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Two patients with ‘Dropped head syndrome’ due to mutations in LMNA or SEPN1 genes
Neuromuscular Disorders 15 (2005) 521–524 www.elsevier.com/locate/nmd
Case report
Two patients with ‘Dropped head syndrome’ due to mutations in LMNA or SEPN1 genes A. D’Amicoa, G. Haliloglub, P. Richardc, B. Talimd, S. Maugenrec, A. Ferreiroc, P. Guicheneyc, I. Mendittoe, S. Benedettie, E. Bertinia,*, G. Bonnec, H. Topaloglub a
Unit of Molecular Medicine, Department of Laboratory Medicine, Bambino Gesu’ Children’s Research Hospital, Rome, Italy b Department of Child Neurology, Hacettepe Children’s Hospital, Ankara, Turkey c INSERM U582, Institut de Myologie, IFR 14 Hoˆpital de la Salpeˆtrie´re, Paris, France d Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey e Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Milan, Italy Received 18 January 2005; received in revised form 11 March 2005; accepted 24 March 2005
Abstract Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy. q 2005 Elsevier B.V. All rights reserved. Keywords: Dropped head; Congenital muscular dystrophy; Lamin A/C; SEPN1
1. Introduction Prominent neck extension weakness is an uncommon clinical entity, also termed ‘Dropped head syndrome’, that may be part of a generalized neuromuscular disorder such as myasthenia gravis, polymyositis, amyotrophic lateral sclerosis, nemaline myopathy, chronic inflammatory demyelinating polyneuropathy, hypothyroidism, or mitochondrial disease [1–6]. Neck extensor weakness however may also be an isolated and relatively benign condition with a non-progressive course and unknown aetiology in a proportion of patients. Dropped head syndrome caused by a non-inflammatory myopathy limited to neck extensor muscles has been reported in elderly people [7,8]. However, isolated neck involvement has never been reported in children as isolated symptom or as a first and predominant symptom of a neuromuscular disease. We report here two * Corresponding author. Tel.: C39 06 6859 2266; fax: C39 06 6859 2024. E-mail address: [email protected] (E. Bertini).
0960-8966/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2005.03.006
children with Dropped head syndrome with mutations in two different genes, lamin A/C (LMNA) and selenoprotein N (SEPN1), thus adding new genetic conditions to the list of this heterogeneous syndrome.
2. Case reports 2.1. Case 1 A 18-months-old boy was the only child of healthy nonconsanguineous parents. There was no family history of any neuromuscular disease. The primary motor milestones were within the normal range; he acquired head control at 3 months and was sitting unsupported at 6–7 months. At the age of 12 months the parents noted that he had difficulty in holding his head up, with disability in walking independently. Neurological examination at 15 months confirmed significant neck extensor weakness and only mild axial and limb girdle weakness (Fig. 1A). The boy was able to walk alone, to raise his arms, and to walk up stairs or to rise from a chair with minimal trunk support. No significant decrease in muscular strength was present in
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A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
Analysis of the coding region of the LMNA gene revealed a de novo heterozygous c.94_96delAAG deletion in exon 1 (Lys 32 del) (Fig. 3A). 2.2. Case 2
Fig. 1. Patient 1 at age 15 months with prominent neck weakness is able to stand independently (A). Patient 2 at 9 years of age. Prominent neck weakness (head tilt), increased lordosis, decreased muscle bulk and pectus excavatum deformity (B).
his distal limb muscles and no contractures or wasting were noted. The remainder of the neurological examination was normal. Holter electrocardiogram and echocardiography were normal too. Serum CK was elevated (1300 UI/l, n.v. !270). A muscle biopsy specimen of the left quadriceps showed mild myopathic changes without inflammatory infiltrates or fibrosis (Fig. 2A). Immunohistochemistry for dystrophin, laminin a2 chain and the main dystrophin glycoprotein complex proteins did not disclose any abnormality.
The patient is a 9 year-old girl, born to healthy related parents (first cousins) who presented a weak head control in early life. She was able to walk without support at the age of 1 year, with a persistent weak head control. When first examined at age 6 she had facial weakness, a high arched palate, pectus excavatum deformity and a dropped neck. She could walk independently but she had generalized weakness with absence of deep tendon reflexes. She had a mild scoliosis, but no contractures (Fig. 1B). Serum CK was normal. Muscle biopsy findings were consistent with merosin positive congenital muscular dystrophy with mild myopathic changes, including variation in fiber size and fatty tissue infiltration (Fig. 2B). There was no evidence for minicores. The patient was found to be homozygous for five SEPN1 flanking and intragenic markers. Analysis of SEPN1 gene allowed to identify a homozygous c.817GOA nucleotide change corresponding to the missense G273R substitution in the selenoprotein N (Fig. 3B). Patient 2 has been revaluated at the age of 9 years. At this age she was still free of spinal deformities apart from the already present but still not progressive mild scoliosis. However she began to experience frequent chest infections. Her forced vital capacity was 69%.
