Neuropediatrics 2023; 54(02): 120-125
DOI: 10.1055/s-0042-1760366
Original Article

A Novel Homozygous Splice Site Variant in AIMP1 Gene Causing Hypomyelinating Leukodystrophy: Case Report and Review of the Literature

1   Department of Medical Genetics, Centro Hospitalar Universitário de São João, Porto, Portugal
Mafalda Sampaio
2   Department of Neuropediatrics, Centro Hospitalar Universitário de São João, Porto, Portugal
Isabel Alonso
3   Genetyca-ICM, Instituto de Estudos Celulares e Moleculares, Porto, Portugal
Sofia Quental
4   IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
5   Institute for Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal
Miguel Leão
1   Department of Medical Genetics, Centro Hospitalar Universitário de São João, Porto, Portugal
Raquel Sousa
2   Department of Neuropediatrics, Centro Hospitalar Universitário de São João, Porto, Portugal
› Author Affiliations


Background Biallelic pathogenic variants in AIMP1 gene cause hypomyelinating leukodystrophy type 3, a severe neurodegenerative disorder with early onset characterized by microcephaly, axial hypotonia, epilepsy, spasticity, and developmental delay.

Methods Clinical exome sequence was performed on patient's DNA and Sanger sequencing was used to confirm the candidate variant. To better characterize the effect of the genetic variant, functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) was performed.

Results We report a case of 2-year-old girl with microcephaly, significant global developmental delay, refractory epilepsy, flaccid paralysis, hypomyelination, leukodystrophy, and cerebral atrophy on brain magnetic resonance imaging (MRI). Clinical exome sequencing revealed a novel splice site variant c.603 + 1G > A in homozygosity in the AIMP1 gene. Studies on patient's cDNA showed that the variant disrupts the canonical donor splice site of intron 5, with the recognition of a cryptic splice site within exon 5, leading to the skipping of the last 24 nucleotides of this exon together with the flanking intron. This alteration is predicted to cause an in-frame deletion of eight amino acids (p.Val194_Gln201del) belonging to the tRNA-biding domain of the protein.

Conclusion To the best of our knowledge, this is the first report of a splice site variant in the AIMP1 gene causing hypomyelinating leukodystrophy. The description of this patient not only expands the mutational spectrum of AIMP1 but also provides deeper insights on genotype–phenotype correlation by comparing the clinical features of our patient with previously reported affected individuals.

Ethical Approval

Written informed consent was obtained from the legal representative of the patient.

Publication History

Received: 04 September 2022

Accepted: 21 October 2022

Article published online:
18 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Charzewska A, Wierzba J, Iżycka-Świeszewska E. et al. Hypomyelinating leukodystrophies - a molecular insight into the white matter pathology. Clin Genet 2016; 90 (04) 293-304
  • 2 Pouwels PJW, Vanderver A, Bernard G. et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol 2014; 76 (01) 5-19
  • 3 Wolf NI, Ffrench-Constant C, van der Knaap MS. Hypomyelinating leukodystrophies - unravelling myelin biology. Nat Rev Neurol 2021; 17 (02) 88-103
  • 4 Feinstein M, Markus B, Noyman I. et al. Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation. Am J Hum Genet 2010; 87 (06) 820-828
  • 5 Armstrong L, Biancheri R, Shyr C. et al. AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset. Neurogenetics 2014; 15 (03) 157-159
  • 6 Accogli A, Guerrero K, D'Agostino MD. et al; Care4Rare Canada Consortium. Biallelic loss-of-function variants in AIMP1 cause a rare neurodegenerative disease. J Child Neurol 2019; 34 (02) 74-80
  • 7 Accogli A, Russell L, Sébire G. et al. Pathogenic variants in AIMP1 cause pontocerebellar hypoplasia. Neurogenetics 2019; 20 (02) 103-108
  • 8 Khan A, Bennett J, Scantlebury MH, Wei X-C, Kerr M. AIMP1 mutation long-term follow-up, with decreased brain N-acetylaspartic acid and secondary mitochondrial abnormalities. Child Neurol Open 2019; 6: X19829520
  • 9 Hori I, Ieda D, Ito S. et al. Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant. Brain Dev 2021; 43 (04) 590-595
  • 10 Gupta S, Schwab M, Valdez-Gonzalez K, Segal E. Rare homozygous nonsense variant in AIMP1 causing early onset epileptic encephalopathy with burst suppression (EOEE-BS). Eur J Med Genet 2020; 63 (09) 103970
  • 11 Iqbal Z, Püttmann L, Musante L. et al. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration. Eur J Hum Genet 2016; 24 (03) 392-399
  • 12 BoAli A, Tlili-Graiess K, AlHashem A, AlShahwan S, Zuccoli G, Tabarki B. Novel homozygous mutation of the AIMP1 gene: a milder neuroimaging phenotype with preservation of the deep white matter. Pediatr Neurol 2019; 91: 57-61
  • 13 Zhu X, Liu Y, Yin Y. et al. MSC p43 required for axonal development in motor neurons. Proc Natl Acad Sci U S A 2009; 106 (37) 15944-15949
  • 14 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
  • 15 Gonzaga-Jauregui C, Harel T, Gambin T. et al; Baylor-Hopkins Center for Mendelian Genomics. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep 2015; 12 (07) 1169-1183
  • 16 Padgett RA. New connections between splicing and human disease. Trends Genet 2012; 28 (04) 147-154