Brain Advance Access originally published online on July 8, 2004
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Brain, Vol. 127, No. 9, 2124-2130,
September 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh232
The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V
1 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, 2 Division of Neurology, University Hospital Antwerp, Antwerp, 3 Service de Neurologie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium, 4 Neuromuscular Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy, 5 Unité de Génétique Médicale, Brussels, 6 Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, Belgium and 7 Institute of Medical Biology and Human Genetics, Medical University Graz, Austria
J. Irobi, P. Van den Bergh and L. Merlini contributed equally to this work
Correspondence to: Professor Dr P. De Jonghe, MD, PhD, Peripheral Neuropathy Group, Department of Molecular Genetics (VIB8), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: peter.dejonghe{at}ua.ac.be
Received March 9, 2004. Accepted May 9, 2004.
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Summary |
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 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
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Silver syndrome is a rare autosomal dominant neurodegenerative disorder characterized by marked amyotrophy and weakness of small hand muscles and spasticity in the lower limbs. The locus for Silver syndrome (SPG17) was assigned to a 13 cM region on chromosome 11q12-q14 in a single large pedigree. We recently found heterozygous mutations in the Berardinelli–Seip congenital lipodystrophy (BSCL2, seipin) gene causing SPG17 and distal hereditary motor neuropathy type V (distal HMN V). Here we report the clinical features of two families with heterozygous BSCL2 mutations. Interestingly, both families show a clinical phenotype different from classical Silver syndrome, and in some patients the phenotype is also different from distal HMN V. Patients in the first family had marked spasticity in the lower limbs and very striking distal amyotrophy that always started in the legs. Patients in the second family had distal amyotrophy sometimes starting and predominating in the legs, but no pyramidal tract signs. These observations broaden the clinical phenotype of disorders associated with BSCL2 mutations, having consequences for molecular genetic testing.
Key Words: BSCL2; clinical heterogeneity; distal HMN V; mutation analysis; seipin gene; Silver syndrome; SPG17
Abbreviations: ALS = amyotrophic lateral sclerosis; BSCL gene = Berardinelli–Seip congenital lipodystrophy gene; CMAP = compound muscle action potential; distal HMN = distal hereditary motor neuropathy; HSP = hereditary spastic paraplegia; NCV = nerve conduction velocity; OMIM = Online Mendelian Inheritance in Man; SNAP = sensory nerve action potential; SPG17 = locus for Silver syndrome
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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In 1966, J. R. Silver described two families with a complicated form of hereditary spastic paraplegia (HSP) (Silver, 1966a
, b). Patients' major presenting complaint was severe wasting of the small muscles of the hands, starting between 15 and 30 years of age. Occasionally, muscle wasting spread to involve the shoulder girdle. Most patients also noted stiffness in the legs, cramps and tripping over small objects when walking. On clinical examination most patients had brisk reflexes and Babinski signs. In both families, the pyramidal disturbance in the lower limbs was relatively minor and did not lead to great disability. In one of the families, some patients had marked muscle wasting in the lower third of the calves, but not of the hands, indicating phenotypic variability within the same family. The locus for Silver syndrome was assigned to a 13 cM linkage region on chromosome 11q12-q14 in one of the originally reported families. Furthermore, evidence for genetic heterogeneity was provided by exclusion of the second family from the 11q12-q14 locus (Patel et al., 2001). Since Silver syndrome is considered to be a complicated variant of HSP, the locus was designated SPG17 [Online Mendelian Inheritance in Man (OMIM) #270685]. Recently, heterozygous mutations in the Berardinelli–Seip congenital lipodystrophy (BSCL2) gene were shown in SPG17 families and families with distal hereditary motor neuropathy type V (distal HMN V) (Windpassinger et al., 2004). Here we report the clinical phenotype of two families with BSCL2 mutations. Interestingly, most patients have a clinical phenotype that is different from classical Silver syndrome and distal HMN V. |
Patients and methods |
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Family data
The clinical and genealogical studies for family CMT-I were performed by P.V.D.B., C.V. and L.V.M., and for family CMT-206 by L.M. (Figs 1 and 2). The Institutional Review Board of the University of Antwerp approved this study. Informed consent was obtained from all family members according to the Declaration of Helsinki.