3. Material and methods Muscle biopsies were processed according to standard histological and histochemical techniques [9]. A panel of proteins was also examined immunohistochemically, including dystrophin, sarcoglycans, laminin a2 chain and collagen VI. Genomic DNA was extracted from peripheral blood and screened for LMNA mutations by DHPLC and sequencing
Fig. 2. Muscle biopsies from patient 1 (A) and patient 2 (B) showing variation in fiber size and central nuclei. Fatty infiltration is also present in patient 2. Bar: 25 mm.
A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
523
Fig. 3. Sequence chromatograms show the heterozygous c.94_96delAAG substitution leading to 32 deletion in the LMNA gene (A) and the homozygous G273R mutation (GGA-OAGA) in the SEPN1 gene (B).
as described [10]. All SEPN1 exons and the SECIS element were screened for mutation by direct sequencing as described [11].
4. Discussion Here we describe two children affected by a congenital muscular dystrophy mainly characterized by weakness of extensor neck muscles, which has been defined as dropped head syndrome. Patient 1 did not present any other clear sign of muscle weakness than a disability in controlling the vertical positioning of his head. The moderate increase of CK and the mild myopathic changes found in the muscle biopsy suggested us to analyse the LMNA gene. Mutations in LMNA genes have been associated to a heterogeneous group of disorders collectively known as ‘ laminopathies’ [12–19] and a form of severe myopathy with congenital onset and axial weakness with poor head control, has been recently reported [20]. LMNA analysis in patient 1 revealed a heterozygous c.94_96 deletion in exon 1 which had been previously reported in two families associated with a classical Emery–Dreifuss muscular dystrophy phenotype [21,22]. Patient 2 displayed an head and axial muscles involvement and mild changes at muscle biopsy compatible with a ‘SEPN1-related myopathy’. This entity includes three autosomal recessive, early onset myopathies [23], due to mutations of SEPN1 gene that share similar clinical
features but mat have different morphological aspects. The first one has been described in patients with early rigidity of the spine, predominant axial muscle weakness, contractures, and restrictive respiratory insufficiency requiring nocturnal ventilation, originally referred to as rigid spine muscular dystrophy (RSMD1) [11]. The second condition includes the most severe cases of the ‘classical’ form of multiminicore disease (MmD), and the third one, a desminrelated myopathy with Mallory body-like inclusions, is clinically characterized by neonatal hypotonia, axial and proximal muscle weakness, scoliosis, and normal or mildly elevated creatine kinase levels [24]. Patient 2 was found to carry the homozygous G273R substitution in the SEPN1 gene although minicores or ‘Mallory-body’ inclusions were not detected by routine histology. Dropped head syndrome is an unusual presentation of a neuromuscular disease and can be extremely disabling. Given its clinical heterogeneity, a search for an underlying neuromuscular disease—myopathy, neuropathy or neuromuscular junction disorders—is important. Although the involvement of neck and axial and muscles appears to be frequent in ‘laminopathies’ and in ‘SEPN relatedmyopathy’ [11,20,24,25] the association of dropped head syndrome with these conditions has not been reported. This report expands the list of the inherited neuromuscular conditions associated with a dropped head syndrome.
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A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
Acknowledgements This work was supported by funds from the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Ricerca Corrente Ministero della Salute, Association Franc¸aise contre les Myopathies (AFM), and the GIS-Institut des Maladies Rares.
