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Rare myelin protein zero sequence variant in late onset CMT1B
Journal of the Neurological Sciences 263 (2007) 177 – 179 www.elsevier.com/locate/jns
Short communication
Rare myelin protein zero sequence variant in late onset CMT1B Nizar Souayah a,⁎, W.K. Seltzer b , Thomas H. Brannagan c , Russell L. Chin c , Howard W. Sander c,d,e a
Department of Neurology, Department, New Jersey Medical School, 90 Bergen Street DOC 8128, Newark, NJ 071011, USA b Athena Diagnostics Inc, Worcester, MA, USA c Department of Neurology, Weill College of Medicine of Cornell University, New York, NY, USA d Department of Neurology, St. Vincent's Hospital Manhattan, New York, NY, USA e Department of Neurology, New York Medical College, Valhalla, NY, USA Received 7 January 2007; received in revised form 19 April 2007; accepted 23 May 2007 Available online 28 June 2007
Abstract Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s – to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A–C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate–severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s – to normal. Their mother had an abnormal gait and conduction velocities of 29–30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His–Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles). © 2007 Published by Elsevier B.V. Keywords: Charcot–Marie–Tooth; Myelin protein 0; Mutation; Hereditary; Neuropathy; Axonal
1. Introduction Myelin protein 0 (MPZ) is a major peripheral nervous system protein responsible for myelin compaction and the adherence of myelin wraps to each other [1,2]. Mutations in its gene cause Charcot–Marie–Tooth disease (CMT), an inherited demyelinating polyneuropathy with a large spectrum of clinical phenotypes from severe neonatal sensorimotor deficit to a mild adult form with minimal nerve conduction studies changes. A MPZ mutation with A–C transversion Abbreviations: CMT, Charcot–Marie–Tooth; MPZ, myelin protein 0; CMAP, compound muscle action potential; SNAP, sensory nerve action potential; m/s, meter per second; CV, conduction velocity. ⁎ Corresponding author. Tel.: +1 973 972 8577; fax: +1 973 972 8738. 0022-510X/$ - see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.jns.2007.05.020
(nucleotide: 116, codon: 10, histidine-to-proline) has been reported by Shy et al. to cause adult onset CMT. We report the first family with genetic confirmation of this mutation and assess its frequency in suspected CMT. 2. Methods Case series. 3. Results 3.1. Patient 1 A 65-year-old woman developed numbness and weakness in her feet at the age of 47 years that has been slowly progressive.
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N. Souayah et al. / Journal of the Neurological Sciences 263 (2007) 177–179
At the age of 51 years, she began to use an ankle–foot orthosis. She also reported tinnitus and progressive hearing loss for the past 7 years. Her sister (Case 2) and mother (Case 3) were diagnosed with CMT. Her grand mother was reported to have difficulty walking. She has a third sister who is clinically and genetically unaffected. The patient has a daughter and son who are clinically asymptomatic. The patient has a history of hypertension and hypothyroidism. Neurological examination was significant for decreased auditory acuity, weakness of all hand intrinsic muscles (4/5), bilateral tibialis anterior (4+/5), bilateral inversion and eversion (4/5), bilateral great toe extension (4/5), bilateral great toe flexion (0/5), right toe digits 2–5 flexion (3/5). There was distal atrophy with a stork-like appearance, mild-tomoderate in the legs, and mild–early moderate in the intrinsic hand muscles. There was leg areflexia and arm hyporeflexia. There was light touch and pin perception impairment in a stocking distribution to the proximal third of the both calves, with preservation of vibration and join position. There was impaired heel, toe, and tandem walking. Electrodiagnostic studies demonstrated a severe axonal length dependent sensorimotor polyneuropathy (see Table 1). Her CMT neuropathy score [3] was 17.
