SHORT COMMUNICATION
Contribution of copy number variations in CMT1X: a retrospective study S. Capponia, A. Geroldia, I. Pezzinia, R. Gullia, P. Ciottia, G. Ursinob, M. Lampa, L. Renib, A. Schenoneb, M. Grandisb, P. Mandicha and E. Bellonea a Section of Medical Genetics, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa; and bSection of Neurology, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
EUROPEAN JOURNAL OF NEUROLOGY
Keywords:
CMT1X, genotypephenotype correlation, GJB1 deletion Received 8 January 2014 Accepted 6 March 2014 European Journal of Neurology 2015, 22: 406–409 doi:10.1111/ene.12434
Background and purpose: CharcotMarieTooth disease type 1X (CMT1X) is an X-linked dominant hereditary motor-sensory peripheral neuropathy, which results from mutations in the Gap Junction B1 (GJB1) gene. In a few cases, gene deletions have been linked to the disease, but their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Herein a retrospective study to establish the incidence of gene deletions is described. Methods: Copy number variation analysis was performed by multiplex ligation-dependent probe amplification, whilst the breakpoints were defined by Sanger sequencing. Results: A novel GJB1 deletion was identified in a family presenting with a classical CMT1X phenotype. The rearrangement includes the coding and the regulatory regions of GJB1. Conclusions: GJB1 deletions appear to be a rare but not insignificant cause of CMT1X and are associated with a typical disease phenotype. Accordingly, patients negative for point mutations whose pedigree and clinical records strongly suggest the possibility of CMT1X should be tested for GJB1 copy number variations.
Introduction The X-linked form of CharcotMarieTooth disease (CMT1X, OMIM 302800) is the second most common form of inherited motor-sensory peripheral neuropathy, accounting for 10%–20% of the total CMT population [1]. Clinically, it presents with progressive muscle wasting, weakness, areflexia, variable sensory abnormalities and intermediate slowing of nerve conduction velocities. CMT1X is a dominant disorder: females display a variable disease severity, usually with a later onset and a milder phenotype than males. Moreover, the neuropathy is predominantly demyelinating in males and axonal in females [2]. CMT1X results from mutations in Gap Junction B1 (GJB1) [3,4]. It encodes connexin32, a protein involved in the formation of reflexive gap junctions between the layers of a Schwann cell myelin sheath [2]. Correspondence: S. Capponi, DINOGMI, Section of Medical Genetics, University of Genoa, Viale Benedetto XV, Genoa, Italy (tel.: +39 0103537957; fax: +39 0103538972; e-mail: simona.capponi@ unige.it).
406
Although more than 400 mutations have been reported [2], only a few GJB1 deletions have been described (reviewed in [ 5]) and their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Here a retrospective study of 45 CMT1X females to estimate the incidence of GJB1 deletions is reported. Copy number variations (CNVs) in this locus might provide further insight into the aetiology of CMT1X, accounting for a portion of missing heritability.
Patients and methods Forty-five females were selected from an initial series of 211 index cases with family history, clinical and electrophysiological features compatible with CMT1X, negative for mutations in the GJB1 coding region, the nerve-specific non-coding exon 1B (P2) and the upstream promoter. Families where only females were affected or the DNA of the affected males was not available were included. Males were excluded since a
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
RETROSPECTIVE STUDY OF CNVS IN CMT1X
GJB1 deletion would have been detected as a lack of gene amplification. Mutations in the major genes associated with axonal and intermediate CMT were also excluded. Informed consent was obtained from all participants and the study was approved by the local ethics committee. Genomic DNA was isolated from peripheral blood using standard procedures. The CNV analysis was performed with multiplex ligation-dependent probe amplification (MLPA) (SALSA MLPA P129, MRCHolland, Amsterdam, the Netherlands) and confirmed by quantitative polymerase chain reaction (qPCR). The breakpoints were sequenced on a 3130xl Genetic Analyser and aligned with SeqScape v2.7 (Life Technologies, Carlsbad, CA, USA) (reference sequence NM_001097642.2).