[14]
[15]
[16]
References [1] Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Annu NY Acad Sci 1981; 377:652–69. [2] DeVere R, Bradley WG. Polymyositis: its presentation, morbidity and mortality. Brain 1975;98:637–66. [3] Ringel SP. Clinical presentations in neuromuscular disease. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. New York: Elsevier; 1979. p. 295–348. [4] Lomen-Hoerth C, Simmons ML, DeArmond SJ, et al. Adult-onset nemaline myopathy: another cause of dropped head. Muscle Nerve 1999;22:1146–50. [5] Finsterer J. Dropped head syndrome in mitochondriopathy. Eur Spine J 2004;13:652–6. [6] Askmark H, Olsson Y, Rossitti S. Treatable dropped head syndrome in hypothyroidism. Neurology 2000;55(6):896–7. [7] Suarez GA, Kelly JJ. The dropped head syndrome. Neurology 1992; 42:1625–7. [8] Katz JS, Wolfe GI, Burns DK, et al. Isolated neck extensor myopathy: a common cause of dropped head syndrome. Neurology 1996;46: 917–21. [9] Dubowitz V. Muscle biopasy: a pratical approach. 2nd ed. Eastbourne: Bailliere Tindall; 1985. [10] Vytopil M, Benedetti S, Ricci E, et al. Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. J Med Genet 2003;40:e132. [11] Moghadaszadeh B, Petit N, Jaillard C, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 2001;29(1):17–18. [12] Bonne G, Mercuri E, Muchir A, et al. Clinical and molecular genetic spectrum of autosomal dominant Emery–Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 2000;48(2): 170–80. [13] 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
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453–9. Fatkin D, MacRae C, Sasaki T, Wolff MR, 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. Speckman RA, Garg A, Du F, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular Cterminal domain of lamin A/C. Am J Hum Genet 2000;66:1192–8. 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. Novelli G, Muchir A, Sangiuolo F, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002;71:426–31. Mounkes LC, Kozlov S, Hernandez L, et al. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 2003;423: 298–301. Caux F, Dubosclard E, Lascols O, et al. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulinresistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab 2003;88:1006–13. Mercuri E, Poppe M, Quinlivan R, et al. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. Arch Neurol 2004;61(5):690–4. Muchir A, Medioni J, Laluc M, et al. Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. Muscle Nerve 2004;30(4):444–50. Vytopil M, Ricci E, Dello Russo A, et al. Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss muscular dystrophy. Neuromuscul Disord 2002;12(10):958–63. Petit N, Lescure A, Rederstroff M, et al. Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern. Hum Mol Genet 2003;12:1045–53. Ferreiro A, Ceuterick-de Groote C, Marks JJ, et al. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004;55(5):676–86. Ferreiro A, Quijano-Roy S, Pichereau C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002;71(4):739–49.
Case report
Two patients with ‘Dropped head syndrome’ due to mutations in LMNA or SEPN1 genes A. D’Amicoa, G. Haliloglub, P. Richardc, B. Talimd, S. Maugenrec, A. Ferreiroc, P. Guicheneyc, I. Mendittoe, S. Benedettie, E. Bertinia,*, G. Bonnec, H. Topaloglub a
Unit of Molecular Medicine, Department of Laboratory Medicine, Bambino Gesu’ Children’s Research Hospital, Rome, Italy b Department of Child Neurology, Hacettepe Children’s Hospital, Ankara, Turkey c INSERM U582, Institut de Myologie, IFR 14 Hoˆpital de la Salpeˆtrie´re, Paris, France d Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey e Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Milan, Italy Received 18 January 2005; received in revised form 11 March 2005; accepted 24 March 2005
Abstract Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy. q 2005 Elsevier B.V. All rights reserved. Keywords: Dropped head; Congenital muscular dystrophy; Lamin A/C; SEPN1
1. Introduction Prominent neck extension weakness is an uncommon clinical entity, also termed ‘Dropped head syndrome’, that may be part of a generalized neuromuscular disorder such as myasthenia gravis, polymyositis, amyotrophic lateral sclerosis, nemaline myopathy, chronic inflammatory demyelinating polyneuropathy, hypothyroidism, or mitochondrial disease [1–6]. Neck extensor weakness however may also be an isolated and relatively benign condition with a non-progressive course and unknown aetiology in a proportion of patients. Dropped head syndrome caused by a non-inflammatory myopathy limited to neck extensor muscles has been reported in elderly people [7,8]. However, isolated neck involvement has never been reported in children as isolated symptom or as a first and predominant symptom of a neuromuscular disease. We report here two * Corresponding author. Tel.: C39 06 6859 2266; fax: C39 06 6859 2024. E-mail address: [email protected] (E. Bertini).
0960-8966/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2005.03.006
children with Dropped head syndrome with mutations in two different genes, lamin A/C (LMNA) and selenoprotein N (SEPN1), thus adding new genetic conditions to the list of this heterogeneous syndrome.
