X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

Miyake, Noriko, Wolf, Nicole I., Cayami, Ferdy K., Crawford, Joanna, Bley, Annette, Bulas, Dorothy, Conant, Alex, Bent, Stephen J., Gripp, Karen W., Hahn, Andreas, Humphray, Sean, Kimura-Ohba, Shihoko, Kingsbury, Zoya, Lajoie, Bryan R., Lal, Dennis, Micha, Dimitra, Pizzino, Amy, Sinke, Richard J., Sival, Deborah, Stolte-Dijkstra, Irene, Superti-Furga, Andrea, Ulrick, Nicole, Taft, Ryan J., Ogata, Tsutomu, Ozono, Keiichi, Matsumoto, Naomichi, Neubauer, Bernd A., Simons, Cas and Vanderver, Adeline (2017) X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics, 18 4: 185-194. doi:10.1007/s10048-017-0520-x

Author Miyake, Noriko
Wolf, Nicole I.
Cayami, Ferdy K.
Crawford, Joanna
Bley, Annette
Bulas, Dorothy
Conant, Alex
Bent, Stephen J.
Gripp, Karen W.
Hahn, Andreas
Humphray, Sean
Kimura-Ohba, Shihoko
Kingsbury, Zoya
Lajoie, Bryan R.
Lal, Dennis
Micha, Dimitra
Pizzino, Amy
Sinke, Richard J.
Sival, Deborah
Stolte-Dijkstra, Irene
Superti-Furga, Andrea
Ulrick, Nicole
Taft, Ryan J.
Ogata, Tsutomu
Ozono, Keiichi
Matsumoto, Naomichi
Neubauer, Bernd A.
Simons, Cas
Vanderver, Adeline
Title X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1
Journal name Neurogenetics   Check publisher's open access policy
ISSN 1364-6753
Publication date 2017-08-26
Year available 2017
Sub-type Article (original research)
DOI 10.1007/s10048-017-0520-x
Open Access Status DOI
Volume 18
Issue 4
Start page 185
End page 194
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
2804 Cellular and Molecular Neuroscience
Abstract 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.
Keyword AIFM1 gene
Mitochondrial leukodystrophy
Spondylometaphyseal dysplasia
Whole exome sequencing (WES)
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Institute for Molecular Bioscience - Publications
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Created: Thu, 23 Nov 2017, 23:51:44 EST