Genetic testing for MPZ mutation was performed by PCR amplification and automated sequencing of both DNA strands for exons 2 through 6 coding for the mature protein. Exon 1 of the MPZ gene was not evaluated as it codes for a leader sequence not present in the mature protein. The highly conserved exon–intron splice junctions (e.g. GT…GA) between exons 2 and 6 were also examined by sequencing. The technical analysis, as performed here, is greater than 99% accurate. Genetic testing revealed a MPZ mutation with A–C transversion (nucleotide: 116, codon: 10, histidine-toproline). Genetic testing was normal for: peripheral myelin protein P22, connexin 32, early growth response 2, neurofilament light, periaxin, ganglioside-induced differentiation associated protein, lipopolysaccharide-induced tumor necrosis factor-α, mitofusin 2. 3.2. Patient 2 The 61-year-old sister of Patient 1 developed early fatigue when cycling, intermittent calf cramping, and intermittent foot paresthesias starting at age 45. She has a history of muscle pain after exercise since she was a teenager. Her neurological examination demonstrated high arches, mild
Table 1 Patients' profile
Age (years) when last neurological examination was performed Age (years) of symptom onset Age of onset of walking Sensory symptoms Motor symptoms in arms Motor symptoms in legs Pin sensation Vibration Strength in legs
Strength in arms Clinical course Other feature Genetic testing Ulnar CMAP – CV Ulnar SNAP – CV Median CMAP – CV Median SNAP – CV Tibial CMAP – CV Sural SNAP – CV Peroneal CMAP – CV Superficial peroneal SNAP – CV CMT neuropathy score
Patient 1
Patient 2
Patient 3
65
61
74
47
45
71
Normal Limited to feet Normal Ankle–foot orthosis Reduced to mid calves Normal
Normal Limited to feet Normal Calf cramping
Normal Normal Normal Foot drop
Normal Reduced in toes
Reduced dorsiflexion and plantar flexion Reduced hand strength Slow progression Reduced auditory acuity MPZ mutation: histidine-toproline, codon 10 8.7 mV – 49 m/s Absent 2.9 mV – 42 m/s Absent 0.03 mV – 25 m/s Absent Absent Absent 17
Reduced big toe extension
Reduced below knee Reduced below knee Reduced leg strength
Normal Slow progression –
Reduced distal arm strength Slow progression –
MPZ mutation: histidine-toproline, codon 10 5.3 mV – 47 m/s 25 μV – 55 m/s 5.5 mV – 54 m/s 23 μV – 49 m/s 1.98 mV – 40 m/s 9.8 μV – 42 m/s 0.43 mV – 36 m/s Absent 6
MPZ not tested. Normal CMT1A genetic study Not available Not available Not available Not available Not available – 30 m/s Not available Not available – 29 m/s Not available Approximately 10
CMAP – compound muscle action potential amplitude; CMT – Charcot–Marie–Tooth; CV – conduction velocity; SNAP – sensory nerve action potential amplitude; m/s – meters per second; mV – millivolts; µV – microvolt.
N. Souayah et al. / Journal of the Neurological Sciences 263 (2007) 177–179
weakness of the extensor hallucis longus bilaterally, ankle areflexia, and left knee hyporeflexia. Sensory examination revealed minimal loss of vibratory perception in the toes, with normal pin perception. Electrodiagnostic studies revealed a mild axonal predominantly motor polyneuropathy (see Table 1). Her CMT neuropathy score was 6. Genetic testing, performed with the same method described in Patient 1, revealed the same MPZ mutation. The additional studies mentioned for Patient 1 were also normal. 3.3. Patient 3 The mother of Patients 1 and 2 died at the age of 84 with Alzheimer's disease. At 74, she consulted a neurologist because of difficulty walking, bilateral leg weakness, and foot drop. She reported difficulty with walking. Neurological examination revealed distal leg more than arm weakness, with leg atrophy, areflexia, and stocking and glove diminution to all sensory modalities. Electrodiagnostic studies showed a conduction velocity of 29 m/s and 30 m/s in the peroneal and tibial nerve, respectively. No other information is available about the electrodiagnostic study. Genetic testing was negative for CMT1A. Genetic testing for MPZ mutation was not performed.
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In a series of patients tested for possible CMT at Athena Diagnostic Laboratory, the frequency of MPZ His–Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles). Shy et al. previously described four patients with this mutation, and a sibling who was not genetically tested [6]. Their age of onset was 30–70, similar to our patients. They have mild–moderate motor deficits and CMT neuropathy scores (9, 16, 17, 17), similar to our patients (17, 6, 10). Their electrodiagnostic studies were also similar to our patients, with a predominantly axonal N demyelinating findings in all four patients with conduction velocities between 24 m/s and normal. Recently, Li et al. reported a 73-year-old woman with a late-onset neuropathy caused by a MPZ mutation, who was found at autopsy to have axonal loss and reorganization of the axolemmal molecular architecture [7]. 5. Conclusion This is the first report with genetic confirmation of a family with an A–C transversion (nucleotide: 116, codon: 10, histidine-to-proline) MPZ mutation, and is confirmatory of the findings in the 4 previously reported patients. This mutation is rare with an allele frequency of 0.11% among suspected CMT patients.
