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

Noriko Miyake, Nicole I. Wolf, Ferdy K. Cayami, Joanna Crawford, Annette Bley, Dorothy Bulas, Alex Conant, Stephen J. Bent, Karen W. Gripp, Andreas Hahn, Sean Humphray, Shihoko Kimura-Ohba, Zoya Kingsbury, Bryan R. Lajoie, Dennis Lal, Dimitra Micha, Amy Pizzino, Richard J. Sinke, Deborah Sival, Irene Stolte-Dijkstra & 9 others Andrea Superti-Furga, Nicole Ulrick, Ryan J. Taft, Tsutomu Ogata, Keiichi Ozono, Naomichi Matsumoto, Bernd A. Neubauer, Cas Simons, Adeline Vanderver

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)185-194
Number of pages10
JournalNeurogenetics
Volume18
Issue number4
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

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. / X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. In: Neurogenetics. 2017 ; Vol. 18, No. 4. pp. 185-194.
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title = "X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1",
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)",
author = "Noriko Miyake and Wolf, {Nicole I.} and Cayami, {Ferdy K.} and Joanna Crawford and Annette Bley and Dorothy Bulas and Alex Conant and Bent, {Stephen J.} and Gripp, {Karen W.} and Andreas Hahn and Sean Humphray and Shihoko Kimura-Ohba and Zoya Kingsbury and Lajoie, {Bryan R.} and Dennis Lal and Dimitra Micha and Amy Pizzino and Sinke, {Richard J.} and Deborah Sival and Irene Stolte-Dijkstra and Andrea Superti-Furga and Nicole Ulrick and Taft, {Ryan J.} and Tsutomu Ogata and Keiichi Ozono and Naomichi Matsumoto and Neubauer, {Bernd A.} and Cas Simons and Adeline Vanderver",
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Miyake, N, Wolf, NI, Cayami, FK, Crawford, J, Bley, A, Bulas, D, Conant, A, Bent, SJ, Gripp, KW, Hahn, A, Humphray, S, Kimura-Ohba, S, Kingsbury, Z, Lajoie, BR, Lal, D, Micha, D, Pizzino, A, Sinke, RJ, Sival, D, Stolte-Dijkstra, I, Superti-Furga, A, Ulrick, N, Taft, RJ, Ogata, T, Ozono, K, Matsumoto, N, Neubauer, BA, Simons, C & Vanderver, A 2017, 'X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1' Neurogenetics, vol. 18, no. 4, pp. 185-194. https://doi.org/10.1007/s10048-017-0520-x

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; Vanderver, Adeline.

In: Neurogenetics, Vol. 18, No. 4, 01.12.2017, p. 185-194.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

AU - Miyake, Noriko

AU - Wolf, Nicole I.

AU - Cayami, Ferdy K.

AU - Crawford, Joanna

AU - Bley, Annette

AU - Bulas, Dorothy

AU - Conant, Alex

AU - Bent, Stephen J.

AU - Gripp, Karen W.

AU - Hahn, Andreas

AU - Humphray, Sean

AU - Kimura-Ohba, Shihoko

AU - Kingsbury, Zoya

AU - Lajoie, Bryan R.

AU - Lal, Dennis

AU - Micha, Dimitra

AU - Pizzino, Amy

AU - Sinke, Richard J.

AU - Sival, Deborah

AU - Stolte-Dijkstra, Irene

AU - Superti-Furga, Andrea

AU - Ulrick, Nicole

AU - Taft, Ryan J.

AU - Ogata, Tsutomu

AU - Ozono, Keiichi

AU - Matsumoto, Naomichi

AU - Neubauer, Bernd A.

AU - Simons, Cas

AU - Vanderver, Adeline

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - AIFM1 gene

KW - Hypomyelination

KW - Mitochondrial leukodystrophy

KW - Myelin

KW - Spondylometaphyseal dysplasia

KW - Whole exome sequencing (WES)

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U2 - 10.1007/s10048-017-0520-x

DO - 10.1007/s10048-017-0520-x

M3 - Article

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JO - Neurogenetics

JF - Neurogenetics

SN - 1364-6745

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