X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1
Open accessAbstract
An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.
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Reanalysis identified a de novo missense variant in H3F3B, a hemizygous synonymous variant in AIFM1, and biallelic variants in HIKESHI, NKX6-2, and SPATA5, all previously associated with prominent white matter disease in multiple affected individuals.
“These included a de novo missense variant in H3F3B (OMIM:601058) (LD_0246), 11 a hemizygous, synonymous variant in AIFM1 (OMIM:300169) (LD_0500),12 and biallelic variants in HIKESHI (OMIM:614908) (LD_0162),13 NKX6‐2 (OMIM:605955) (LD_0527), 14 and SPATA5 (OMIM:613940) (LD_0808),15 all previously associated with prominent white matter disease in multiple affected individuals.”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [12]
Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1, HIKESHI, H3F3B, NKX6-2, and SPATA5, and genes missed in the previous analysis (L1CAM).
“Reanalysis by genome sequencing also led to the identification of variants in recently described disease genes AIFM1,12 HIKESHI, 13 H3F3B, 11 NKX6‐2, 14 and SPATA5, 15 and genes missed in the previous analysis (L1CAM).”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [12]
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Cites
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
Update on leukodystrophies: A historical perspective and adapted definition
Kevelam, S., Steenweg, M., Srivastava, S., Helman, G., Naidu, S., Schiffmann, R., Blaser, S., Vanderver, A., Wolf, N., & van der Knaap, M. (2016) · Neuropediatrics · doi:10.1055/s-0036-1588020 · Cited by 112 · see citing works
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Research works printed but not linked: 24
- [2]Pouwels PJ Vanderver A Bernard G Wolf NI Dreha-Kulczewksi SF Deoni SC Bertini E Kohlschutter A Richardson W Ffrench-Constant C Hypomyelinating leukodystrophies: translational research progress and prospects Ann Neurol 2014 76 5 19 10.1002/ana.24194 24916848 · DOI
- [4]Neubauer BA Stefanova I Hubner CA Neumaier-Probst E Bohl J Oppermann HC Sto H Hahn A Stephani U Kohlschutter A A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27 Neurology 2006 67 587 591 10.1212/01.wnl.0000230133.11951.75 16924009 · DOI
- [5]Kimura-Ohba S Kagitani-Shimono K Hashimoto N Nabatame S Okinaga T Murakami A Miyake N Matsumoto N Osaka H Hojo K A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia Am J Med Genet A 2013 161A 203 207 10.1002/ajmg.a.35686 23239615 · DOI
- [6]Bieganski T Dawydzik B Kozlowski K Spondylo-epimetaphyseal dysplasia: a new X-linked variant with mental retardation Eur J Pediatr 1999 158 809 814 10.1007/s004310051211 10486082 · DOI
- [7]Mierzewska H Rydzanicz M Bieganski T Kosinska J Mierzewska-Schmidt M Lugowska A Pollak A Stawinski P Walczak A Kedra A Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease Clin Genet 2017 91 30 37 10.1111/cge.12792 27102849 · DOI
- [8]Micha D Voermans E Eekhoff ME van Essen HW Zandieh-Doulabi B Netelenbos C Rustemeyer T Sistermans EA Pals G Bravenboer N Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease Bone 2016 84 169 180 10.1016/j.bone.2016.01.004 26769004 · DOI
- [9]Gregory CA Gunn WG Peister A Prockop DJ An alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction Anal Biochem 2004 329 77 84 10.1016/j.ab.2004.02.002 15136169 · DOI