2. Case reports 2.1. Case 1 A 18-months-old boy was the only child of healthy nonconsanguineous parents. There was no family history of any neuromuscular disease. The primary motor milestones were within the normal range; he acquired head control at 3 months and was sitting unsupported at 6–7 months. At the age of 12 months the parents noted that he had difficulty in holding his head up, with disability in walking independently. Neurological examination at 15 months confirmed significant neck extensor weakness and only mild axial and limb girdle weakness (Fig. 1A). The boy was able to walk alone, to raise his arms, and to walk up stairs or to rise from a chair with minimal trunk support. No significant decrease in muscular strength was present in
522
A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
Analysis of the coding region of the LMNA gene revealed a de novo heterozygous c.94_96delAAG deletion in exon 1 (Lys 32 del) (Fig. 3A). 2.2. Case 2
Fig. 1. Patient 1 at age 15 months with prominent neck weakness is able to stand independently (A). Patient 2 at 9 years of age. Prominent neck weakness (head tilt), increased lordosis, decreased muscle bulk and pectus excavatum deformity (B).
his distal limb muscles and no contractures or wasting were noted. The remainder of the neurological examination was normal. Holter electrocardiogram and echocardiography were normal too. Serum CK was elevated (1300 UI/l, n.v. !270). A muscle biopsy specimen of the left quadriceps showed mild myopathic changes without inflammatory infiltrates or fibrosis (Fig. 2A). Immunohistochemistry for dystrophin, laminin a2 chain and the main dystrophin glycoprotein complex proteins did not disclose any abnormality.
The patient is a 9 year-old girl, born to healthy related parents (first cousins) who presented a weak head control in early life. She was able to walk without support at the age of 1 year, with a persistent weak head control. When first examined at age 6 she had facial weakness, a high arched palate, pectus excavatum deformity and a dropped neck. She could walk independently but she had generalized weakness with absence of deep tendon reflexes. She had a mild scoliosis, but no contractures (Fig. 1B). Serum CK was normal. Muscle biopsy findings were consistent with merosin positive congenital muscular dystrophy with mild myopathic changes, including variation in fiber size and fatty tissue infiltration (Fig. 2B). There was no evidence for minicores. The patient was found to be homozygous for five SEPN1 flanking and intragenic markers. Analysis of SEPN1 gene allowed to identify a homozygous c.817GOA nucleotide change corresponding to the missense G273R substitution in the selenoprotein N (Fig. 3B). Patient 2 has been revaluated at the age of 9 years. At this age she was still free of spinal deformities apart from the already present but still not progressive mild scoliosis. However she began to experience frequent chest infections. Her forced vital capacity was 69%.
3. Material and methods Muscle biopsies were processed according to standard histological and histochemical techniques [9]. A panel of proteins was also examined immunohistochemically, including dystrophin, sarcoglycans, laminin a2 chain and collagen VI. Genomic DNA was extracted from peripheral blood and screened for LMNA mutations by DHPLC and sequencing
Fig. 2. Muscle biopsies from patient 1 (A) and patient 2 (B) showing variation in fiber size and central nuclei. Fatty infiltration is also present in patient 2. Bar: 25 mm.
A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
523
Fig. 3. Sequence chromatograms show the heterozygous c.94_96delAAG substitution leading to 32 deletion in the LMNA gene (A) and the homozygous G273R mutation (GGA-OAGA) in the SEPN1 gene (B).
as described [10]. All SEPN1 exons and the SECIS element were screened for mutation by direct sequencing as described [11].