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Molecular genetic studies
Mutation analysis of BSCL2 was performed on the genomic DNA in both families according to methods described by Windpassinger et al. (2004)
. Briefly, PCR products were cleaned up with the Exonuclease1-Shrimp alkaline phosphatase enzyme (USB Corporation, OH, USA) before cycle sequencing. Automated DNA sequencing was performed with the Dye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Foster City CA, USA) and processed with the ABI 3700 DNA sequencer (Applied Biosystems). The Lasergene 99 software (DNA Star, Inc. Madison, WI, USA) was used for sequence and trace file comparisons. |
Results |
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Clinical findings
The clinical data for both families are summarized in Table 1. Family CMT-I has been reported previously, 44 years ago (Moya and and Huet, 1960
). In all patients the presenting symptom was a spastic gait. The age at onset ranged from 2 to 40 years. All patients except the young individual V.1 had pyramidal tract signs consisting of either brisk reflexes in the lower limbs and/or a Babinski sign. The spastic gait was further complicated by severe weakness and atrophy of the distal muscle groups in the legs often leading to a complete distal paralysis. Many patients lost ambulation sometimes from the second decade of life. Pes cavus was almost invariably present. All patients except the young individual V.1 developed atrophy and weakness of the hands. The involvement of the hands was often severe and always started later than or simultaneously with weakness and atrophy in the legs. In none of the patients did the disease start or predominate in the hands. Paraesthesiae, sensory loss and sphincter disturbances were absent. Electrophysiological studies were performed in individuals III.11 and IV.11. Motor and sensory nerve conduction velocities (NCV) were normal in the upper and lower extremities. Sensory nerve action potential amplitudes (SNAP) were normal but compound muscle action potential amplitudes (CMAP) were markedly reduced in upper and lower extremities. Concentric needle EMG showed evidence of chronic denervation in distal muscles. MRI of the brain was normal but the spinal cord was diffusely atrophic in IV.11 (data not shown).
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In family CMT-206 the age of disease onset ranged from 7 to 40 years. In some patients (IV.1, IV.3 and IV.6) the disease started with weakness in the lower limbs. However, in patient III.3 upper limb involvement predated lower limb involvement by 10 years. Also, individuals III.9, IV.3 and IV.4 showed a more prominent involvement of hand muscles. Individual V.1 noticed weakness of the hands starting at the age of 10 years. Although she considered her strength in the lower limbs to be normal, clinical examination showed slight weakness, demonstrating that it is difficult to pinpoint the exact onset of weakness and wasting. All symptomatic individuals had foot deformity. Individual III.5 is an obligate carrier with a normal neurological examination at the age of 71 years. Sometimes older or severely affected patients had a mild reduction of sensation in the feet. Nerve conduction studies were performed in five individuals (IV.1, IV.3, IV.11, V.1 and V.3). The motor NCVs were normal but the CMAPs were sometimes severely reduced. The sensory NCVs were normal and the SNAPs had normal amplitudes.
Mutation analysis of BSCL2 and functional consequences of mutations
In the Italian CMT-206 family we found a c.263A
G (N88S) transition mutation, and in the Belgian CMT-I family we detected a c.269CT (S90L) transition mutation. Both missense mutations co-segregated perfectly in both families and were absent in a panel of 1100 control chromosomes (Windpassinger et al., 2004). Two-point LOD scores between mutation and disease were 3.84 and 3.63 in CMT-I and CMT-206, respectively. Interestingly, in CMT-206, an obligate carrier (person III.5) with a normal clinical examination carried the c.263AG BSCL2 mutation. Transfection studies and protein analysis showed that both mutations (N88S and S90L) affect glycosylation of seipin and result in aggregate formation, thereby leading to neurodegeneration (Windpassinger et al., 2004).
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Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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The clinical features of Silver syndrome were first described in 1966 in two unrelated English families. In both families, the disease was characterized by distal amyotrophy that started in the hands and spasticity in the legs (Silver, 1966a
, b). The disorder followed a different course in the two English (K and A) families. In the K family, the wasting of the hands never became so severe that the individuals could not dress or carry on with jobs, but the pyramidal disturbances in the lower limbs did give rise to cramps and a stiff gait after many years (Silver, 1966a, b). In the A family, the wasting of the hands was more severe and disabling; several affected individuals had the greatest difficulty in dressing and writing, but none complained of any cramps in the legs (Silver, 1966a, b). Of note is that the pyramidal disturbance in the lower limbs was only minor in nature, since no member of either family complained of weakness or unsteadiness, although, when questioned directly, several members of the K family said they had difficulty in walking and cramps in the legs at night. However, the disorder carries a benign prognosis, and does not shorten life or lead to great disability. In the K family, the locus was assigned to chromosome 11q12-q14 and designated as SPG17 since the disease was considered to be a complicated form of HSP (Patel et al., 2001). The fact that the second family did not show linkage to the SPG17 locus indicates that this syndrome is genetically heterogeneous.
Recently, we demonstrated that heterozygous BSCL2 mutations are associated with SPG17 and distal HMN V (Windpassinger et al., 2004). Homozygous and missense BSCL2 mutations have previously been described in patients with Berardinelli–Seip syndrome (OMIM #269700), an autosomal recessive congenital generalized lipodystrophy syndrome (Magre et al., 2001). Berardinelli–Seip syndrome is characterized by a 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 exhibit mental retardation, no spastic paraplegia or peripheral neuropathy has been described in a large series of patients with BSCL2 mutations (Van Maldergem et al., 2002). Of note is the fact that the families we report in this study have no clinical evidence of lipodystrophy or abnormal body fat distribution.
In this study we investigated two families that showed linkage to the SPG17 locus (data not shown) and observed two heterozygous BSCL2 mutations, i.e. the c.263AG (N88S) and c.269CT (S90L) transition mutations. Both mutations showed perfect co-segregation in the families, reaching conclusive two-point LOD scores between the disease and the mutation. In addition, both mutations were absent in a large panel of control individuals, indicating that these mutations are pathogenic and not mere polymorphisms. Finally, functional studies demonstrated the deleterious effect of the mutant proteins, underscoring their pathogenic nature (Windpassinger et al., 2004).
