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C gene
Neuromuscular Disorders 15 (2005) 618–621 www.elsevier.com/locate/nmd
Peripheral nerve lesions associated with a dominant missense mutation, E33D, of the lamin A/C gene Anne Vitala,c,*, Xavier Ferrerb, Cyril Goizetb, Marie Rouanet-Larrivie`reb, Sandrine Eimera, Gise`le Bonned, Claude Vitala,c a
Neuropathology Department, Bordeaux 2 University, Bordeaux cedex, France b Neurology Department, Bordeaux 2 University, Bordeaux cedex, France c Laboratoire de Neurobiologie des Affections de la Mye´line, Bordeaux 2 University, Bordeaux cedex, France d INSERM UR153, Paris, France Received 15 April 2005; received in revised form 20 June 2005; accepted 27 June 2005
Abstract Some mutations of the lamin A/C gene may be responsible for a combination of distinct phenotypes, such as muscular dystrophy and peripheral neuropathy. We describe muscle and peripheral nerve lesions in a patient with a dominant lamin A/C missense mutation, E33D. Myopathic and neurogenic patterns coexisted on muscle biopsy specimens, whereas the peripheral nerve presented a mixture of axonopathy and Schwann cell hypertrophy. A few abnormal nuclei were found in muscle fibers and Schwann cells. Our morphological findings in this case attest to the predominant axonal damage, but suggest possible involvement of Schwann cells in neuropathies related to laminopathies. q 2005 Elsevier B.V. All rights reserved. Keywords: Laminopathy; Muscular dystrophy; Charcot–Marie-Tooth disease; Axonopathy; Schwann cell; Ultrastructure
1. Introduction Various mutations of the LMNA (lamin A/C) gene are responsible for several distinct disorders now called laminopathies, including dominant or recessive Emery– Dreifuss muscular dystrophy [1,2], dominant limb girdle muscular dystrophy type 1B [3], dilated cardiomyopathy [4], and autosomal recessive Charcot–Marie-Tooth type 2 (CMT2) [5–7]. Some patients may have a combination of these different phenotypes [8]. Members of a family with a dominant LMNA missense mutation, E33D, shared clinical features including axonal neuropathy, muscular dystrophy, cardiac disease and leukonychia [9]. Muscle and peripheral nerve lesions observed in patient II-5 from this family are described in the present paper.
* Corresponding author. Address: Laboratoire de Neuropathologie BP 42, Universite´ Victor Segalen-Bordeaux 2, 146, rue Le´o-Saignat, 33076 Bordeaux cedex, France. Tel.: C33 557 57 16 69; fax: C33 557 57 16 70. E-mail address: [email protected] (A. Vital).
0960-8966/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2005.06.016
2. Case report 2.1. Clinical investigations Onset of symptoms occurred as a teenager, and the patient was 55 years old when investigated. He presented pelvic and distal muscle weakness and wasting with pes cavus, distal sensory abnormalities in the lower limbs, and generalized areflexia. He also suffered from atrial fibrillation and bradycardia. His fingernails exhibited leukonychia. Creatine phosphokinase level was 1.8 times the upper normal value. The muscle CT scan showed wasting and marked fatty infiltration predominating in paraspinal, vasti, harmstring and gastrocnemius muscles. Nerve conduction studies evidenced an axonal sensorimotor neuropathy. Compound motor action potential was very reduced bilaterally on deep peroneal and tibialis nerves. Sensory nerve action potential was abolished on the left sural nerve and bilaterally on the musculocutaneous nerves. Needle electromyography was performed on deltoid and first interosseous muscles in the arms, on rectus femoris and tibialis anterior in the legs. Recruitment pattern and motor unit potential configuration suggested chronic denervation
A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
619
Fig. 1. Peroneous brevis muscle biopsy illustrating angular atrophic fibers (a, modified trichrome stain) and fiber type grouping (b, ATPase pH 4.6).
