Mutations of the LMNA gene can mimic autosomal dominant proximal ...

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Neurogenetics (2007) 8:137–142 DOI 10.1007/s10048-006-0070-0

ORIGINAL ARTICLE

Mutations of the LMNA gene can mimic autosomal dominant proximal spinal muscular atrophy Sabine Rudnik-Schöneborn & Elke Botzenhart & Thomas Eggermann & Jan Senderek & Benedikt G. H. Schoser & Rolf Schröder & Manfred Wehnert & Brunhilde Wirth & Klaus Zerres

Received: 3 May 2006 / Accepted: 12 October 2006 / Published online: 29 November 2006 # Springer-Verlag 2006

Abstract The molecular basis of autosomal dominant spinal muscular atrophy (AD-SMA) is largely unknown. Because the phenotypic spectrum of diseases caused by LMNA mutations is extremely broad and includes myopathies, neuropathies, and cardiomyopathies designated as class 1 laminopathies, we sequenced the LMNA gene in index patients with the clinical picture of proximal SMA, who had a family history suggestive of autosomal dominant inheritance. Among the 19 families investigated, two showed pathogenic mutations of the LMNA gene, resulting in the diagnosis of a class 1 laminopathy in about 10% of our series. We found one novel truncating mutation (c.1477C>T, Q493X) and one previously described missense mutation (c.1130G>T, R377H) in the LMNA gene of two unrelated patients with adult-onset proximal SMA

followed by cardiac involvement 14 and 22 years after the onset of weakness. The pedigrees of both families revealed a high frequency of cardiac abnormalities or sudden deaths. Our findings extend the spectrum of laminopathies and are of relevance for genetic counseling and clinical care of families presenting with adult-onset proximal SMA. Particularly, if neurogenic atrophy is combined with a cardiac disease in a family, this should prompt LMNA mutation analysis. Keywords Autosomal dominant spinal muscular atrophy . Emery–Dreifuss muscular dystrophy . LMNA mutation . Cardiac complications

Introduction S. Rudnik-Schöneborn (*) : E. Botzenhart : T. Eggermann : J. Senderek : K. Zerres Institute for Human Genetics, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany e-mail: [email protected] B. G. H. Schoser Friedrich-Baur-Institute, University of Munich, Munich, Germany R. Schröder Clinic of Neurology, University of Bonn, Bonn, Germany M. Wehnert Institute for Human Genetics, University of Greifswald, Greifswald, Germany B. Wirth Institute for Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

Proximal spinal muscular atrophy (SMA) is genetically heterogeneous; both autosomal recessive and autosomal dominant forms are described. While infantile SMA is one of the most common inherited diseases leading to death in early infancy, autosomal dominant SMA (AD-SMA) is extremely rare. Vertical transmission of childhood-onset SMA is an exception, but autosomal dominant transmission can be found in about two-thirds of hereditary adult-onset proximal SMA [1, own series]. Deletions or mutations of the telomeric copy of the survival motor neuron (SMN1) gene are responsible for autosomal recessive infantile and juvenile SMA [2]. More than 95% of patients with SMA types I–III show homozygous deletions, gene conversions, or subtle mutations of the SMN1 gene. The molecular defects of AD-SMA are largely unknown. Linkage with genetic markers of the region for autosomal recessive SMA on chromosome 5q has been excluded [3].

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Adult-onset SMA-type Finkel in Brazil was shown to be allelic with amyotrophic lateral sclerosis type 8 caused by mutations in the VAPB gene [4]. One founder mutation of Portuguese ancestry was detected in various branches of an extended pedigree. The clinical presentation is variable and ranges from proximal SMA with a mean onset of 40 years and an atypical ALS. Emery–Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block [5]. The genes for X-linked (X-EDMD) and autosomal dominant EDMD (AD-EDMD) have been identified [6, 7]. Genotype– phenotype studies of LMNA gene mutations detected in AD-EDMD revealed that the clinical picture can be quite different from the typical EMD triad [8, 9]. This led us to hypothesize that the LMNA gene is a good candidate for families with the diagnosis of AD-SMA.