Results Molecular analysis
The MLPA and qPCR analyses revealed the presence of one novel GJB1 deletion in one patient out of 45.
(a)
407
The patient had a positive family history for neurological conditions (Fig. 1a) and the subsequent recruitment of her affected son allowed the CNV segregation to be confirmed. The rearrangement, spanning 11.7 kb, included the coding region, the P2 and the promoter (Fig. 1b) and presented a microhomology of three base pairs at the junction (Fig. 1c). Moreover, the 50 breakpoint was located in the proximity of an AluY element, whilst the 30 breakpoint was inserted within an AluSp sequence. Case report
The proband (II-2, Fig. 1a) presented with progressive gait disturbances since the age of 13. Neurological examination (57 years) showed bilateral pes cavus and foot drop, severe distal muscle weakness and atrophy of the lower limbs (LLs), moderate hand muscle atrophy and slightly decreased strength of the upper limbs (ULs). Sensory modalities and coordination were unaffected. Deep tendon reflexes were absent in the LLs and reduced in the ULs; CMT neuropathy score was 11/36. Electrophysiological findings showed an
(b)
(c)
Figure 1 A novel GJB1 deletion identified in an Italian CMT1X family. (a) Proband’s family pedigree; (b) MLPA results; (c) breakpoint junction.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
408
S. CAPPONI ET AL.
Table 1 Electrophysiological studies of patients II-2 and III-1 II-2 (disease duration 44 years) Motor nerves r-Median l-Median r-Ulnar
l-Ulnar
r-Peroneal l-Peroneal
E-W E-W Ax-Ab. E Ab. E-Bel. E E-W Ax- Ab. E Ab. E-Bel. E E-W PF-FH PF-FH
NCV (m/s)
dL (ms)
CMAP (mV)
NCV (m/s)
dL (ms)
CMAP (mV)
36.5 32.1 53.8 48.8 44.7 63.1 71.4 47.7 Absent 43
5.8 6.5 3.8 3.8 3.8 2.8 2.8 2.8 Absent 4.3
0.2 0.4 3.1 2.7 4 3.4 3.4 5.4 Absent 2.3
Absent 26.5 27.6 37.5 36 31.3 38.9 28.3 Absent Absent
Absent 9.8 4.5 4.5 4.5 4.2 4.2 4.2 Absent Absent
Absent 0.6 2.5 2.5 4.7 2.8 2.8 2.8 Absent Absent
Sensory nerves r-Sural l-Sural r-Median l-Median r-Ulnar l-Ulnar
III-1 (disease duration 9 years)
A-SURA A-SURA IF-W IF-W VF-W VF-W
NCV (m/s)
SAP (lV)
NCV (m/s)
SAP (lV)
29.7 33.3 33.3 35.7 32.8 23.2
4.4 7 3.1 1.9 3.4 2.3
33 36.7 34.1 34.8 34.6 34.9
0.2 0.5 2.6 2.3 1.6 3.8
r-, right; l-, left; NCV, nerve conduction velocity; dL, distal latency; CMAP, compound muscle action potential; SAP, sensory action potential; E, elbow; W, wrist; Ax, axilla; Ab. E, above elbow; Bel. E, below elbow; PF, popliteal fossa; FH, fibula head; A, ankle; SURA, calf of the leg; IF, first finger; VF, fifth finger.
intermediate slowing of nerve conduction velocities (Table 1). The proband’s son developed gait difficulties and fatigue at the age of 14, requiring ankle-foot orthoses. Neurological examination (17 years) showed lumbar scoliosis, wide-based steppage, bilateral foot drop, pes cavus and hammer toes, LL distal hypotrophy, mild atrophy of hand muscles and slightly decreased strength at the ULs. CMT neuropathy score was 10/ 36. Electrophysiological studies showed a mixed demyelinating and axonal neuropathy (Table 1). Clinical features of the other 44 patients are summarized in Table S1.