in both proximal and distal muscles. The family pedigree, additional data for other affected members, and the results of genetic analysis were previously presented [9]. A LMNA heterozygous missense mutation, E33D, was identified in the patient and his affected daughter. 2.2. Pathological investigations The patient first underwent a deltoid muscle biopsy, and a year later he agreed to superficial peroneal nerve and peroneus brevis muscle biopsies by one incision on the antero-lateral part of the leg. Paraffin sections of the nerve were not informative, and moderate variations in muscle fiber size were visible on both deltoid and peroneus brevis muscles. Histochemical techniques on deltoid muscle showed variations in muscle fiber size due to atrophy and hypertrophy of fibers, with some internal nuclei, but no fiber type grouping. In the peroneus brevis muscle, groups of angular atrophic fibers (Fig. 1a) and fiber type grouping (Fig. 1b) were evident. Nerve semi-thin examination and quantification showed a severe loss of myelinated fibers (1200/mm2; lower limit of normal: 7000/mm2) predominating in the larger ones (Fig. 2a and b). Electron microscopy of the peroneus brevis muscle evidenced nonspecific myofibrillar alterations, and we observed an abnormal distribution of heterochromatin in a few muscle fiber nuclei. Ultrastructural lesions of the superficial peroneal nerve were dominated by features of axonal degeneration. Indeed, (a)
several myelinated and unmyelinated axons were packed with organelles (Fig. 3a). A number of unmyelinated fibers also exhibited ‘Schwannian crystalline-like inclusions bodies’ (Fig. 3b). A few Bu¨ngner bands and clusters of regenerating myelinated fibers were observed. A surprising finding was the presence of several ‘onion bulb formations’ composed of Schwann cell processes surrounding either isolated myelinated axons (Fig. 4a) or clusters of regenerating myelinated or unmyelinated axons. Although segmental demyelination was not a prominent feature, some isolated axons with abnormally thin myelin sheaths were observed. A few Schwann cells presented abnormally condensed heterochromatin or a nuclear cleft (Fig. 4b).
3. Discussion A locus for an axonal form of autosomal recessive Charcot–Marie-Tooth disease (CMT2B1 [MIM 605588]) [10] maps to chromosome 1q21.2-q21.3 [11], and the R298C mutation in the LMNA gene was reported in affected families [5–7]. Peripheral nerve biopsies in these cases showed a severe loss of myelinated and unmyelinated fibers, with almost complete absence of large myelinated fibers, and without Schwann cell proliferation. Our case, with a dominant LMNA missense mutation, E33D, in the LMNA gene presented clinical and morphological evidence of concomitant muscular and nerve degeneration. (b) 400 350
MF/mm2
300 250 200 150 100 50 0
1 2 3 4 5 6 7 8 9 10 11 12 D(µ)
Fig. 2. Semi-thin section of the superficial peroneal nerve (a) and histogram (b) showing the severe loss of myelinated fibers predominating on the larger ones. MF/mm2, number of myelinated fibers per mm2 of endoneurial area; D(m), diameter of myelinated fibers.
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A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
Fig. 3. Superficial peroneal nerve biopsy. Electron microscopy showing a single and rather large axon packed with mitochondria (a, !9600), and a ‘Schwannian crystalline-like inclusion body’ (b, !32,000).
