- Email: [email protected]
N88S mutation in the BSCL2 gene in a Serbian family with distal hereditary motor neuropathy type V or Silver syndrome
Journal of the Neurological Sciences 296 (2010) 107–109
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
N88S mutation in the BSCL2 gene in a Serbian family with distal hereditary motor neuropathy type V or Silver syndrome V. Rakočević-Stojanović a,⁎, V. Milić-Rašić b, S. Perić a, J. Baets c,e,f, V. Timmerman d,e, I. Dierick d,e, S. Pavlović a, P. De Jonghe c,e,f a
Institute of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, 6, Dr Subotica Street, 11000 Belgrade, Serbia Clinic of Child Neurology and Psychiatry, School of Medicine, Univeristy of Belgrade, Serbia Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium d Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium e Neurogenetics laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium f Division of Neurology, University Hospital Antwerp, Antwerpen, Belgium b c
a r t i c l e
i n f o
Article history: Received 21 March 2010 Received in revised form 14 June 2010 Accepted 15 June 2010 Available online 3 July 2010 Keywords: BSCL2 gene Distal hereditary motor neuropathy type V (dHMN-V) Silver syndrome
a b s t r a c t Background: Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or Seipin. Aim: To report the first Serbian family with a BSCL2 mutation showing variable expression within the family. Patients and methods: A 55-year-old woman presented with weakness of both hands at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in her legs. Physical examination revealed atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs. There was generalized hyperreflexia with the exception of ankle reflexes which were diminished. Her 25 year-old son had only stiffness of both legs at the age of 22. Physical examination revealed only generalized hyporeflexia. The third affected member in this family was her 55 year-old cousin who showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract features. Results: In all three patients sensory nerve conduction velocities (NCV) were normal in all extremities. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients. Concentric needle EMG showed evidence of chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients. Conclusion: This report is further confirmation of phenotypic heterogenity due to the N88S mutation of BSCL2 gene in the same family. © 2010 Published by Elsevier B.V.
Introduction Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene [1]. dHMN-V is characterized by marked and progressive weakness and wasting of distal muscles of the upper limbs [2]. Foot deformity and peroneal muscle weakness may also be present [2]. Sensory disturbances occur rarely in advanced stages of dHMN-V [2]. Silver syndrome (SS) is a rare autosomal dominant neurodegenerative disorder presenting with both spasticity of the lower limbs and
⁎ Corresponding author. Tel.: +381 11 306 4230; fax: +381 11 268 4577. E-mail address: [email protected] (V. Rakočević-Stojanović). 0022-510X/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.jns.2010.06.015
amyotrophy of the small hand muscles [3]. In a number of families diagnosed as either dHMN-V or SS, two heterozygous mutations (N88S, S90L) located in exon 3 in the BSCL2 gene were identified [3]. Despite extensive screenings in various dominantly inherited motor neuropathies, no other mutations have been found apart from these two missense mutations in exon 3 [1]. However in the allelic recessive disorder Berardinelli-Seip Congenital Lipodystrophy, several loss of function mutations in BSCL2 have been described [4]. Clinical examination of more than 90 patients with the BSCL2 N88S substitution showed that it is most often associated with a dHMN-V phenotype and less frequently, additional prominent spasticity and mild sensory disturbances are found in the lower limbs [5]. Up to date, the S90L substitution was only described in five families and often resulted in a spastic paraplegia phenotype with marked weakness and wasting in the hands suggesting the clinical diagnosis of SS [1]. We report the first Serbian family with the BSCL2 mutation showing variable clinical expression within the family.
108
V. Rakočević-Stojanović et al. / Journal of the Neurological Sciences 296 (2010) 107–109
Fig. 1. Pedigree of the family. Circle – female; square – male; diagonal line – deceased; black symbol – genetically confirmed N88S mutation in BSCL2 gene; grey symbol – asymptomatic family member with no N88S mutation in BSCL2 gene; patterned symbol – symptomatic family member, genetical analysis was not performed.
