight One Sequencing Panel (https://www.illumina.com), leading to identification of two compound heterozygous genotypes, that clearly underneath disease, of ALS2 mutations Q982SfsX19 and R704X in F1 and R640X and G49R in F2. They are presented in Figs. 1 and 2 with the available clinical data of the patients as well as in Fig. 3 to show its location in the alsin sequence together with many of the ALS2 mutations described from 2001 to 2018 [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20].
F1 mutations Q982SfsX19 and R704X have been identified for the first time as far as we know. However, they are considered pathogenic taking into account their deleterious nature, location, and familial segregation. They are indeed frameshift (Q982SfsX19, paternal derived) and nonsense (R704X, maternal) variants like most of pathogenic ALS2 mutations that predict truncated defective proteins and are located in DH/PH domain near to pathogenic variants of similar type such as E724GfsX26 and Q715X. Of these, E724GfsX26 was described with variant G437VfsX9 of RCC1 domain in a compound heterozygous genotype in two Chinese siblings with IAHSP [18], whereas the homozygous nonsense mutation Q715X was reported in two sibs claimed to be the first IAHSP cases from northwestern Europe [12]. Besides, the pathogenic nature of ALS2 F1 mutations is pointed out by its segregation. Each mutation is clinically silent in the parents but together in a compound heterozygous genotype is associated to disease in the siblings though with remarkable differences. Whereas index case would be an apparent typical IAHSP case, that of his old sister much more severe might suggest the consideration of an early-onset JPLS. A similar of severe picture has recently been observed in a young girl of Seville (Spain) homozygous for the R704X mutation (Nogueira E, unpublished).
F2 patient would be a typical IAHSP case due to a compound heterozygous ALS2 genotype of two previously reported mutations, R640X, of paternal derivation, and G49R, maternal. The nonsense R640X mutation that lies in a sequence between RCC1 and DH domains has been found in homozygosis in two Pakistani siblings considered IAHSP cases [19]. On the other hand, the missense mutation G49R located upstream of RCC1 domain has also been described as part of a compound heterozygous ALS2 genotype, together with mutation G477AfsX19 in a boy described as first Portuguese IAHSP case [16]. In addition to its segregation in the Portuguese and our F2 cases, the relevant nature of G49R is suggested by its very rare occurrence (only twice in genomAD databases, with 0.0004% global allelic frequency) and by affecting a very conserved residue (Gly49) whose non-conservative substitution (by Arg) would probably have conformational and functional consequences, a presumption congruent with the pathogenic prediction of a majority of in silico analyses as described in knowledge base VarSome (https://varsome.com). Thus, according to the ACMG evaluation criteria, G49R might be considered a pathogenic or likely pathogenic variant. It would increase the small number of missense variants described in different ALS2 disorders, such as S100I, C157Y, and G540E with proposed association to cases of JALS, IAHSP, and JPLS, respectively (Fig. 3). According to recent data, the pathogenic nature of missense mutations would be due to altered oligomerization and/or destabilization of the mutant alsin molecules impairing its endosomal localization [21].
The finding of ALS2 mutations in our F1 and F2 families allowed a precise diagnosis of the patients despite of the scarce clinical data suggesting cases of spastic paraplegia. They would be ALS2-related disorders of the UMN spectrum, most probably of IAHSP type although considering the marked affectation differences of F1 siblings, and it is tempting to speculate that same genotype (Q982SfsX19/R704X) might be associated to different disorders, being that of index case a typical example of IAHSP whereas that of his old sister would also be compatible with diagnosis of an early-onset JPLS. Such an observation is in line with the known intra- and interfamilial phenotypic variability of ALS2-related disorders, noted among others in 11 IAHSP patients of three unrelated consanguineous Iranian families homozygous for mutation c.1640+1G>A of ALS2 [20]. Of them, three siblings from one family exhibited dystonia not been in families with IAHSP, only previously described in unrelated consanguineous families with JALS/ALS2 [16, 20]. A marked phenotypic variability has also been observed in two siblings homozygous for ALS2 variant c.2980-2A>G, considered JPL cases, one of them began using a wheelchair at the age of two whereas the other began using it at age 50 [13].
Further, the distribution of F1 and F2 mutations as well as other ALS2 mutations (illustrated by Fig. 3) is in favor of a lack of both mutation hotspots and a precise domain involvement in the different ALS2-related disorders that otherwise due to considerable clinical overlap led to divergent diagnosis, in particular of UMN spectrum disorders being in some instances similar pictures called either IAHSP or JPLS [1]. These observations and the phenotypic variability of same genotypes suggest the consideration of a decisive contribution of additional factors in the pathogenesis of ALS2 disorders, mainly of genes coding for molecules interacting with alsin along its multiple functions, particularly in the endolysosomal pathway [21], that may display functional variations due even to subtle changes, no necessarily to pathogenic variants, attributable to diversity of the genomic dotation of ALS2 mutation carriers including of siblings.