4. Discussion References MPZ is a transmembrane protein with extracellular and intracellular domains responsible for myelin compaction and adherence of adjacent wraps of myelin sheets [1,4]. It is also involved in the signal transduction cascade responsible for interaction between the Schwann cell and axon, as well as regulation of myelin-specific gene expression [5]. MPZ mutations cause hereditary neuropathy with phenotypic clustering into two major clinical, electrodiagnostic, and pathologic entities [6]. The early onset form causes severe neuropathy in infancy with delayed motor milestones, slow conduction velocities in the demyelinating range and predominant demyelination on nerve biopsy. It seems that mutations that significantly disturb the tertiary structure of MPZ are responsible for this phenotype. The late onset form presents in adulthood with neuropathy that is slowly progressive, with axonal features to a greater extent than demyelinating features on electrodiagnostic and nerve biopsy studies. Mutations that subtly affect the MPZ structure may interfere with Schwann cell– axon interaction and cause this phenotype [6]. Our patients developed an autosomal-dominant, adult onset, axonal N demyelinating neuropathy, with very slow progression. Genetic testing revealed a histidine-to-proline mutation on codon 10 in the extracellular domain of MPZ.
[1] Giese KP, Martini R, Lemke G, Soriano P, Schachner M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell Nov 13 1992;71(4):565–76. [2] Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA. Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron Sep 1996;17(3):435–49. [3] Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology Apr 12 2005;64(7):1209–14. [4] Xu W, Shy M, Kamholz J, Elferink L, Xu G, Lilien J, et al. Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination. J Cell Biol Oct 29 2001;155(3):439–46. [5] Menichella DM, Arroyo EJ, Awatramani R, Xu T, Baron P, Vallat JM, et al. Protein zero is necessary for E-cadherin-mediated adherens junction formation in Schwann cells. Mol Cell Neurosci Dec 2001;18 (6):606–18. [6] Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, et al. Phenotypic clustering in MPZ mutations. Brain Feb 2004;127(Pt 2):371–84. [7] Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A, et al. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol Sep 10 2006;498(2):252–65.
Short communication
Rare myelin protein zero sequence variant in late onset CMT1B Nizar Souayah a,⁎, W.K. Seltzer b , Thomas H. Brannagan c , Russell L. Chin c , Howard W. Sander c,d,e a
Department of Neurology, Department, New Jersey Medical School, 90 Bergen Street DOC 8128, Newark, NJ 071011, USA b Athena Diagnostics Inc, Worcester, MA, USA c Department of Neurology, Weill College of Medicine of Cornell University, New York, NY, USA d Department of Neurology, St. Vincent's Hospital Manhattan, New York, NY, USA e Department of Neurology, New York Medical College, Valhalla, NY, USA Received 7 January 2007; received in revised form 19 April 2007; accepted 23 May 2007 Available online 28 June 2007
Abstract Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s – to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A–C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate–severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s – to normal. Their mother had an abnormal gait and conduction velocities of 29–30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His–Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles). © 2007 Published by Elsevier B.V. Keywords: Charcot–Marie–Tooth; Myelin protein 0; Mutation; Hereditary; Neuropathy; Axonal
1. Introduction Myelin protein 0 (MPZ) is a major peripheral nervous system protein responsible for myelin compaction and the adherence of myelin wraps to each other [1,2]. Mutations in its gene cause Charcot–Marie–Tooth disease (CMT), an inherited demyelinating polyneuropathy with a large spectrum of clinical phenotypes from severe neonatal sensorimotor deficit to a mild adult form with minimal nerve conduction studies changes. A MPZ mutation with A–C transversion Abbreviations: CMT, Charcot–Marie–Tooth; MPZ, myelin protein 0; CMAP, compound muscle action potential; SNAP, sensory nerve action potential; m/s, meter per second; CV, conduction velocity. ⁎ Corresponding author. Tel.: +1 973 972 8577; fax: +1 973 972 8738. 0022-510X/$ - see front matter © 2007 Published by Elsevier B.V. doi:10.1016/j.jns.2007.05.020
(nucleotide: 116, codon: 10, histidine-to-proline) has been reported by Shy et al. to cause adult onset CMT. We report the first family with genetic confirmation of this mutation and assess its frequency in suspected CMT. 2. Methods Case series. 3. Results 3.1. Patient 1 A 65-year-old woman developed numbness and weakness in her feet at the age of 47 years that has been slowly progressive.