Patients and methods Patient 1 (III-10, Fig. 1), has been previously reported [1]. This 55year-old woman presented with weakness of both hands at the age of 45. At age 47 she noticed distal weakness and muscle atrophy in her legs, equinovarus feet and ankle deformity. Physical examination revealed generalized hyperreflexia with the exception of absent ankle tendon reflexes. Plantar reflexes were in flexion. She had marked atrophy and weakness of small hand muscles (thenar and interossesus I; grade 3 according to MRC scale) and mild atrophy and weakness of the lower limbs (grade 4 according to MRC scale) with mild steppage gait. There were no dysaesthesias, sensory loss, or sphincter disturbances. Patient 2 (IV–14, Fig. 1): the 25 year-old son of the proband only noticed stiffness in both legs at the age of 22. Physical examination revealed only generalized hyporeflexia without weakness or muscle atrophy. Patient 3 (IV-9, Fig. 1): the 55 year-old cousin of the proband showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles. There were no pyramidal tract signs or sensory loss. At age 35 she noticed mild pes cavus foot deformity; at age 45 she had mild distal weakness and atrophy in her legs and at age 50 she had mild weakness of hand muscles with moderate distal weakness and muscle atrophy in her legs. Physical examination revealed muscle atrophy and mild distal weakness in her hands (grade 4 according to MRC scale) and muscle atrophy and moderate distal weakness in her legs (grade 3/4 according to MRC scale) with hyporeflexia. Active dorsiflexion of feet was reduced, and moderate pes cavus foot deformity was observed. She had a steppage gait and was unable to walk on her heels. Concentric needle electromyography (EMG) and nerve conduction velocity (NCV) studies were performed in the upper and lower limbs by standard procedures. Genetic analysis was also performed in two asymptomatic family members (III-9 and IV-15, Fig. 1). After informed consent genomic DNA was extracted from peripheral blood samples by standard techniques. DNA analysis was performed by sequencing of the PCR amplicon of exon 3 of BSCL2 gene as previously described [1]. Since BSCL2 mutations causing HMN are restricted to the two missense mutations in exon 3, screening can be confined to these hotspots [1]. Results In all our patients sensory NCVs were normal, with normal sensory nerve action potential (SNAP) amplitudes, in both upper and lower extremities. Motor NCVs were slightly decreased in Patient 1 and Patient 3. There were no conduction blocks or temporal dispersion on proximal stimulation. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients (Table 1). EMG showed chronic denervation in distal muscles in all of our patients. Molecular genetic analysis revealed a heterozygous c.263A N G (p.N88S) missense mutation in BSCL2 in all three patients. Genetic
analysis in other asymptomatic family members (III-9 and IV-15, Fig. 1) were normal.
Discussion Distal hereditary motor neuropathy type V and Silver syndrome share the unusual characteristic of prominent hand-muscle weakness and wasting occuring early in the course of the disease. A shared linkage region already suggested that these two disorders might be allelic [6–8]. Subsequently, Windpassinger et al. reported two heterozygous missense mutations (N88S, S90L) in the BSCL2 gene in patients with dHMN type V and Silver syndrome [7]. These amino acid supstitutions affect glycosylation of seipin and result in accumulation of unfolded mutant seipin in the endoplasmatic reticulum (ER) [9]. Expression of mutant seipin increases the level of ER stress-mediated molecules and induces apoptosis leading to neurodegeneration [9]. The range of phenotypic manifestations in mutation carriers varied from asymptomatic individuals to severely affected patients showing either a dHMN type V or Silver syndrome phenotype [3]. In addition, in a large pedigree some patients showed a classical dHMN phenotype or isolated spasticity resembling Hereditary Spastic Paraplegia [5]. Homozygous or compound heterozygous deletions and nonsense BSCL2 mutations have previously been described in patients with Berardinelli–Seip syndrome, an autosomal recessive congenital generalized lipodystrophy syndrome [4]. Berardinelli–Seip syndrome is characterized by near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridaemia. Although most patients exhibited mental retardation, no spastic paraplegia or peripheral neuropathy has been described in a large series of patients with Berardinelli–Seip syndrome [4,11]. It should