References
Orrell RW (1993–2017) ALS2-related disorders. 2005 Oct 21 [Updated 2016 Jan 28]. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews [Internet]. University of Washington, Seattle. Available from https://www.ncbi.nlm.nih.gov/books/NBK1243. Accessed 8 Nov 2020
Brugman F, Eymard-Pierre E, van den Berg LH et al (2007) Adult-onset primary lateral sclerosis is not associated with mutations in the ALS2 gene. Neurology 69:702–704
Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH Jr, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE (2001) A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29:166–173
Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (2001) 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 29:160–165
Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, Boespflug-Tanguy O (2002) Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 71:518–527
Devon RS, Helm JR, Rouleau GA, Leitner Y, Lerman-Sagie T, Lev D, Hayden MR (2003) 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 64:210–215
Gros-Louis F, Meijer IA, Hand CK, Dubé MP, MacGregor DL, Seni MH, Devon RS, Hayden MR, Andermann F, Andermann E, Rouleau GA (2003) An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann Neurol 53:144–145
Kress JA, Kühnlein P, Winter P, Ludolph AC, Kassubek J, Müller U, Sperfeld AD (2005) Novel mutation in the ALS2 gene in juvenile amyotrophic lateral sclerosis. Ann Neurol 58:800–803
Eymard-Pierre E, Yamanaka K, Haeussler M, Kress W, Gauthier-Barichard F, Combes P, Cleveland DW, Boespflug-Tanguy O (2006) Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis. Ann Neurol 59:976–980
Panzeri C, De Palma C, Martinuzzi A et al (2006) The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain 129:1710–1719
Sztriha L, Panzeri C, Kálmánchey R, Szabó N, Endreffy E, Túri S, Baschirotto C, Bresolin N, Vekerdy Z, Bassi MT (2008) First case of compound heterozygosity in ALS2 gene in infantile-onset ascending spastic paralysis with bulbar involvement. Clin Genet 73:591–593
Verschuuren-Bemelmans CC, Winter P, Sival DA, Elting JW, Brouwer OF, Müller U (2008) 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 16:1407–1411
Mintchev N, Zamba-Papanicolaou E, Kleopa KA, Christodoulou K (2009) A novel ALS2 splice-site mutation in a Cypriot juvenile-onset primary lateral sclerosis family. Neurology 72:28–32
Shirakawa K, Suzuki H, Ito M, Kono S, Uchiyama T, Ohashi T, Miyajima H (2009) Novel compound heterozygous als2 mutations cause juvenile amyotrophic lateral sclerosis in Japan. Neurology 73:2124–2126
Luigetti M, Lattante S, Conte A, Romano A, Zollino M, Marangi G, Sabatelli M (2013) A novel compound heterozygous ALS2 mutation in two Italian siblings with juvenile amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14:470–472
Flor-de-Lima F, Sampaio M, Nahavandi N (2014) Alsin related disorders: literature review and case study with novel mutations. Case Rep Genet 2014:691515
Siddiqi S, Foo JN, Vu A, Azim S, Silver DL, Mansoor A, Tay SKH, Abbasi S, Hashmi AH, Janjua J, Khalid S, Tai ES, Yeo GW, Khor CC (2014) A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias. PLoS One 9:e113258
Xie F, Cen ZD, Xiao JF, Luo W (2015) Novel compound heterozygous ALS2 mutations in two Chinese siblings with infantile ascending hereditary spastic paralysis. Neurol Sci 36:1279–1280
Tariq H, Mukhtar S, Naz S (2017) A novel mutation in ALS2 associated with severe and progressive infantile onset of spastic paralysis. J Neurogenet 31:26–29
Helal M, Mazaheri N, Shalbafan B, Malamiri RA, Dilaver N, Buchert R, Mohammadiasl J, Golchin N, Sedaghat A, Mehrjardi MYV, Haack TB, Riess O, Chung WK, Galehdari H, Shariati G, Maroofian R (2018) Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant. Neurol Sci 39:1917–1925
Sato K, Otomo A, Ueda MT, Hiratsuka Y, Suzuki-Utsunomiya K, Sugiyama J, Murakoshi S, Mitsui S, Ono S, Nakagawa S, Shang HF, Hadano S (2018) Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function. J Biol Chem 293:17135–17153
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interests.
Ethical approval
None.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Nogueira, E., Alarcón, J., Garma, C. et al. ALS2-related disorders in Spanish children. Neurol Sci 42, 2091–2094 (2021). https://doi.org/10.1007/s10072-020-04899-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-020-04899-0