The myopathic pattern observed in the initial deltoid biopsy was replaced by features suggesting neurogenic atrophy on the peroneus brevis muscle. Similar features of neurogenic atrophy were reported in patients with a deletion of the LMNA initiator codon leading to a clinical phenotype that shared features of both autosomal dominant Emery– Dreifuss muscular dystrophy and CMT2 [8]. Our patient presented a neuropathy which was considered as axonal on electrophysiological examination, but morphological findings at ultrastructural level were rather complex with a mixture of axonopathy and Schwann cell hypertrophy. Indeed, the presence of myelinated and unmyelinated axons packed with organelles attested to an axonopathic process. ‘Schwannian crystalline-like inclusions bodies (Fardeau– Engel bodies)’ were reported in various conditions, mainly with axonal lesions [12]. Their significance remains obscure
and a matter of debate as some authors suggest a mitochondrial origin [13], whereas others think it likely that they correspond to degenerated unmyelinated axons with packed ‘en block’ filaments or tubules [12]. The Schwann cell hypertrophy, surrounding either isolated myelinated axons or clusters of regenerating myelinated or unmyelinated axons, was unexpected. This observation differs from previous neuropathological reports in patients with the R298C mutation in the LMNA gene [5–7]. Given that the LMNA gene encodes the nuclear envelope proteins lamin A and lamin C, morphological nuclear abnormalities are expected in laminopathies and have been previously evidenced in muscle biopsies from patients with autosomal dominant Emery–Dreifuss muscular dystrophy [14]. We found morphological nuclear abnormalities in some muscle fibers and Schwann cells from our case, but
Fig. 4. Superficial peroneal nerve biopsy. Electron microscopy evidencing flattened Schwann cell processes surrounding a single myelinated axon (a, !6700), and an abnormal Schwann cell nucleus with a large cleft which may represent either an invaginated severely dilated nuclear envelope, or a cytoplasmic pseudonuclear inclusion (b, !9600).
A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
these features were not prominent and must be interpreted cautiously as they may be secondary effects of nonspecific pathological processes. To conclude, our morphological findings in this case attest to the predominant axonal damage, but suggest involvement of Schwann cells in neuropathies related to laminopathies.
Acknowledgements The authors wish to thank C. Brechenmacher and M.H. Canron for expert technical assistance. This work was supported by the Association Franc¸aise contre les Myopathies (AFM).
References [1] Bonne G, di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nat Genet 1999;21:285–8. [2] di Barletta MR, Ricci E, Galluzzi G, et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 2000; 66: 1407-1412. [3] Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453–9. [4] Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715–24.
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[5] De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot– Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002;70: 726–36. [6] Chaouch M, Allal Y, de Sandre-Giovannoli A, et al. The phenotypic manifestations of autosomal recessive axonal Charcot–Marie-Tooth due to a mutation in lamin A/C gene. Neuromuscul Disord 2003;13: 60–7. [7] Tazir M, Azzedine H, Assami S, et al. Phenotypic variability in autosomal recessive axonal Charcot–Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain 2004;127:154–63. [8] Walter MC, Witt TN, Schlotter Weigel B, et al. Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery–Dreifuss muscular dystrophy. Neuromuscul Disord 2005;15:40–4. [9] Goizet C, Ben Yaou R, Demay L, et al. A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia. J Med Genet 2004;41:E29. [10] Hamroun D, Be´roud C, Fontaine B, Kaplan JC. Introducing the online version of the gene table for neuromuscular disease (nuclear genes only). Neuromuscul Disord 2005;15:88–114. [11] Bouhouche A, Benomar A, Birouk N, et al. A locus for an axonal form of autosomal recessive Charcot–Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am J Hum Genet 1999;65:722–7. [12] Vital C, Bouillot S, Canron MH, Vital A. Schwannian crystalline-like inclusions bodies (Fardeau–Engel bodies) revisited in peripheral neuropathies. Ultrastruct Pathol 2002;26:9–13. [13] Schro¨der JM, Sommer C. Mitochondrial abnormalities in human sural nerves: fine structural evaluation of cases with mitochondrial myopathy, hereditary and non-hereditary neuropathies, and review of the literature. Acta Neuropathol 1991;82:471–82. [14] Sewry CA, Brown SC, Mercuri E, et al. Skeletal muscle pathology in autosomal dominant Emery–Dreifuss muscular dystrophy with lamin A/C mutations. Neuropath Appl Neurobiol 2001;27:281–90.