4. Discussion Here we describe two children affected by a congenital muscular dystrophy mainly characterized by weakness of extensor neck muscles, which has been defined as dropped head syndrome. Patient 1 did not present any other clear sign of muscle weakness than a disability in controlling the vertical positioning of his head. The moderate increase of CK and the mild myopathic changes found in the muscle biopsy suggested us to analyse the LMNA gene. Mutations in LMNA genes have been associated to a heterogeneous group of disorders collectively known as ‘ laminopathies’ [12–19] and a form of severe myopathy with congenital onset and axial weakness with poor head control, has been recently reported [20]. LMNA analysis in patient 1 revealed a heterozygous c.94_96 deletion in exon 1 which had been previously reported in two families associated with a classical Emery–Dreifuss muscular dystrophy phenotype [21,22]. Patient 2 displayed an head and axial muscles involvement and mild changes at muscle biopsy compatible with a ‘SEPN1-related myopathy’. This entity includes three autosomal recessive, early onset myopathies [23], due to mutations of SEPN1 gene that share similar clinical
features but mat have different morphological aspects. The first one has been described in patients with early rigidity of the spine, predominant axial muscle weakness, contractures, and restrictive respiratory insufficiency requiring nocturnal ventilation, originally referred to as rigid spine muscular dystrophy (RSMD1) [11]. The second condition includes the most severe cases of the ‘classical’ form of multiminicore disease (MmD), and the third one, a desminrelated myopathy with Mallory body-like inclusions, is clinically characterized by neonatal hypotonia, axial and proximal muscle weakness, scoliosis, and normal or mildly elevated creatine kinase levels [24]. Patient 2 was found to carry the homozygous G273R substitution in the SEPN1 gene although minicores or ‘Mallory-body’ inclusions were not detected by routine histology. Dropped head syndrome is an unusual presentation of a neuromuscular disease and can be extremely disabling. Given its clinical heterogeneity, a search for an underlying neuromuscular disease—myopathy, neuropathy or neuromuscular junction disorders—is important. Although the involvement of neck and axial and muscles appears to be frequent in ‘laminopathies’ and in ‘SEPN relatedmyopathy’ [11,20,24,25] the association of dropped head syndrome with these conditions has not been reported. This report expands the list of the inherited neuromuscular conditions associated with a dropped head syndrome.
524
A. D’Amico et al. / Neuromuscular Disorders 15 (2005) 521–524
Acknowledgements This work was supported by funds from the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Ricerca Corrente Ministero della Salute, Association Franc¸aise contre les Myopathies (AFM), and the GIS-Institut des Maladies Rares.
[14]
[15]
[16]
References [1] Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Annu NY Acad Sci 1981; 377:652–69. [2] DeVere R, Bradley WG. Polymyositis: its presentation, morbidity and mortality. Brain 1975;98:637–66. [3] Ringel SP. Clinical presentations in neuromuscular disease. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. New York: Elsevier; 1979. p. 295–348. [4] Lomen-Hoerth C, Simmons ML, DeArmond SJ, et al. Adult-onset nemaline myopathy: another cause of dropped head. Muscle Nerve 1999;22:1146–50. [5] Finsterer J. Dropped head syndrome in mitochondriopathy. Eur Spine J 2004;13:652–6. [6] Askmark H, Olsson Y, Rossitti S. Treatable dropped head syndrome in hypothyroidism. Neurology 2000;55(6):896–7. [7] Suarez GA, Kelly JJ. The dropped head syndrome. Neurology 1992; 42:1625–7. [8] Katz JS, Wolfe GI, Burns DK, et al. Isolated neck extensor myopathy: a common cause of dropped head syndrome. Neurology 1996;46: 917–21. [9] Dubowitz V. Muscle biopasy: a pratical approach. 2nd ed. Eastbourne: Bailliere Tindall; 1985. [10] Vytopil M, Benedetti S, Ricci E, et al. Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. J Med Genet 2003;40:e132. [11] Moghadaszadeh B, Petit N, Jaillard C, et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 2001;29(1):17–18. [12] Bonne G, Mercuri E, Muchir A, et al. Clinical and molecular genetic spectrum of autosomal dominant Emery–Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 2000;48(2): 170–80. [13] 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
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453–9. Fatkin D, MacRae C, Sasaki T, Wolff MR, 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. Speckman RA, Garg A, Du F, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular Cterminal domain of lamin A/C. Am J Hum Genet 2000;66:1192–8. 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. Novelli G, Muchir A, Sangiuolo F, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 2002;71:426–31. Mounkes LC, Kozlov S, Hernandez L, et al. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 2003;423: 298–301. Caux F, Dubosclard E, Lascols O, et al. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulinresistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab 2003;88:1006–13. Mercuri E, Poppe M, Quinlivan R, et al. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. Arch Neurol 2004;61(5):690–4. Muchir A, Medioni J, Laluc M, et al. Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. Muscle Nerve 2004;30(4):444–50. Vytopil M, Ricci E, Dello Russo A, et al. Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss muscular dystrophy. Neuromuscul Disord 2002;12(10):958–63. Petit N, Lescure A, Rederstroff M, et al. Selenoprotein N: an endoplasmic reticulum glycoprotein with an early developmental expression pattern. Hum Mol Genet 2003;12:1045–53. Ferreiro A, Ceuterick-de Groote C, Marks JJ, et al. Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene. Ann Neurol 2004;55(5):676–86. Ferreiro A, Quijano-Roy S, Pichereau C, et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002;71(4):739–49.