- [10]Naaijkens BA Niessen HW Prins HJ Krijnen PA Kokhuis TJ de Jong N van Hinsbergh VW Kamp O Helder MN Musters RJ Human platelet lysate as a fetal bovine serum substitute improves human adipose-derived stromal cell culture for future cardiac repair applications Cell Tissue Res 2012 348 119 130 10.1007/s00441-012-1360-5 22395775 PMC3316780 · DOI
- [11]Wang YH Liu Y Maye P Rowe DW Examination of mineralized nodule formation in living osteoblastic cultures using fluorescent dyes Biotechnol Prog 2006 22 1697 1701 10.1002/bp060274b 17137320 PMC2538552 · DOI
- [12]Golub EE Harrison G Taylor AG Camper S Shapiro IM The role of alkaline phosphatase in cartilage mineralization Bone Miner 1992 17 273 278 10.1016/0169-6009(92)90750-8 1611320 · DOI
- [13]Desmet FO Hamroun D Lalande M Collod-Beroud G Claustres M Beroud C Human splicing finder: an online bioinformatics tool to predict splicing signals Nucleic Acids Res 2009 37 e67 10.1093/nar/gkp215 19339519 PMC2685110 · DOI
- [15]Ferreira P Villanueva R Martinez-Julvez M Herguedas B Marcuello C Fernandez-Silva P Cabon L Hermoso JA Lostao A Susin SA Structural insights into the coenzyme mediated monomer-dimer transition of the pro-apoptotic apoptosis inducing factor Biochemistry 2014 53 4204 4215 10.1021/bi500343r 24914854 · DOI
- [16]Sevrioukova IF Apoptosis-inducing factor: structure, function, and redox regulation Antioxid Redox Signal 2011 14 2545 2579 10.1089/ars.2010.3445 20868295 PMC3096518 · DOI
- [17]Vahsen N Cande C Briere JJ Benit P Joza N Larochette N Mastroberardino PG Pequignot MO Casares N Lazar V AIF deficiency compromises oxidative phosphorylation EMBO J 2004 23 4679 4689 10.1038/sj.emboj.7600461 15526035 PMC533047 · DOI
- [18]Sevrioukova IF Structure/function relations in AIFM1 variants associated with neurodegenerative disorders J Mol Biol 2016 428 3650 3665 10.1016/j.jmb.2016.05.004 27178839 · DOI
- [19]Diodato D Tasca G Verrigni D D'Amico A Rizza T Tozzi G Martinelli D Verardo M Invernizzi F Nasca A A novel AIFM1 mutation expands the phenotype to an infantile motor neuron disease Eur J Hum Genet 2016 24 463 466 10.1038/ejhg.2015.141 26173962 PMC4755377 · DOI
- [20]Zong L Guan J Ealy M Zhang Q Wang D Wang H Zhao Y Shen Z Campbell CA Wang F Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder J Med Genet 2015 52 523 531 10.1136/jmedgenet-2014-102961 25986071 PMC4518735 · DOI
- [21]Ardissone A Piscosquito G Legati A Langella T Lamantea E Garavaglia B Salsano E Farina L Moroni I Pareyson D A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders Neurology 2015 84 2193 2195 10.1212/WNL.0000000000001613 25934856 PMC4451043 · DOI
- [22]Ghezzi D Sevrioukova I Invernizzi F Lamperti C Mora M D'Adamo P Novara F Zuffardi O Uziel G Zeviani M Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor Am J Hum Genet 2010 86 639 649 10.1016/j.ajhg.2010.03.002 20362274 PMC2850437 · DOI
- [23]Cowchock FS Duckett SW Streletz LJ Graziani LJ Jackson LG X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder Am J Med Genet 1985 20 307 315 10.1002/ajmg.1320200214 3856385 · DOI
- [24]Rinaldi C Grunseich C Sevrioukova IF Schindler A Horkayne-Szakaly I Lamperti C Landoure G Kennerson ML Burnett BG Bonnemann C Cowchock syndrome is associated with a mutation in apoptosis-inducing factor Am J Hum Genet 2012 91 1095 1102 10.1016/j.ajhg.2012.10.008 23217327 PMC3516602 · DOI
- [25]Nilius B Voets T The puzzle of TRPV4 channelopathies EMBO Rep 2013 14 152 163 10.1038/embor.2012.219 23306656 PMC3566843 · DOI