Peripheral nerve lesions associated with a dominant missense mutation, E33D, of the lamin A/C gene Anne Vitala,c,*, Xavier Ferrerb, Cyril Goizetb, Marie Rouanet-Larrivie`reb, Sandrine Eimera, Gise`le Bonned, Claude Vitala,c a
Neuropathology Department, Bordeaux 2 University, Bordeaux cedex, France b Neurology Department, Bordeaux 2 University, Bordeaux cedex, France c Laboratoire de Neurobiologie des Affections de la Mye´line, Bordeaux 2 University, Bordeaux cedex, France d INSERM UR153, Paris, France Received 15 April 2005; received in revised form 20 June 2005; accepted 27 June 2005
Abstract Some mutations of the lamin A/C gene may be responsible for a combination of distinct phenotypes, such as muscular dystrophy and peripheral neuropathy. We describe muscle and peripheral nerve lesions in a patient with a dominant lamin A/C missense mutation, E33D. Myopathic and neurogenic patterns coexisted on muscle biopsy specimens, whereas the peripheral nerve presented a mixture of axonopathy and Schwann cell hypertrophy. A few abnormal nuclei were found in muscle fibers and Schwann cells. Our morphological findings in this case attest to the predominant axonal damage, but suggest possible involvement of Schwann cells in neuropathies related to laminopathies. q 2005 Elsevier B.V. All rights reserved. Keywords: Laminopathy; Muscular dystrophy; Charcot–Marie-Tooth disease; Axonopathy; Schwann cell; Ultrastructure
1. Introduction Various mutations of the LMNA (lamin A/C) gene are responsible for several distinct disorders now called laminopathies, including dominant or recessive Emery– Dreifuss muscular dystrophy [1,2], dominant limb girdle muscular dystrophy type 1B [3], dilated cardiomyopathy [4], and autosomal recessive Charcot–Marie-Tooth type 2 (CMT2) [5–7]. Some patients may have a combination of these different phenotypes [8]. Members of a family with a dominant LMNA missense mutation, E33D, shared clinical features including axonal neuropathy, muscular dystrophy, cardiac disease and leukonychia [9]. Muscle and peripheral nerve lesions observed in patient II-5 from this family are described in the present paper.
* Corresponding author. Address: Laboratoire de Neuropathologie BP 42, Universite´ Victor Segalen-Bordeaux 2, 146, rue Le´o-Saignat, 33076 Bordeaux cedex, France. Tel.: C33 557 57 16 69; fax: C33 557 57 16 70. E-mail address: [email protected] (A. Vital).
0960-8966/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2005.06.016
2. Case report 2.1. Clinical investigations Onset of symptoms occurred as a teenager, and the patient was 55 years old when investigated. He presented pelvic and distal muscle weakness and wasting with pes cavus, distal sensory abnormalities in the lower limbs, and generalized areflexia. He also suffered from atrial fibrillation and bradycardia. His fingernails exhibited leukonychia. Creatine phosphokinase level was 1.8 times the upper normal value. The muscle CT scan showed wasting and marked fatty infiltration predominating in paraspinal, vasti, harmstring and gastrocnemius muscles. Nerve conduction studies evidenced an axonal sensorimotor neuropathy. Compound motor action potential was very reduced bilaterally on deep peroneal and tibialis nerves. Sensory nerve action potential was abolished on the left sural nerve and bilaterally on the musculocutaneous nerves. Needle electromyography was performed on deltoid and first interosseous muscles in the arms, on rectus femoris and tibialis anterior in the legs. Recruitment pattern and motor unit potential configuration suggested chronic denervation
A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
619
Fig. 1. Peroneous brevis muscle biopsy illustrating angular atrophic fibers (a, modified trichrome stain) and fiber type grouping (b, ATPase pH 4.6).