178
N. Souayah et al. / Journal of the Neurological Sciences 263 (2007) 177–179
At the age of 51 years, she began to use an ankle–foot orthosis. She also reported tinnitus and progressive hearing loss for the past 7 years. Her sister (Case 2) and mother (Case 3) were diagnosed with CMT. Her grand mother was reported to have difficulty walking. She has a third sister who is clinically and genetically unaffected. The patient has a daughter and son who are clinically asymptomatic. The patient has a history of hypertension and hypothyroidism. Neurological examination was significant for decreased auditory acuity, weakness of all hand intrinsic muscles (4/5), bilateral tibialis anterior (4+/5), bilateral inversion and eversion (4/5), bilateral great toe extension (4/5), bilateral great toe flexion (0/5), right toe digits 2–5 flexion (3/5). There was distal atrophy with a stork-like appearance, mild-tomoderate in the legs, and mild–early moderate in the intrinsic hand muscles. There was leg areflexia and arm hyporeflexia. There was light touch and pin perception impairment in a stocking distribution to the proximal third of the both calves, with preservation of vibration and join position. There was impaired heel, toe, and tandem walking. Electrodiagnostic studies demonstrated a severe axonal length dependent sensorimotor polyneuropathy (see Table 1). Her CMT neuropathy score [3] was 17.
Genetic testing for MPZ mutation was performed by PCR amplification and automated sequencing of both DNA strands for exons 2 through 6 coding for the mature protein. Exon 1 of the MPZ gene was not evaluated as it codes for a leader sequence not present in the mature protein. The highly conserved exon–intron splice junctions (e.g. GT…GA) between exons 2 and 6 were also examined by sequencing. The technical analysis, as performed here, is greater than 99% accurate. Genetic testing revealed a MPZ mutation with A–C transversion (nucleotide: 116, codon: 10, histidine-toproline). Genetic testing was normal for: peripheral myelin protein P22, connexin 32, early growth response 2, neurofilament light, periaxin, ganglioside-induced differentiation associated protein, lipopolysaccharide-induced tumor necrosis factor-α, mitofusin 2. 3.2. Patient 2 The 61-year-old sister of Patient 1 developed early fatigue when cycling, intermittent calf cramping, and intermittent foot paresthesias starting at age 45. She has a history of muscle pain after exercise since she was a teenager. Her neurological examination demonstrated high arches, mild
Table 1 Patients' profile
Age (years) when last neurological examination was performed Age (years) of symptom onset Age of onset of walking Sensory symptoms Motor symptoms in arms Motor symptoms in legs Pin sensation Vibration Strength in legs
Strength in arms Clinical course Other feature Genetic testing Ulnar CMAP – CV Ulnar SNAP – CV Median CMAP – CV Median SNAP – CV Tibial CMAP – CV Sural SNAP – CV Peroneal CMAP – CV Superficial peroneal SNAP – CV CMT neuropathy score
Patient 1
Patient 2
Patient 3
65
61
74
47
45
71
Normal Limited to feet Normal Ankle–foot orthosis Reduced to mid calves Normal
Normal Limited to feet Normal Calf cramping
Normal Normal Normal Foot drop
Normal Reduced in toes
Reduced dorsiflexion and plantar flexion Reduced hand strength Slow progression Reduced auditory acuity MPZ mutation: histidine-toproline, codon 10 8.7 mV – 49 m/s Absent 2.9 mV – 42 m/s Absent 0.03 mV – 25 m/s Absent Absent Absent 17
Reduced big toe extension
Reduced below knee Reduced below knee Reduced leg strength
Normal Slow progression –
Reduced distal arm strength Slow progression –
MPZ mutation: histidine-toproline, codon 10 5.3 mV – 47 m/s 25 μV – 55 m/s 5.5 mV – 54 m/s 23 μV – 49 m/s 1.98 mV – 40 m/s 9.8 μV – 42 m/s 0.43 mV – 36 m/s Absent 6
MPZ not tested. Normal CMT1A genetic study Not available Not available Not available Not available Not available – 30 m/s Not available Not available – 29 m/s Not available Approximately 10
CMAP – compound muscle action potential amplitude; CMT – Charcot–Marie–Tooth; CV – conduction velocity; SNAP – sensory nerve action potential amplitude; m/s – meters per second; mV – millivolts; µV – microvolt.