Table 1 Nerve conduction study in reported patients. CV – conduction velocity (m/s), CMAP – compound muscle action potential amplitude (mV), SNAP – sensory nerve action potential amplitude (uV), abnormal values are given in bold, * – analysis not performed. Patient 1 Patient 2 Patient 3 reference values Median nerve Ulnar nerve Peroneal nerve Sensory nerves Median nerve conduction Ulnar study nerve Sural nerve
Motor nerves conduction study
CV (m/s) CMAP (mV) CV (m/s) CMAP (mV) CV (m/s) CMAP (mV) CV (m/s) SNAP (uV) CV (m/s) SNAP (uV) CV (m/s) SNAP (uV)
49.0 2.0 63.5 15.0 35.5 0.2 56.5 40.0 54.9 14.8 65.0 12.0
57.2 5.3 * * 46.5 0.6 54.0 42.7 47.7 34.8 41.3 13.6
57.0 1.0 64.5 11.0 40.5 3.5 59.0 30.0 66.5 24.0 54.0 10.0
51.0 3.0 51.0 3.5 42.0 1.5 49.0 5.0 44.0 5.0 40.0 4.0
V. Rakočević-Stojanović et al. / Journal of the Neurological Sciences 296 (2010) 107–109
be noted that our patients had no lipodystrophy or abnormal body fat distribution. In this study we present a Serbian family with the heterozygous missense N88S BSCL2 mutation showing variable phenotypic expression even within this nuclear family. In one patient we found marked atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs with hyperreflexia resembling Silver syndrome. The second patient was almost asymptomatic and his clinical examination was unremarkable. However, the third patient showed a more prominent involvement of legs muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract signs suggesting a diagnosis of classical dHMN. These findings confirms incomplete penetrance of disorders associated with BSCL2 mutations. Reduced penetrance was already noted by Patel and co-workers in a Silver syndrome family [12]. Windpassinger et al. reported a family with Silver syndrome and the N88S mutation which is also present in our family [6]. However, Irobi et al. observed the same mutation in a family with pure distal motor neuropathy [10]. None of their patients had spastic gait, nor signs of upper motor neuron involvement on clinical examination [10]. Regarding our family, it appears that the same mutation can be associated with different phenotypes even in the same pedigree. Striking inter- and intrafamilial variability seems to be a frequent finding in patients with BSCL2 mutations. It is currently unknown whether this variablity stems from acquired or genetic factors or a combination of both. These clinically heterogeneous BSCL2 families may indeed present nice opportunities to search for genetic modifiers in a neurodegenerative disorder. Acknowledgements JB is supported by a PhD fellowship of the FWO-Flanders.
109
References [1] Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype–phenotype correlation study. Brain 2008;131: 1217–27. [2] Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, et al. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain 2000;123:1612–23. [3] Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 2009;132:8–15. [4] Magre J, Delepine M, Khallouf E, Gedde-Dahl Jr T, Van Maldergem L, Sobel E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001;28:365–70. [5] Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, AuerGrumbach P, Fischer R, et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol 2005;57:415–24. [6] Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004;36:271–6. [7] Windpassinger C, Wagner K, Petek E, Fischer R, Auer-Grumbach M. Refinement of the Silver syndrome locus on chromosome 11q12-q14 in four families and exclusion of eight candidate genes. Hum Genet 2003;114:99–109. [8] Cho HJ, Sung DH, Ki CS. Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy. Muscle Nerve 2007;36:384–6. [9] Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol 2007;61:237–50. [10] Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, et al. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 2004;127:2124–30. [11] Van Maldergem L, Magre J, Khallouf E, Gedde-Dahl Jr T, Delepine M, Trygstad O, et al. Genotype–phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 2002;39:722–33. [12] Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, et al. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12q14, with evidence for genetic heterogenity within this subtype. Am J Hum Genet 2001;69:209–15.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