in both proximal and distal muscles. The family pedigree, additional data for other affected members, and the results of genetic analysis were previously presented [9]. A LMNA heterozygous missense mutation, E33D, was identified in the patient and his affected daughter. 2.2. Pathological investigations The patient first underwent a deltoid muscle biopsy, and a year later he agreed to superficial peroneal nerve and peroneus brevis muscle biopsies by one incision on the antero-lateral part of the leg. Paraffin sections of the nerve were not informative, and moderate variations in muscle fiber size were visible on both deltoid and peroneus brevis muscles. Histochemical techniques on deltoid muscle showed variations in muscle fiber size due to atrophy and hypertrophy of fibers, with some internal nuclei, but no fiber type grouping. In the peroneus brevis muscle, groups of angular atrophic fibers (Fig. 1a) and fiber type grouping (Fig. 1b) were evident. Nerve semi-thin examination and quantification showed a severe loss of myelinated fibers (1200/mm2; lower limit of normal: 7000/mm2) predominating in the larger ones (Fig. 2a and b). Electron microscopy of the peroneus brevis muscle evidenced nonspecific myofibrillar alterations, and we observed an abnormal distribution of heterochromatin in a few muscle fiber nuclei. Ultrastructural lesions of the superficial peroneal nerve were dominated by features of axonal degeneration. Indeed, (a)
several myelinated and unmyelinated axons were packed with organelles (Fig. 3a). A number of unmyelinated fibers also exhibited ‘Schwannian crystalline-like inclusions bodies’ (Fig. 3b). A few Bu¨ngner bands and clusters of regenerating myelinated fibers were observed. A surprising finding was the presence of several ‘onion bulb formations’ composed of Schwann cell processes surrounding either isolated myelinated axons (Fig. 4a) or clusters of regenerating myelinated or unmyelinated axons. Although segmental demyelination was not a prominent feature, some isolated axons with abnormally thin myelin sheaths were observed. A few Schwann cells presented abnormally condensed heterochromatin or a nuclear cleft (Fig. 4b).
3. Discussion A locus for an axonal form of autosomal recessive Charcot–Marie-Tooth disease (CMT2B1 [MIM 605588]) [10] maps to chromosome 1q21.2-q21.3 [11], and the R298C mutation in the LMNA gene was reported in affected families [5–7]. Peripheral nerve biopsies in these cases showed a severe loss of myelinated and unmyelinated fibers, with almost complete absence of large myelinated fibers, and without Schwann cell proliferation. Our case, with a dominant LMNA missense mutation, E33D, in the LMNA gene presented clinical and morphological evidence of concomitant muscular and nerve degeneration. (b) 400 350
MF/mm2
300 250 200 150 100 50 0
1 2 3 4 5 6 7 8 9 10 11 12 D(µ)
Fig. 2. Semi-thin section of the superficial peroneal nerve (a) and histogram (b) showing the severe loss of myelinated fibers predominating on the larger ones. MF/mm2, number of myelinated fibers per mm2 of endoneurial area; D(m), diameter of myelinated fibers.
620
A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
Fig. 3. Superficial peroneal nerve biopsy. Electron microscopy showing a single and rather large axon packed with mitochondria (a, !9600), and a ‘Schwannian crystalline-like inclusion body’ (b, !32,000).