Materials and methods Nineteen index patients with proximal SMA and a positive family history suggesting autosomal dominant inheritance were recruited for molecular analysis. Some families had been described previously [10, 11]. Ages of onset ranged between 2 and 40 years, and affected subjects showed marked intrafamilial variability. All patients fulfilled the clinical and laboratory criteria of proximal SMA defined by the International SMA Consortium [12, 13]. None had cardiac problems at the time of diagnosis, and SMA 5q was excluded by deletion and mutation analysis as previously described [14] or by linkage studies. LMNA gene mutation screening was undertaken in DNA samples from venous blood samples. The 12 exons of the LMNA gene were sequenced using the BigDye™ Terminator Cycle Sequencing Ready Reaction Kit, version 1.1 (Applied Biosystems, Darmstadt, Germany). Primers and PCR conditions can be asked from the authors.

Results Among the 19 families tested, two (∼10%) showed pathogenic mutations of the LMNA gene. The index patients of both hitherto unpublished families were followed up from the 80s and early 90s, at a time when the diagnosis of adult proximal SMA was made on the basis of the clinical picture, laboratory findings, electrophysiology, and muscle biopsy.

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Case reports Family 1 The index patient was a German woman who had first walking difficulties at 39 years of age. Neurological examinations revealed proximal muscular atrophy with normal function of the upper extremity. She noted slowly progressive worsening over the years and was diagnosed with proximal SMA at the age of 45 years. At that time, proximal weakness and atrophy of the legs were present with reduced tendon reflexes, while strength and reflexes in the arms were normal. CK activity was within the normal range, and EMG showed polyphasic potentials with reduced amplitudes and was considered as myopathic. Electroneurographically, normal motor conduction velocities and normal amplitudes were obtained. In 1986, the patient underwent a muscle biopsy of the quadriceps muscle which was considered neurogenic. Small group atrophy was seen beneath the areas of compensatory fiber hypertrophy. Both fiber types were atrophic, and type 2 fiber predominance was present. In addition, mild type grouping and targetoid phenomena were described (Fig. 1). Unfortunately, no material was available 20 years after the muscle biopsy, which could have been used for further investigations and for a better demonstration of the findings described above. SMN1 gene analysis was undertaken in this patient at 54 years to clarify the genetic risks to her offspring. From her family history, it was known that her mother has had walking difficulties from the age of 40 years and died in 1967 at the age of 54 years from a heart attack. Neurological examinations of the mother had not been undertaken, and medical reports were not available. The family was advised that autosomal dominantly inherited SMA was most likely. Ten years later, a novel nonsense mutation c.1477C>T in exon 8 of the LMNA gene (Fig. 2a) was detected, which causes a truncation of the protein synthesis (Q493X). Mutations in exon 8 of LMNA affect the C-terminal globular domain of the lamin A/C protein and are reported in various types of laminopathies [15]. Follow-up information of the patient at the age of 64 revealed that leg muscle weakness had slowly progressed, and walking was still possible on even floors. Upper arm muscles were also affected from age 60. Peroneal weakness or contractures were not seen. At an examination at age 54, CK was 72 U/l (normal value T) of the LMNA gene was detected. This mutation resulted in a substitution of histidine for arginine at codon 377 (R377H) and was reported in other families with limb girdle muscular dystrophy type 1B [16, 17]. The R377H mutation is localized in exon 6 of the LMNA gene, which encodes part of the coil 2 helical domain of the lamin A/C protein. The pathogenic nature of this mutation was clearly proven by cell transfection experiments. Charniot et al. [17] showed that the R377H mutation leads to mislocalization of both lamin and emerin. After the molecular diagnosis in the patient, the mutation was also detected in the only living affected cousin, the

Fig. 3 Pedigree of family 2. Arrow indicates index patient 2. DCM Dilated cardiomyopathy

† 52 y

† 70 y

† 59 y

† 62 y

2

† 54 y

?

† 66 y

DCM, pacemaker 62 y

? † 36 y sudden death

37 y symptom-free

WW II † 40 y

Muscle weakness only Cardiac disease only Full picture Mutation carrier

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Fig. 4 Muscle biopsy (m. biceps) of index patient 2. H&E staining showed a bimodal pattern of the fiber diameters, atrophic fibers in small groups, and multiple hypertrophic fibers

daughter of the paternal uncle (Fig. 3). One nephew, who underwent predictive genetic testing, was a mutation carrier and was still unaffected when last contacted at 37 years.