N88S mutation in the BSCL2 gene in a Serbian family with distal hereditary motor neuropathy type V or Silver syndrome V. Rakočević-Stojanović a,⁎, V. Milić-Rašić b, S. Perić a, J. Baets c,e,f, V. Timmerman d,e, I. Dierick d,e, S. Pavlović a, P. De Jonghe c,e,f a
Institute of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, 6, Dr Subotica Street, 11000 Belgrade, Serbia Clinic of Child Neurology and Psychiatry, School of Medicine, Univeristy of Belgrade, Serbia Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium d Peripheral Neuropathy Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium e Neurogenetics laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium f Division of Neurology, University Hospital Antwerp, Antwerpen, Belgium b c
a r t i c l e
i n f o
Article history: Received 21 March 2010 Received in revised form 14 June 2010 Accepted 15 June 2010 Available online 3 July 2010 Keywords: BSCL2 gene Distal hereditary motor neuropathy type V (dHMN-V) Silver syndrome
a b s t r a c t Background: Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene or Seipin. Aim: To report the first Serbian family with a BSCL2 mutation showing variable expression within the family. Patients and methods: A 55-year-old woman presented with weakness of both hands at the age of 45. At age 47, she noticed distal muscle weakness and atrophy in her legs. Physical examination revealed atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs. There was generalized hyperreflexia with the exception of ankle reflexes which were diminished. Her 25 year-old son had only stiffness of both legs at the age of 22. Physical examination revealed only generalized hyporeflexia. The third affected member in this family was her 55 year-old cousin who showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract features. Results: In all three patients sensory nerve conduction velocities (NCV) were normal in all extremities. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients. Concentric needle EMG showed evidence of chronic denervation in distal muscles. DNA sequencing of BSCL2 was performed and a heterozygous N88S missense mutation in BSCL2 gene was detected in all three patients. Conclusion: This report is further confirmation of phenotypic heterogenity due to the N88S mutation of BSCL2 gene in the same family. © 2010 Published by Elsevier B.V.
Introduction Distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene [1]. dHMN-V is characterized by marked and progressive weakness and wasting of distal muscles of the upper limbs [2]. Foot deformity and peroneal muscle weakness may also be present [2]. Sensory disturbances occur rarely in advanced stages of dHMN-V [2]. Silver syndrome (SS) is a rare autosomal dominant neurodegenerative disorder presenting with both spasticity of the lower limbs and
⁎ Corresponding author. Tel.: +381 11 306 4230; fax: +381 11 268 4577. E-mail address: [email protected] (V. Rakočević-Stojanović). 0022-510X/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.jns.2010.06.015
amyotrophy of the small hand muscles [3]. In a number of families diagnosed as either dHMN-V or SS, two heterozygous mutations (N88S, S90L) located in exon 3 in the BSCL2 gene were identified [3]. Despite extensive screenings in various dominantly inherited motor neuropathies, no other mutations have been found apart from these two missense mutations in exon 3 [1]. However in the allelic recessive disorder Berardinelli-Seip Congenital Lipodystrophy, several loss of function mutations in BSCL2 have been described [4]. Clinical examination of more than 90 patients with the BSCL2 N88S substitution showed that it is most often associated with a dHMN-V phenotype and less frequently, additional prominent spasticity and mild sensory disturbances are found in the lower limbs [5]. Up to date, the S90L substitution was only described in five families and often resulted in a spastic paraplegia phenotype with marked weakness and wasting in the hands suggesting the clinical diagnosis of SS [1]. We report the first Serbian family with the BSCL2 mutation showing variable clinical expression within the family.
108
V. Rakočević-Stojanović et al. / Journal of the Neurological Sciences 296 (2010) 107–109
Fig. 1. Pedigree of the family. Circle – female; square – male; diagonal line – deceased; black symbol – genetically confirmed N88S mutation in BSCL2 gene; grey symbol – asymptomatic family member with no N88S mutation in BSCL2 gene; patterned symbol – symptomatic family member, genetical analysis was not performed.