The myopathic pattern observed in the initial deltoid biopsy was replaced by features suggesting neurogenic atrophy on the peroneus brevis muscle. Similar features of neurogenic atrophy were reported in patients with a deletion of the LMNA initiator codon leading to a clinical phenotype that shared features of both autosomal dominant Emery– Dreifuss muscular dystrophy and CMT2 [8]. Our patient presented a neuropathy which was considered as axonal on electrophysiological examination, but morphological findings at ultrastructural level were rather complex with a mixture of axonopathy and Schwann cell hypertrophy. Indeed, the presence of myelinated and unmyelinated axons packed with organelles attested to an axonopathic process. ‘Schwannian crystalline-like inclusions bodies (Fardeau– Engel bodies)’ were reported in various conditions, mainly with axonal lesions [12]. Their significance remains obscure
and a matter of debate as some authors suggest a mitochondrial origin [13], whereas others think it likely that they correspond to degenerated unmyelinated axons with packed ‘en block’ filaments or tubules [12]. The Schwann cell hypertrophy, surrounding either isolated myelinated axons or clusters of regenerating myelinated or unmyelinated axons, was unexpected. This observation differs from previous neuropathological reports in patients with the R298C mutation in the LMNA gene [5–7]. Given that the LMNA gene encodes the nuclear envelope proteins lamin A and lamin C, morphological nuclear abnormalities are expected in laminopathies and have been previously evidenced in muscle biopsies from patients with autosomal dominant Emery–Dreifuss muscular dystrophy [14]. We found morphological nuclear abnormalities in some muscle fibers and Schwann cells from our case, but
Fig. 4. Superficial peroneal nerve biopsy. Electron microscopy evidencing flattened Schwann cell processes surrounding a single myelinated axon (a, !6700), and an abnormal Schwann cell nucleus with a large cleft which may represent either an invaginated severely dilated nuclear envelope, or a cytoplasmic pseudonuclear inclusion (b, !9600).
A. Vital et al. / Neuromuscular Disorders 15 (2005) 618–621
these features were not prominent and must be interpreted cautiously as they may be secondary effects of nonspecific pathological processes. To conclude, our morphological findings in this case attest to the predominant axonal damage, but suggest involvement of Schwann cells in neuropathies related to laminopathies.
Acknowledgements The authors wish to thank C. Brechenmacher and M.H. Canron for expert technical assistance. This work was supported by the Association Franc¸aise contre les Myopathies (AFM).
References [1] Bonne G, di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nat Genet 1999;21:285–8. [2] di Barletta MR, Ricci E, Galluzzi G, et al. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 2000; 66: 1407-1412. [3] Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453–9. [4] Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715–24.
621
[5] De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot– Marie-Tooth disorder type 2) and mouse. Am J Hum Genet 2002;70: 726–36. [6] Chaouch M, Allal Y, de Sandre-Giovannoli A, et al. The phenotypic manifestations of autosomal recessive axonal Charcot–Marie-Tooth due to a mutation in lamin A/C gene. Neuromuscul Disord 2003;13: 60–7. [7] Tazir M, Azzedine H, Assami S, et al. Phenotypic variability in autosomal recessive axonal Charcot–Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain 2004;127:154–63. [8] Walter MC, Witt TN, Schlotter Weigel B, et al. Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery–Dreifuss muscular dystrophy. Neuromuscul Disord 2005;15:40–4. [9] Goizet C, Ben Yaou R, Demay L, et al. A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia. J Med Genet 2004;41:E29. [10] Hamroun D, Be´roud C, Fontaine B, Kaplan JC. Introducing the online version of the gene table for neuromuscular disease (nuclear genes only). Neuromuscul Disord 2005;15:88–114. [11] Bouhouche A, Benomar A, Birouk N, et al. A locus for an axonal form of autosomal recessive Charcot–Marie-Tooth disease maps to chromosome 1q21.2-q21.3. Am J Hum Genet 1999;65:722–7. [12] Vital C, Bouillot S, Canron MH, Vital A. Schwannian crystalline-like inclusions bodies (Fardeau–Engel bodies) revisited in peripheral neuropathies. Ultrastruct Pathol 2002;26:9–13. [13] Schro¨der JM, Sommer C. Mitochondrial abnormalities in human sural nerves: fine structural evaluation of cases with mitochondrial myopathy, hereditary and non-hereditary neuropathies, and review of the literature. Acta Neuropathol 1991;82:471–82. [14] Sewry CA, Brown SC, Mercuri E, et al. Skeletal muscle pathology in autosomal dominant Emery–Dreifuss muscular dystrophy with lamin A/C mutations. Neuropath Appl Neurobiol 2001;27:281–90.