Discussion On the basis of a large series of families with an AD-SMA phenotype collected in Germany over about 20 years, we estimate that about 10% of families diagnosed with ADSMA are due to mutations of the LMNA gene. We found one novel truncating mutation and one previously described missense mutation in two index patients with adult-onset proximal SMA followed by cardiac involvement 14 and 22 years after the onset of weakness. The phenotypic spectrum of diseases caused by LMNA mutations (designated as laminopathies) is extremely broad and includes myopathies, neuropathies, and cardiopathies designated as class 1 laminopathies and partial lipodystrophy, progeria syndromes, and mandibuloacral dysplasia summarized as class 2 laminopathies [18]. While a nonrandom relationship between the laminopathy class and LMNA mutation position was found, there are no clear-cut genotype–phenotype correlations. The mutations causing class 1 laminopathies are scattered throughout the gene, encompassing both amino- and carboxy-terminal globular domains, as well as the central rod domain. Because distinct phenotypes can be associated with the same mutation, different mechanisms have been suggested to explain the effects of LMNA mutations [15]. Nuclear fragility, anomalous nuclear positioning, tissue-specific altered gene expression, and perturbation of the endoplasmatic reticulum might explain the various cardiac and skeletal muscle pathologies [15].

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Although the pathogenesis seems to be more of myogenic than neurogenic nature in laminopathies, neurogenic atrophy have recently come into focus in other families with LMNA mutations. One family with a novel LMNA deletion, 3del15, resulting in the loss of 15 nucleotides of the gene, had a clinical picture suggestive of AD-EDMD, as early contractures of elbows ankles and neck were noted as initial symptoms in the reported individuals [19]. The muscle biopsies of the m. biceps in two patients showed a similar neurogenic pattern with angular atrophic fibers and fiber-type grouping. An Italian family was reported who had clinical findings resembling Charcot-Marie-Tooth neuropathy with foot deformities and distally pronounced weakness. Nerve conduction studies showed severely reduced motor action potentials and a slightly reduced nerve conduction velocity. Sural nerve biopsy showed loss of large myelinated fibers and scattered fibers with onion-bulb formation. A heterozygous missense mutation causing an R571C substitution was found, which had previously been detected in a family with DCM and atrial fibrillation [20]. The authors present a second patient with severe atrioventricular conduction block from age 25 who developed walking difficulties at age 33. Her muscle biopsy revealed similar neurogenic changes as compared to our patients. The patient had a heterozygous frameshift deletion in exon 5 (c.864_867del) of the LMNA gene [20]. The R377H mutation, detected in our family 2, had been previously described in a Caribbean family with slowly progressive limb girdle muscular dystrophy and age-related atrioventricular conduction disturbances and DCM [16]. Another extended family from France harboring this mutation differed from this phenotype as cardiac features such as arrhythmia, progressive conduction disease, and DCM preceded neuromuscular disease in all the affected individuals. The muscular phenotype was classified as a new quadriceps-restricted myopathy. Muscle biopsy showed variable muscle fiber sizes, angular fibers with abnormal structure, and no signs of denervation [17]. The clinical picture of class 1 laminopathies is characterized by a highly variable expressivity, as illustrated in our two families, with some patients developing no muscle disease at all and others with a few decades between the onset of weakness and cardiac complications. Because LMNA mutations causing class 1 laminopathies bear a high risk of cardiac involvement, mutation carriers require constant cardiologic supervision. The cardiac features are variable combinations of supraventricular arrhythmias, disorders of atrioventricular conduction, ventricular arrhythmias, dilated and nondilated cardiomyopathy, and sudden cardiac death despite pacemaker implant [21, 22]. The time interval between onset of muscle weakness and cardiac disease ranged from 7 to 35 years in an Italian study [21].

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Sudden death in pacemaker recipients has become an increasingly recognized problem in class 1 laminopathies; its mechanism is still unclear and warrants further investigations. In a large metaanalysis comprising 299 mutation carriers of AD-EDMD, DCM, and LGMD1B, sudden death was the most frequent cause of death and occurred in 46% of the patients, of whom 46% had a pacemaker and 54% had none [22]. It was concluded that pacemaker therapy alone is not sufficient to prevent sudden death, probably due to tachyarrhythmias. In patients who need a pacemaker, it might be advisable to use a device suitable to switch to an implantable cardioverter-defibrillator, but further studies are required whether this strategy proves to be effective. Our findings extend the spectrum of phenotypes due to LMNA gene mutations and are of relevance for genetic counseling and clinical care of families with assumed ADSMA. Particularly, if neurogenic atrophy is combined with a cardiomyopathy or cardiac conduction disturbance in a family, this should prompt LMNA mutation analysis. Because de novo LMNA mutations are frequently encountered [8, 9], it is in our view important to screen also sporadic patients with the phenotype of juvenile-and adultonset proximal SMA, who do not show SMN1 gene defects. Acknowledgments The authors wish to thank the affected families for their participation in the study. MW was supported by a grant of the BMBF 01GM0302, MD-NET.