The originally reported Silver syndrome family K, linked to 11q12-q14, was recently shown to have a heterozygous c.263AG (N88S) transition mutation (Windpassinger et al., 2004). We observed the same mutation in family CMT-206, but haplotype analysis showed that these families are not closely related (Windpassinger et al., 2004). Remarkably, the clinical phenotype of CMT-206 differs from classical Silver syndrome, since in CMT-206 the disorder presents as a pure distal motor neuropathy. None of the patients had a spastic gait, and on clinical examination signs of upper motor neuron involvement were absent. Interestingly, in some patients weakness and wasting started in the hands, while in others amyotrophy started in the legs. Only one older patient (II.5) became wheelchair dependent. Person III.5, an obligate carrier who also carries the c.263AG mutation, was completely normal on clinical examination. This observation further supports the incomplete penetrance of the disorders associated with BSCL2 mutations. Reduced penetrance was already noted by Patel and co-workers in the Silver syndrome family linked to the SPG17 locus (Patel et al., 2001).
The Belgian CMT-I family showed a c.269CT (S90L) transition mutation. Again, the phenotype differed from classical Silver syndrome and from the distal pure motor neuropathy phenotype observed in family CMT-206. In CMT-I, several patients showed a very early onset, even before the age of 5 years. In most of the patients of CMT-I, the clinical phenotype was dominated by a severe spastic gait. In addition, most patients developed severe amyotrophy of hand and feet muscles. Muscle wasting usually started in the legs, but some patients mentioned a simultaneous onset in legs and arms. Weakness and atrophy of distal leg and hand muscles was often severe and led to complete paralysis of hands and feet in several patients. The combination of a pronounced spastic gait and severe weakness and wasting in distal leg muscles resulted in loss of ambulation in a minority of patients. Overall, severity of the phenotype in CMT-I family is much more pronounced than in classical Silver syndrome family K or in family CMT-206.
Our clinical observations broaden the spectrum of phenotypes associated with BSCL2 mutations by adding two new forms: first, a variant characterized by a distal amyotrophy without pyramidal tract signs; and secondly, a variant characterized by a spastic paraplegia with distal amyotrophy in the hands and legs. Of interest is the observation that the same mutation can be associated with different phenotypes, raising the possibility of a modifier effect.
Our observation raises issues about the nosological classification of distal motor neuropathies. The phenotype in CMT-206 of a distal pure motor peripheral neuropathy is usually diagnosed as distal HMN or spinal form of Charcot–Marie–Tooth disease. Distal HMN is a clinically and genetically heterogeneous syndrome (European CMT Consortium, 1998). In distal HMN II, patients present with symmetrical distal weakness and wasting starting in the legs (Timmerman et al., 1992), while in distal HMN V the phenotype is characterized by a distal amyotrophy that starts and predominates in the hands (Christodoulou et al., 1995; Auer-Grumbach et al., 2000). Individual patients in family CMT-206 could therefore be diagnosed as either distal HMN II or distal HMN V. In some distal HMN subtypes such as distal HMN V or amyotrophic lateral sclerosis type 4 (ALS4), signs of upper motor neuron involvement can be present to a variable extent, but never so prominent as in family CMT-I. Recently, mutations in glycyl tRNA synthetase (GARS) (OMIM #600287) (Antonellis et al., 2003) have been identified as the cause of distal HMN V linked to chromosome 7 (Christodoulou et al., 1995). We recently demonstrated that mutations in the small heat shock 22k Da Protein 8 (HSP22, HSPB8) (Irobi et al., 2004) and senataxin (SETX) (Chen et al., 2004) and responsible for distal HMN II and ALS4 respectively.
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Acknowledgements |
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We gratefully acknowledge the cooperation and participation of all patients and their relatives in this study. We also appreciate the contribution of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/). This research project was supported by the Fund for Scientific Research-Flanders (FWO), the University of Antwerp (UA), the Geneeskundige Stichting Koningin Elisabeth (GSKE) and the Association Belge contre les Maladies Neuro-Musculaires (ABMM), Belgium, Muscular Dystrophy Association (MDA), USA and Fonds zur Förderung der Wissenschaftlichen Forschung (FWF), Austria and Fonds zur Förderung der wissenschaftlichen Forschung (FWF P15378), Austria, Tom-Wahlig-Stiftung Jena (TWS-FSP), Germany, Muscular Dystrophy Association (MDA), USA, Fachabteilung 6A—Wissenschaft und Forschung of the Land Steiermark and the Italian Ministry of Health and the FIRB (RBNE01JJ45-005). This research was also performed within the frame of the Interuniversity Attraction Poles (IUAP) programme P5/19 of the Belgian Federal Science Policy (POD). A.J. received fellowships from POD and FWO/NATO. N.V. and I.D. are supported by a PhD fellowship from the Institute of Science and Technology (IWT), Belgium.
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