Discussion In this study, the contribution of GJB1 deletions in the pathogenesis of CMT1X was evaluated. A novel deletion was identified in one family and, to the best of our knowledge, this is the first European family in which a GJB1 CNV has been identified. The breakpoint analysis suggested the rearrangement to be sustained by a synergic model where two divergent Alu repeats facilitate a microhomology-mediated event. Interestingly, Gonzaga-Jauregui and collaborators previously showed that GJB1 deletions are sustained by microhomology-based events, although reporting different breakpoints [5]. The CNV herein described is an additional confirmation that GJB1 deletions are non-recurrent, but the frequency of microhomology-
mediated events at this locus may partially reflect the genomic architecture of the Xq13.1 region, which might stimulate structural rearrangements. CMT disease mainly results from mutations in more than 70 genes, and although the first genetic defect identified was the 17p11.2 duplication [6], nonCMT1A CNVs play a minor role [7]. Recently, CNVs have gained more attention, with the identification of MPZ multiplication and MFN2 exons 78 deletion [8,9]. The description of these rearrangements makes indispensable the introduction of specific assays to detect CNVs in the routine diagnostics of CMT, since structural variations might account for a portion of missing heritability. This is even more important for CMT1X, since literature data highlight how the phenotype of patients with point mutations is similar to those with a gene deletion and that no clinical feature can drive towards one molecular defect or the other [10]. The clinical presentation of our family confirms this observation: the phenotype was very suggestive of a CMT1X, supporting once more how GJB1 mutations result in a loss-of-function effect [10]. In the molecular flowchart of CMT1X, CNVs appear to be a rare cause, compared with GJB1 point mutations. In our series, coding and regulatory mutations account for 20% (data not shown), whilst the whole gene deletion only represents 0.5% (1/211). Nevertheless, considering the GJB1 genomic architecture, prone to rearrange, and the absence of any genotypephenotype correlation, clinicians should be alerted to the possibility
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
RETROSPECTIVE STUDY OF CNVS IN CMT1X
of investigating GJB1 copy number in CMT1X patients, negative for coding and regulatory mutations.
Acknowledgements The authors thank the patients, ACMT-rete and CMT@live associations for their kind cooperation and support.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Main features of female patients included in the CNV analysis.
References 1. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. CharcotMarieTooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69: 22–33.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
409
2. Scherer SS, Kleopa KA. X-linked CharcotMarie Tooth disease. J Peripher Nerv Syst 2012; 17(Suppl 3): 9–13. 3. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked CharcotMarieTooth disease. Science 1993; 262: 2039–2042. 4. Ionasescu VV, Searby C, Ionasescu R, Neuhaus IM, Werner R. Mutations of the noncoding region of the connexin32 gene in X-linked dominant CharcotMarieTooth neuropathy. Neurology 1996; 47: 541–544. 5. Gonzaga-Jauregui C, Zhang F, Towne CF, Batish SD, Lupski JR. GJB1/connexin 32 whole gene deletions in patients with X-linked CharcotMarieTooth disease. Neurogenetics 2010; 11: 465–470. 6. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with CharcotMarieTooth disease type 1A. Cell 1991; 66: 219–232. 7. Huang J, Wu X, Montenegro G, et al. Copy number variations are a rare cause of non-CMT1A CharcotMarieTooth disease. J Neurol 2010; 257: 735–741. 8. Maeda MH, Mitsui J, Soong BW, et al. Increased gene dosage of myelin protein zero causes Charcot MarieTooth disease. Ann Neurol 2012; 71: 84–92. 9. Polke JM, Laur a M, Pareyson D, et al. Recessive axonal CharcotMarieTooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 2011; 77: 168–173. 10. Shy ME, Siskind C, Swan ER, et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology 2007; 68: 849–855.
Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Contribution of copy number variations in CMT1X: a retrospective study S. Capponia, A. Geroldia, I. Pezzinia, R. Gullia, P. Ciottia, G. Ursinob, M. Lampa, L. Renib, A. Schenoneb, M. Grandisb, P. Mandicha and E. Bellonea a Section of Medical Genetics, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa; and bSection of Neurology, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
EUROPEAN JOURNAL OF NEUROLOGY
Keywords:
CMT1X, genotypephenotype correlation, GJB1 deletion Received 8 January 2014 Accepted 6 March 2014 European Journal of Neurology 2015, 22: 406–409 doi:10.1111/ene.12434
Background and purpose: CharcotMarieTooth disease type 1X (CMT1X) is an X-linked dominant hereditary motor-sensory peripheral neuropathy, which results from mutations in the Gap Junction B1 (GJB1) gene. In a few cases, gene deletions have been linked to the disease, but their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Herein a retrospective study to establish the incidence of gene deletions is described. Methods: Copy number variation analysis was performed by multiplex ligation-dependent probe amplification, whilst the breakpoints were defined by Sanger sequencing. Results: A novel GJB1 deletion was identified in a family presenting with a classical CMT1X phenotype. The rearrangement includes the coding and the regulatory regions of GJB1. Conclusions: GJB1 deletions appear to be a rare but not insignificant cause of CMT1X and are associated with a typical disease phenotype. Accordingly, patients negative for point mutations whose pedigree and clinical records strongly suggest the possibility of CMT1X should be tested for GJB1 copy number variations.
Introduction The X-linked form of CharcotMarieTooth disease (CMT1X, OMIM 302800) is the second most common form of inherited motor-sensory peripheral neuropathy, accounting for 10%–20% of the total CMT population [1]. Clinically, it presents with progressive muscle wasting, weakness, areflexia, variable sensory abnormalities and intermediate slowing of nerve conduction velocities. CMT1X is a dominant disorder: females display a variable disease severity, usually with a later onset and a milder phenotype than males. Moreover, the neuropathy is predominantly demyelinating in males and axonal in females [2]. CMT1X results from mutations in Gap Junction B1 (GJB1) [3,4]. It encodes connexin32, a protein involved in the formation of reflexive gap junctions between the layers of a Schwann cell myelin sheath [2]. Correspondence: S. Capponi, DINOGMI, Section of Medical Genetics, University of Genoa, Viale Benedetto XV, Genoa, Italy (tel.: +39 0103537957; fax: +39 0103538972; e-mail: simona.capponi@ unige.it).
406
Although more than 400 mutations have been reported [2], only a few GJB1 deletions have been described (reviewed in [ 5]) and their relative contribution in the pathogenesis of CMT1X has not been assessed yet. Here a retrospective study of 45 CMT1X females to estimate the incidence of GJB1 deletions is reported. Copy number variations (CNVs) in this locus might provide further insight into the aetiology of CMT1X, accounting for a portion of missing heritability.
Patients and methods Forty-five females were selected from an initial series of 211 index cases with family history, clinical and electrophysiological features compatible with CMT1X, negative for mutations in the GJB1 coding region, the nerve-specific non-coding exon 1B (P2) and the upstream promoter. Families where only females were affected or the DNA of the affected males was not available were included. Males were excluded since a
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
RETROSPECTIVE STUDY OF CNVS IN CMT1X
GJB1 deletion would have been detected as a lack of gene amplification. Mutations in the major genes associated with axonal and intermediate CMT were also excluded. Informed consent was obtained from all participants and the study was approved by the local ethics committee. Genomic DNA was isolated from peripheral blood using standard procedures. The CNV analysis was performed with multiplex ligation-dependent probe amplification (MLPA) (SALSA MLPA P129, MRCHolland, Amsterdam, the Netherlands) and confirmed by quantitative polymerase chain reaction (qPCR). The breakpoints were sequenced on a 3130xl Genetic Analyser and aligned with SeqScape v2.7 (Life Technologies, Carlsbad, CA, USA) (reference sequence NM_001097642.2).