N. Souayah et al. / Journal of the Neurological Sciences 263 (2007) 177–179
weakness of the extensor hallucis longus bilaterally, ankle areflexia, and left knee hyporeflexia. Sensory examination revealed minimal loss of vibratory perception in the toes, with normal pin perception. Electrodiagnostic studies revealed a mild axonal predominantly motor polyneuropathy (see Table 1). Her CMT neuropathy score was 6. Genetic testing, performed with the same method described in Patient 1, revealed the same MPZ mutation. The additional studies mentioned for Patient 1 were also normal. 3.3. Patient 3 The mother of Patients 1 and 2 died at the age of 84 with Alzheimer's disease. At 74, she consulted a neurologist because of difficulty walking, bilateral leg weakness, and foot drop. She reported difficulty with walking. Neurological examination revealed distal leg more than arm weakness, with leg atrophy, areflexia, and stocking and glove diminution to all sensory modalities. Electrodiagnostic studies showed a conduction velocity of 29 m/s and 30 m/s in the peroneal and tibial nerve, respectively. No other information is available about the electrodiagnostic study. Genetic testing was negative for CMT1A. Genetic testing for MPZ mutation was not performed.
179
In a series of patients tested for possible CMT at Athena Diagnostic Laboratory, the frequency of MPZ His–Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles). Shy et al. previously described four patients with this mutation, and a sibling who was not genetically tested [6]. Their age of onset was 30–70, similar to our patients. They have mild–moderate motor deficits and CMT neuropathy scores (9, 16, 17, 17), similar to our patients (17, 6, 10). Their electrodiagnostic studies were also similar to our patients, with a predominantly axonal N demyelinating findings in all four patients with conduction velocities between 24 m/s and normal. Recently, Li et al. reported a 73-year-old woman with a late-onset neuropathy caused by a MPZ mutation, who was found at autopsy to have axonal loss and reorganization of the axolemmal molecular architecture [7]. 5. Conclusion This is the first report with genetic confirmation of a family with an A–C transversion (nucleotide: 116, codon: 10, histidine-to-proline) MPZ mutation, and is confirmatory of the findings in the 4 previously reported patients. This mutation is rare with an allele frequency of 0.11% among suspected CMT patients.
4. Discussion References MPZ is a transmembrane protein with extracellular and intracellular domains responsible for myelin compaction and adherence of adjacent wraps of myelin sheets [1,4]. It is also involved in the signal transduction cascade responsible for interaction between the Schwann cell and axon, as well as regulation of myelin-specific gene expression [5]. MPZ mutations cause hereditary neuropathy with phenotypic clustering into two major clinical, electrodiagnostic, and pathologic entities [6]. The early onset form causes severe neuropathy in infancy with delayed motor milestones, slow conduction velocities in the demyelinating range and predominant demyelination on nerve biopsy. It seems that mutations that significantly disturb the tertiary structure of MPZ are responsible for this phenotype. The late onset form presents in adulthood with neuropathy that is slowly progressive, with axonal features to a greater extent than demyelinating features on electrodiagnostic and nerve biopsy studies. Mutations that subtly affect the MPZ structure may interfere with Schwann cell– axon interaction and cause this phenotype [6]. Our patients developed an autosomal-dominant, adult onset, axonal N demyelinating neuropathy, with very slow progression. Genetic testing revealed a histidine-to-proline mutation on codon 10 in the extracellular domain of MPZ.
[1] Giese KP, Martini R, Lemke G, Soriano P, Schachner M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell Nov 13 1992;71(4):565–76. [2] Shapiro L, Doyle JP, Hensley P, Colman DR, Hendrickson WA. Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin. Neuron Sep 1996;17(3):435–49. [3] Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology Apr 12 2005;64(7):1209–14. [4] Xu W, Shy M, Kamholz J, Elferink L, Xu G, Lilien J, et al. Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination. J Cell Biol Oct 29 2001;155(3):439–46. [5] Menichella DM, Arroyo EJ, Awatramani R, Xu T, Baron P, Vallat JM, et al. Protein zero is necessary for E-cadherin-mediated adherens junction formation in Schwann cells. Mol Cell Neurosci Dec 2001;18 (6):606–18. [6] Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, et al. Phenotypic clustering in MPZ mutations. Brain Feb 2004;127(Pt 2):371–84. [7] Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A, et al. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol Sep 10 2006;498(2):252–65.