Patients and methods Patient 1 (III-10, Fig. 1), has been previously reported [1]. This 55year-old woman presented with weakness of both hands at the age of 45. At age 47 she noticed distal weakness and muscle atrophy in her legs, equinovarus feet and ankle deformity. Physical examination revealed generalized hyperreflexia with the exception of absent ankle tendon reflexes. Plantar reflexes were in flexion. She had marked atrophy and weakness of small hand muscles (thenar and interossesus I; grade 3 according to MRC scale) and mild atrophy and weakness of the lower limbs (grade 4 according to MRC scale) with mild steppage gait. There were no dysaesthesias, sensory loss, or sphincter disturbances. Patient 2 (IV–14, Fig. 1): the 25 year-old son of the proband only noticed stiffness in both legs at the age of 22. Physical examination revealed only generalized hyporeflexia without weakness or muscle atrophy. Patient 3 (IV-9, Fig. 1): the 55 year-old cousin of the proband showed a more prominent involvement of leg muscles with mild asymmetrical weakness of hand muscles. There were no pyramidal tract signs or sensory loss. At age 35 she noticed mild pes cavus foot deformity; at age 45 she had mild distal weakness and atrophy in her legs and at age 50 she had mild weakness of hand muscles with moderate distal weakness and muscle atrophy in her legs. Physical examination revealed muscle atrophy and mild distal weakness in her hands (grade 4 according to MRC scale) and muscle atrophy and moderate distal weakness in her legs (grade 3/4 according to MRC scale) with hyporeflexia. Active dorsiflexion of feet was reduced, and moderate pes cavus foot deformity was observed. She had a steppage gait and was unable to walk on her heels. Concentric needle electromyography (EMG) and nerve conduction velocity (NCV) studies were performed in the upper and lower limbs by standard procedures. Genetic analysis was also performed in two asymptomatic family members (III-9 and IV-15, Fig. 1). After informed consent genomic DNA was extracted from peripheral blood samples by standard techniques. DNA analysis was performed by sequencing of the PCR amplicon of exon 3 of BSCL2 gene as previously described [1]. Since BSCL2 mutations causing HMN are restricted to the two missense mutations in exon 3, screening can be confined to these hotspots [1]. Results In all our patients sensory NCVs were normal, with normal sensory nerve action potential (SNAP) amplitudes, in both upper and lower extremities. Motor NCVs were slightly decreased in Patient 1 and Patient 3. There were no conduction blocks or temporal dispersion on proximal stimulation. Compound muscle action potential (CMAP) amplitudes were markedly reduced in all patients (Table 1). EMG showed chronic denervation in distal muscles in all of our patients. Molecular genetic analysis revealed a heterozygous c.263A N G (p.N88S) missense mutation in BSCL2 in all three patients. Genetic
analysis in other asymptomatic family members (III-9 and IV-15, Fig. 1) were normal.
Discussion Distal hereditary motor neuropathy type V and Silver syndrome share the unusual characteristic of prominent hand-muscle weakness and wasting occuring early in the course of the disease. A shared linkage region already suggested that these two disorders might be allelic [6–8]. Subsequently, Windpassinger et al. reported two heterozygous missense mutations (N88S, S90L) in the BSCL2 gene in patients with dHMN type V and Silver syndrome [7]. These amino acid supstitutions affect glycosylation of seipin and result in accumulation of unfolded mutant seipin in the endoplasmatic reticulum (ER) [9]. Expression of mutant seipin increases the level of ER stress-mediated molecules and induces apoptosis leading to neurodegeneration [9]. The range of phenotypic manifestations in mutation carriers varied from asymptomatic individuals to severely affected patients showing either a dHMN type V or Silver syndrome phenotype [3]. In addition, in a large pedigree some patients showed a classical dHMN phenotype or isolated spasticity resembling Hereditary Spastic Paraplegia [5]. Homozygous or compound heterozygous deletions and nonsense BSCL2 mutations have previously been described in patients with Berardinelli–Seip syndrome, an autosomal recessive congenital generalized lipodystrophy syndrome [4]. Berardinelli–Seip syndrome is characterized by near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridaemia. Although most patients exhibited mental retardation, no spastic paraplegia or peripheral neuropathy has been described in a large series of patients with Berardinelli–Seip syndrome [4,11]. It should
