Abstract
Hereditary spastic paraplegias (HSPs) are characterized by various inherited disorders in which weakness and spasticity of the lower extremities are the predominant symptoms. Recently, HSP caused by ALDH18A1 mutations has been reported as SPG9 with autosomal dominant (SPG9A) and autosomal recessive (SPG9B) transmission. In this study, we obtained clinical and genetic findings in two Japanese families with SPG9B. One family had a novel compound heterozygous mutation (c.1321 C > T/c.1994G > A) in the ALDH18A1 gene. The other family had a homozygous mutation (c.383 G > A/c.383 G > A) in the ALDH18A1 gene. To date, only two SPG9B families with ALDH18A1 mutations have been reported. This is the first report of SPG9 in non-Caucasians. Furthermore, we found cerebellar ataxia in one family, although cerebellar ataxia has not been reported in SPG9B so far. SPG9B might involve a complicated HSP including cerebellar ataxia and cognitive impairment. This study expands the clinical and genetic spectrum of ALDH18A1-related disorders.
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References
Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms. Lancet Neurol. 2008;7:1127–38.
Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A, et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015;138:2191–205.
Panza E, Escamilla-Honrubia JM, Marco-Martin C, Gougeard N, De Micheke G, Morra VB, et al. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. Brain. 2016;139:e3.
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
Stavropulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram T, et al. Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine. NPJ Genom Med. 2016;1:15012.
Baumgartner MR, Hu CA, Almashanu S, Steel G, Obie C, Aral B, et al. Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. Hum Mol Genet. 2000;9:2853–8.
Bicknell LS, Pitt J, Aftimos S, Ramadas R, Maw MA, Robertson SP. A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome. Eur J Hum Genet. 2008;16:1176.
Fischer B, Callewaert B, Schröter P, Coucke PJ, Schlack C, Ott CE, et al. Sever congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1. Mol Genet Metab. 2014;112:310–6.
Nozaki F, Kusunoki T, Okamoto N, Yamamoto Y, Miya F, Tsunoda T, et al. ALDH18A-related cutis laxa syndrome with cyclic vomiting. Brain Dev. 2016;38:678–84.
Martinelli D, Häberle J, Rubio V, Giunta C, Hausser I, Carrozzo R, et al. Understanding pyrroline-5-carboxylate synthetase deficiency: clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine. J Inherit Metab Dis. 2012;35:761–76.
Fischer-Zirnsak B, Escande-Beillard N, Ganesh J, Tan YX, Al Bughaili M, Lin AE, et al. Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa. Am J Hum Genet. 2015;97:483–92.
Zampatti S, Castori M, Fischer B, Ferrari P, Garavelli L, Dionisi-Vici C, et al. De Barsy syndrome: a genetically heterogeneous autosomal recessice cutis laxa syndrome related to P5CS and PYCR1 dysfunction. Am J Med Genet A. 2012;158A:927–31.
Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, et al. Genetic diagnosis of mendelian disorders via RNA sequencing. Nat Commun. 2017;8:15824.
Handley MT, Mégarbané A, Meynert AM, Brown S, Freyer E, Taylor MS, et al. Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome. Mol Genet Genomic Med. 2014;2:319–25.
Wolthuis DF, van Asbeck E, Mohamed M, Gardeitchik T, Lim-Melia ER, Wevers RA, et al. Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature. Eur J Paediatr Neurol. 2014;18:511–5.
Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Caupa M, Bertini E, et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002;71:518–27.
Blauw HM, van Rheenen W, Koppers M, Van Damme P, Waibel S, Lemmens R, et al. NIPA1 polyalanine repeats expansions are associated with amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21:2497–502.
Montecchiani C, Pedace L, Lo Giudice T, Casella A, Mearini M, Gaudiello F, et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016;139:73–85.
Tunca C, Akçimen F, Coşkun C, Gündoğdu-Eken A, Kocoglu C,Çevik B, et al. ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree. Eur J Hum Genet. 2018;26:745–8.
Brenner, D, Yilmaz, R, Müller, K, Grehl, T, Petri, S, Meyer, T, et al. Hot-spot KIF5A mutations cause familial ALS. Brain (2018). Epub ahead of print..
Alazami AM, Al-Qattan SM, Faqeih E, Alhashem A, Alshammari M, Alzahrani F, et al. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue. Hum Genet. 2016;135:525–40.
Bhola PT, Hartley T, Bareke E, Nikkel SM, Dyment DA, Care4Rare Canada Consortium. Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1. J Hum Genet. 2017;62:661–3.
Acknowledgements
We thank the participants and cooperating doctors in the Japan Spastic Paraplegia Research Consortium (JASPAC). This work was supported by Grants-in-Aid from the Research Committee for Ataxic Disease (Y.T.), the Ministry of Health, Labor and Welfare, Japan, JSPS KAKENHI Grant Number JP17K17772 (K.K.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and grants for AMED under Grant Numbers JP17ek0109078 (Y.T.), JP16kk0205001h0001 (S.T.), and JP17kk0205001h0002 (S.T.).
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Accession Numbers: The nucleotide sequence data reported are available in the GenBank. database under the accession numbers: MH155295, MH155296, MH155297, MH155298, MH155299, MH155300, MH155301, and MH155302.
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Koh, K., Ishiura, H., Beppu, M. et al. Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment. J Hum Genet 63, 1009–1013 (2018). https://doi.org/10.1038/s10038-018-0477-0
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DOI: https://doi.org/10.1038/s10038-018-0477-0
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