Results Molecular analysis
The MLPA and qPCR analyses revealed the presence of one novel GJB1 deletion in one patient out of 45.
(a)
407
The patient had a positive family history for neurological conditions (Fig. 1a) and the subsequent recruitment of her affected son allowed the CNV segregation to be confirmed. The rearrangement, spanning 11.7 kb, included the coding region, the P2 and the promoter (Fig. 1b) and presented a microhomology of three base pairs at the junction (Fig. 1c). Moreover, the 50 breakpoint was located in the proximity of an AluY element, whilst the 30 breakpoint was inserted within an AluSp sequence. Case report
The proband (II-2, Fig. 1a) presented with progressive gait disturbances since the age of 13. Neurological examination (57 years) showed bilateral pes cavus and foot drop, severe distal muscle weakness and atrophy of the lower limbs (LLs), moderate hand muscle atrophy and slightly decreased strength of the upper limbs (ULs). Sensory modalities and coordination were unaffected. Deep tendon reflexes were absent in the LLs and reduced in the ULs; CMT neuropathy score was 11/36. Electrophysiological findings showed an
(b)
(c)
Figure 1 A novel GJB1 deletion identified in an Italian CMT1X family. (a) Proband’s family pedigree; (b) MLPA results; (c) breakpoint junction.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
408
S. CAPPONI ET AL.
Table 1 Electrophysiological studies of patients II-2 and III-1 II-2 (disease duration 44 years) Motor nerves r-Median l-Median r-Ulnar
l-Ulnar
r-Peroneal l-Peroneal
E-W E-W Ax-Ab. E Ab. E-Bel. E E-W Ax- Ab. E Ab. E-Bel. E E-W PF-FH PF-FH
NCV (m/s)
dL (ms)
CMAP (mV)
NCV (m/s)
dL (ms)
CMAP (mV)
36.5 32.1 53.8 48.8 44.7 63.1 71.4 47.7 Absent 43
5.8 6.5 3.8 3.8 3.8 2.8 2.8 2.8 Absent 4.3
0.2 0.4 3.1 2.7 4 3.4 3.4 5.4 Absent 2.3
Absent 26.5 27.6 37.5 36 31.3 38.9 28.3 Absent Absent
Absent 9.8 4.5 4.5 4.5 4.2 4.2 4.2 Absent Absent
Absent 0.6 2.5 2.5 4.7 2.8 2.8 2.8 Absent Absent
Sensory nerves r-Sural l-Sural r-Median l-Median r-Ulnar l-Ulnar
III-1 (disease duration 9 years)
A-SURA A-SURA IF-W IF-W VF-W VF-W
NCV (m/s)
SAP (lV)
NCV (m/s)
SAP (lV)
29.7 33.3 33.3 35.7 32.8 23.2
4.4 7 3.1 1.9 3.4 2.3
33 36.7 34.1 34.8 34.6 34.9
0.2 0.5 2.6 2.3 1.6 3.8
r-, right; l-, left; NCV, nerve conduction velocity; dL, distal latency; CMAP, compound muscle action potential; SAP, sensory action potential; E, elbow; W, wrist; Ax, axilla; Ab. E, above elbow; Bel. E, below elbow; PF, popliteal fossa; FH, fibula head; A, ankle; SURA, calf of the leg; IF, first finger; VF, fifth finger.
intermediate slowing of nerve conduction velocities (Table 1). The proband’s son developed gait difficulties and fatigue at the age of 14, requiring ankle-foot orthoses. Neurological examination (17 years) showed lumbar scoliosis, wide-based steppage, bilateral foot drop, pes cavus and hammer toes, LL distal hypotrophy, mild atrophy of hand muscles and slightly decreased strength at the ULs. CMT neuropathy score was 10/ 36. Electrophysiological studies showed a mixed demyelinating and axonal neuropathy (Table 1). Clinical features of the other 44 patients are summarized in Table S1.