References 1. Pearn J (1978) Autosomal dominant spinal muscular atrophy. J Neurol Sci 38:263–275 2. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Paslier DL, Frezal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995) Identification and characterization of a spinal muscular atrophydetermining gene. Cell 80:155–165 3. Kausch K, Müller CR, Grimm T, Ricker K, Rietschel M, RudnikSchöneborn S, Zerres K (1991) No evidence for linkage of autosomal dominant proximal spinal muscular atrophies to chromosome 5q markers. Hum Genet 86:317–318 4. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75:822–831 5. Emery AEH, Dreifuss FE (1966) Unusual type of benign Xlinked muscular dystrophy. J Neurol Neurosurg Psychiatry 29:338–342 6. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D (1994) Identification of a novel X-linked gene responsible for Emery–Dreifuss muscular dystrophy. Nature Genet 8:323–327 7. Bonne G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K (1999) Mutations in the gene encoding lamin A/C cause autosomal dominant Emery– Dreifuss muscular dystrophy. Nature Genet 21:285–288

Neurogenetics (2007) 8:137–142 8. Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M, Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, Cuisset JM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C, Toniolo D, Fardeau M, Schwartz K, Muntoni F (2000) Clinical and molecular genetic spectrum of autosomal dominant Emery–Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Ann Neurol 48:170– 180 9. Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, Hausmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D (2000) Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery–Dreifuss muscular dystrophy. Am J Hum Genet 66:1407–1412 10. Rietschel M, Rudnik-Schöneborn S, Zerres K (1992) Clinical variability of autosomal dominant spinal muscular atrophy. J Neurol Sci 107:65–73 11. Rudnik-Schöneborn S, Ricker K, Goebel HH, Zerres K (2001) Autosomal dominant spinal muscular atrophy: update on diagnostic criteria as a basis for molecular genetic studies. Neuromuscul Disord 11:S.O.1 12. International SMA Consortium (1991) Meeting report. Neuromuscul Disord 1:81 13. International SMA Consortium (1999) Workshop report. Neuromuscul Disord 9:272–278 14. Wirth B, Herz M, Wetter A, Moskau S, Hahnen E, RudnikSchöneborn S, Wienker T, Zerres K (1999) Quantitative analysis of SMN copies: identification of subtle SMNt mutations in SMA patients, genotype–phenotype correlation and implications for genetic counseling. Am J Hum Genet 64:1340–1356 15. Novelli G, D’Apice MR (2003) The strange case of the ‘lumper” lamin A/C gene and human premature aging. Trends Mol Med 9:370–375 16. Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K (2000) Identification of mutations encoding lamin A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 9:1453–1459 17. Charniot J-C, Pascal C, Bouchier C, Sébillon P, Salama J, DubosqBidot L, Peuchmaurd M, Desnos M, Artigou J-Y, Komajda M (2003) Functional consequences of an LMNA mutation associated with a new cardiac and non-cardiac phenotype. Hum Mutat 21:473–481 18. Hegele RA (2005) LMNA mutation position predicts organ system involvement in laminopathies. Clin Genet 68:31–34 19. Walter MC, Witt TN, Schlotter-Weigel B, Reilich P, Richard P, Pongratz D, Bonne G, Wehnert MS, Lochmüller H (2005) Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery–Dreifuss muscular dystrophy. Neuromuscul Disord 15:40–44 20. Benedetti S, Bertini E, Angelini C, Trisciani M, Sferrazza B, Carrera P, Comi G, Ferrari M, Quattrini A, Previtali SC (2005) Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry 76:1019–1021 21. Sanna T, Dello Russo A, Toniolo D, Vytopil M, Pelargonio G, De Martino G, Ricci E, Silvestri G, Giglio V, Messano L, Zachara E, Bellocci F (2003) Cardiac features of Emery–Dreifuss muscular dystrophy caused by lamin A/C gene mutations. Eur Heart J 24:2227–2236 22. Van Berlo J, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D, Rossenbacker T, Heidbuchel H, de Visser M, Crijns HJ, Pinto YM (2005) Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 83:79–83