Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/111741
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Type: Journal article
Title: X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1
Author: Miyake, N.
Wolf, N.
Cayami, F.
Crawford, J.
Bley, A.
Bulas, D.
Conant, A.
Bent, S.
Gripp, K.
Hahn, A.
Humphray, S.
Kimura-Ohba, S.
Kingsbury, Z.
Lajoie, B.
Lal, D.
Micha, D.
Pizzino, A.
Sinke, R.
Sival, D.
Stolte-Dijkstra, I.
et al.
Citation: Neurogenetics, 2017; 18(4):185-194
Publisher: Springer
Issue Date: 2017
ISSN: 1364-6745
1364-6753
Statement of
Responsibility: 
Noriko Miyake, Nicole I. Wolf, Ferdy K. Cayami, Joanna Crawford, Annette Bley … Stephen J. Bent … et al.
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.
Keywords: AIFM1 gene
Hypomyelination
Mitochondrial leukodystrophy
Myelin
Spondylometaphyseal dysplasia
Whole exome sequencing (WES)
Rights: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
DOI: 10.1007/s10048-017-0520-x
Grant ID: NHMRC
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