Discussion In this study, the contribution of GJB1 deletions in the pathogenesis of CMT1X was evaluated. A novel deletion was identified in one family and, to the best of our knowledge, this is the first European family in which a GJB1 CNV has been identified. The breakpoint analysis suggested the rearrangement to be sustained by a synergic model where two divergent Alu repeats facilitate a microhomology-mediated event. Interestingly, Gonzaga-Jauregui and collaborators previously showed that GJB1 deletions are sustained by microhomology-based events, although reporting different breakpoints [5]. The CNV herein described is an additional confirmation that GJB1 deletions are non-recurrent, but the frequency of microhomology-
mediated events at this locus may partially reflect the genomic architecture of the Xq13.1 region, which might stimulate structural rearrangements. CMT disease mainly results from mutations in more than 70 genes, and although the first genetic defect identified was the 17p11.2 duplication [6], nonCMT1A CNVs play a minor role [7]. Recently, CNVs have gained more attention, with the identification of MPZ multiplication and MFN2 exons 78 deletion [8,9]. The description of these rearrangements makes indispensable the introduction of specific assays to detect CNVs in the routine diagnostics of CMT, since structural variations might account for a portion of missing heritability. This is even more important for CMT1X, since literature data highlight how the phenotype of patients with point mutations is similar to those with a gene deletion and that no clinical feature can drive towards one molecular defect or the other [10]. The clinical presentation of our family confirms this observation: the phenotype was very suggestive of a CMT1X, supporting once more how GJB1 mutations result in a loss-of-function effect [10]. In the molecular flowchart of CMT1X, CNVs appear to be a rare cause, compared with GJB1 point mutations. In our series, coding and regulatory mutations account for 20% (data not shown), whilst the whole gene deletion only represents 0.5% (1/211). Nevertheless, considering the GJB1 genomic architecture, prone to rearrange, and the absence of any genotypephenotype correlation, clinicians should be alerted to the possibility
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
RETROSPECTIVE STUDY OF CNVS IN CMT1X
of investigating GJB1 copy number in CMT1X patients, negative for coding and regulatory mutations.
Acknowledgements The authors thank the patients, ACMT-rete and CMT@live associations for their kind cooperation and support.
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. Main features of female patients included in the CNV analysis.
References 1. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. CharcotMarieTooth disease subtypes and genetic testing strategies. Ann Neurol 2011; 69: 22–33.
© 2014 The Author(s) European Journal of Neurology © 2014 EAN
409
2. Scherer SS, Kleopa KA. X-linked CharcotMarie Tooth disease. J Peripher Nerv Syst 2012; 17(Suppl 3): 9–13. 3. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked CharcotMarieTooth disease. Science 1993; 262: 2039–2042. 4. Ionasescu VV, Searby C, Ionasescu R, Neuhaus IM, Werner R. Mutations of the noncoding region of the connexin32 gene in X-linked dominant CharcotMarieTooth neuropathy. Neurology 1996; 47: 541–544. 5. Gonzaga-Jauregui C, Zhang F, Towne CF, Batish SD, Lupski JR. GJB1/connexin 32 whole gene deletions in patients with X-linked CharcotMarieTooth disease. Neurogenetics 2010; 11: 465–470. 6. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with CharcotMarieTooth disease type 1A. Cell 1991; 66: 219–232. 7. Huang J, Wu X, Montenegro G, et al. Copy number variations are a rare cause of non-CMT1A CharcotMarieTooth disease. J Neurol 2010; 257: 735–741. 8. Maeda MH, Mitsui J, Soong BW, et al. Increased gene dosage of myelin protein zero causes Charcot MarieTooth disease. Ann Neurol 2012; 71: 84–92. 9. Polke JM, Laur a M, Pareyson D, et al. Recessive axonal CharcotMarieTooth disease due to compound heterozygous mitofusin 2 mutations. Neurology 2011; 77: 168–173. 10. Shy ME, Siskind C, Swan ER, et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology 2007; 68: 849–855.
Copyright of European Journal of Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
