Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

Abstract

Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.

We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.

Keywords

cutis laxa - ALDH18A1 - neurological findings - vascular tortuosity

• References

• 1 Mohamed M, Voet M, Gardeitchik T, Morava E. Cutis laxa. In: Halper J. , ed. Progress in Heritable Soft Connective Tissue Diseases [Internet]. Dordrecht: Springer Netherlands; 2014: 161-184 . (Advances in Experimental Medicine and Biology). Available at: https://doi.org/10.1007/978-94-007-7893-1_11 . Accessed September 26, 2019
• 2 Ritelli M, Cammarata-Scalisi F, Cinquina V, Colombi M. Clinical and molecular characterization of an 18-month-old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review. Mol Genet Genomic Med 2019; 7 (07) e00735
• 3 Wolthuis DFGJ, van Asbeck E, Mohamed M. , et al. Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature. Eur J Paediatr Neurol 2014; 18 (04) 511-515
• 4 Coutelier M, Goizet C, Durr A. , et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 2015; 138 (Pt 8): 2191-2205
• 5 Panza E, Escamilla-Honrubia JM, Marco-Marín C. , et al. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. Brain 2016; 139 (Pt 1): e3-e3
• 6 Kivuva EC, Parker MJ, Cohen MC, Wagner BE, Sobey G. De Barsy syndrome: a review of the phenotype. Clin Dysmorphol 2008; 17 (02) 99-107
• 7 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 (10) 1176-1186
• 8 Lefebvre M, Beaufrere A-M, Francannet C. , et al. Extending the ALDH18A1 clinical spectrum to severe autosomal recessive fetal cutis laxa with corpus callosum agenesis. Am J Med Genet A 2018; 176 (11) 2509-2512
• 9 de Barsy AM, Moens E, Dierckx L. Dwarfism, oligophrenia and degeneration of the elastic tissue in skin and cornea. A new syndrome?. Helv Paediatr Acta 1968; 23 (03) 305-313
• 10 Hoefnagel D, Pomeroy J, Wurster D, Saxon A. Congenital athetosis, mental deficiency, dwarfism and laxity of skin and ligaments. Helv Paediatr Acta 1971; 26 (04) 397-402
• 11 Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ1-pyrroline-5-carboxylate synthase (P5CS) - Skidmore - 2011 - American Journal of Medical Genetics Part A - Wiley Online Library [Internet]. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.34057 . Accessed June 4, 2019
• 12 Fischer-Zirnsak B, Escande-Beillard N, Ganesh J. , 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 (03) 483-492
• 13 Desvignes J-P, Bartoli M, Delague V. , et al. VarAFT: a variant annotation and filtration system for human next generation sequencing data. Nucleic Acids Res 2018; 46 (W1): W545-W553
• 14 Robinson JT, Thorvaldsdóttir H, Winckler W. , et al. Integrative genomics viewer. Nat Biotechnol 2011; 29 (01) 24-26
• 15 Richards S, Aziz N, Bale S. , et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 16 Baumgartner MR, Rabier D, Nassogne M-C. , et al. Δ1-pyrroline-5-carboxylate synthase deficiency: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline. Eur J Pediatr 2005; 164 (01) 31-36
• 17 Fischer B, Callewaert B, Schröter P. , et al. Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1. Mol Genet Metab 2014; 112 (04) 310-316
• 18 Sinnige PF, van Ravenswaaij-Arts CMA, Caruso P. , et al. Imaging in cutis laxa syndrome caused by a dominant negative ALDH18A1 mutation, with hypotheses for intracranial vascular tortuosity and wide perivascular spaces. Eur J Paediatr Neurol 2017; 21 (06) 912-920
• 19 Martinelli D, Häberle J, Rubio V. , 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 (05) 761-776
• 20 Magini P, Marco-Marin C, Escamilla-Honrubia JM. , et al. P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9. Ann Clin Transl Neurol 2019; 6 (08) 1533-1540
• 21 MetaDome. Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains - Wiel - 2019 - Human Mutation - Wiley Online Library [Internet]. Available at: https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23798 . Accessed October 8, 2019