Table 1 Nerve conduction study in reported patients. CV – conduction velocity (m/s), CMAP – compound muscle action potential amplitude (mV), SNAP – sensory nerve action potential amplitude (uV), abnormal values are given in bold, * – analysis not performed. Patient 1 Patient 2 Patient 3 reference values Median nerve Ulnar nerve Peroneal nerve Sensory nerves Median nerve conduction Ulnar study nerve Sural nerve
Motor nerves conduction study
CV (m/s) CMAP (mV) CV (m/s) CMAP (mV) CV (m/s) CMAP (mV) CV (m/s) SNAP (uV) CV (m/s) SNAP (uV) CV (m/s) SNAP (uV)
49.0 2.0 63.5 15.0 35.5 0.2 56.5 40.0 54.9 14.8 65.0 12.0
57.2 5.3 * * 46.5 0.6 54.0 42.7 47.7 34.8 41.3 13.6
57.0 1.0 64.5 11.0 40.5 3.5 59.0 30.0 66.5 24.0 54.0 10.0
51.0 3.0 51.0 3.5 42.0 1.5 49.0 5.0 44.0 5.0 40.0 4.0
V. Rakočević-Stojanović et al. / Journal of the Neurological Sciences 296 (2010) 107–109
be noted that our patients had no lipodystrophy or abnormal body fat distribution. In this study we present a Serbian family with the heterozygous missense N88S BSCL2 mutation showing variable phenotypic expression even within this nuclear family. In one patient we found marked atrophy and weakness of small hand muscles and mild atrophy and weakness of the lower limbs with hyperreflexia resembling Silver syndrome. The second patient was almost asymptomatic and his clinical examination was unremarkable. However, the third patient showed a more prominent involvement of legs muscles with mild asymmetrical weakness of hand muscles and no pyramidal tract signs suggesting a diagnosis of classical dHMN. These findings confirms incomplete penetrance of disorders associated with BSCL2 mutations. Reduced penetrance was already noted by Patel and co-workers in a Silver syndrome family [12]. Windpassinger et al. reported a family with Silver syndrome and the N88S mutation which is also present in our family [6]. However, Irobi et al. observed the same mutation in a family with pure distal motor neuropathy [10]. None of their patients had spastic gait, nor signs of upper motor neuron involvement on clinical examination [10]. Regarding our family, it appears that the same mutation can be associated with different phenotypes even in the same pedigree. Striking inter- and intrafamilial variability seems to be a frequent finding in patients with BSCL2 mutations. It is currently unknown whether this variablity stems from acquired or genetic factors or a combination of both. These clinically heterogeneous BSCL2 families may indeed present nice opportunities to search for genetic modifiers in a neurodegenerative disorder. Acknowledgements JB is supported by a PhD fellowship of the FWO-Flanders.
109
References [1] Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype–phenotype correlation study. Brain 2008;131: 1217–27. [2] Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, et al. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain 2000;123:1612–23. [3] Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 2009;132:8–15. [4] Magre J, Delepine M, Khallouf E, Gedde-Dahl Jr T, Van Maldergem L, Sobel E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 2001;28:365–70. [5] Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G, AuerGrumbach P, Fischer R, et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol 2005;57:415–24. [6] Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 2004;36:271–6. [7] Windpassinger C, Wagner K, Petek E, Fischer R, Auer-Grumbach M. Refinement of the Silver syndrome locus on chromosome 11q12-q14 in four families and exclusion of eight candidate genes. Hum Genet 2003;114:99–109. [8] Cho HJ, Sung DH, Ki CS. Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy. Muscle Nerve 2007;36:384–6. [9] Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol 2007;61:237–50. [10] Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, et al. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 2004;127:2124–30. [11] Van Maldergem L, Magre J, Khallouf E, Gedde-Dahl Jr T, Delepine M, Trygstad O, et al. Genotype–phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 2002;39:722–33. [12] Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, et al. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12q14, with evidence for genetic heterogenity within this subtype. Am J Hum Genet 2001;69:209–15.