- [26]Nishimura G Lausch E Savarirayan R Shiba M Spranger J Zabel B Ikegawa S Superti-Furga A Unger S TRPV4-associated skeletal dysplasias Am J Med Genet C Semin Med Genet 2012 160C 190 204 10.1002/ajmg.c.31335 22791502 · DOI
- [27]Unger S Lausch E Stanzial F Gillessen-Kaesbach G Stefanova I Di Stefano CM Bertini E Dionisi-Vici C Nilius B Zabel B Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy? Am J Med Genet A 2011 155A 2860 2864 10.1002/ajmg.a.34268 21964829 · DOI
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Genome sequencing in persistently unsolved white matter disorders
Helman, G., Lajoie, B. R., Crawford, J., Takanohashi, A., Walkiewicz, M., Dolzhenko, E., Gross, A. M., Gainullin, V. G., Bent, S. J., Jenkinson, E. M., et al. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50957 · Cited by 39 · see citing works
Self-citation
- Authors
- Miyake, N., Wolf, N. I., Cayami, F. K., Crawford, J., Bley, A., Bulas, D., Conant, A., Bent, S. J., Gripp, K. W., Hahn, A., Humphray, S., Kimura-Ohba, S., Kingsbury, Z., Lajoie, B. R., Lal, D., Micha, D., Pizzino, A., Sinke, R. J., Sival, D., Stolte-Dijkstra, I., Superti-Furga, A., Ulrick, N., Taft, R. J., Ogata, T., Ozono, K., Matsumoto, N., Neubauer, B. A., Simons, C., & Vanderver, A.
- Affiliations
- Yokohama City University (JP)
- Amsterdam Neuroscience (NL)
- Diponegoro University (ID)
- The University of Queensland (AU)
- University Medical Center Hamburg-Eppendorf (DE)
- Children's National (US)
- Alfred I. duPont Hospital for Children (US)
- Justus-Liebig-Universität Gießen (DE)
- Illumina (United Kingdom) (GB)
- Illumina (United States) (US)
- Broad Institute (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University Medical Center Groningen (NL)
- Hamamatsu University School of Medicine (JP)
- The University of Osaka (JP)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Wolf, Nicole I.
- ORCID
- Miyake, Noriko
- Wolf, Nicole I.
- Cayami, Ferdy K.
- Crawford, Joanna
- Bley, Annette
- Bulas, Dorothy
- Bent, Stephen J.
- Gripp, Karen W.
- Hahn, Andreas
- Humphray, Sean
- Lajoie, Bryan R.
- Lal, Dennis
- Micha, Dimitra
- Pizzino, Amy
- Sinke, Richard J.
- Sival, Deborah
- Taft, Ryan J.
- Ogata, Tsutomu
- Ozono, Keiichi
- Matsumoto, Naomichi
- Neubauer, Bernd A.
- Simons, Cas
- Vanderver, Adeline
- Venue
- neurogenetics
- Published
- 2017-08-26
- Volume
- 18
- Issue
- 4
- Pages
- 185-194
- ISSN
- 1364-6745 (ISSN-L)
- 1364-6753
- PMC
- PMC5705759
- OpenAlex
- W2748469852
- Cited by
- 48
- References
- 2
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 4
- FWCI
- 3.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Neurogenetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by)
- IRIS (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Stofwisselkracht
- Ministry of Health, Labour and Welfare
- MEXT
- AMED
- National Health and Medical Research Council
- JSPS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- apoptosis-inducing factor, hypomyelinating leukodystrophy, spondylometaphyseal dysplasia, X-linked recessive inheritance, exon 7 mutations, osteoblasts, bone metabolism, myelination, retinopathy, pulmonary hypertension, exome sequencing, genotype-phenotype correlation
- MeSH terms
- Humans, Male, Intellectual Disability, Mutation, Myelin Sheath, Osteochondrodysplasias, Pedigree, Phenotype, Sequence Analysis, DNA, Genetic Predisposition to Disease, Genes, X-Linked, Apoptosis Inducing Factor
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