59th ENMC International Workshop: Spinal Muscular Atrophies: recent progress and revised diagnostic criteria 17–19 April 1998, Soestduinen, The Netherlands
1999; Elsevier BV; Volume: 9; Issue: 4 Linguagem: Inglês
10.1016/s0960-8966(99)00016-4
ISSN1873-2364
Autores Tópico(s)Muscle Physiology and Disorders
ResumoThis 8th SMA workshop followed the ENMC tradition of combining clinical and molecular topics with the aim of not only exchanging current knowledge but also initiating collaborative studies. Despite important milestones in SMA research in the past with the mapping of the gene in 1990 and the identification of important candidate genes, such as the SMN (survival motor neuron) and NAIP (neuronal apoptosis inhibitory protein) genes, in 1995, we are just beginning to understand the pathogenic pathway of SMA. The field of interest is therefore focussed on protein function studies and on clinical aspects in terms of genotype-phenotype studies. The possibility of analyzing the SMN gene allowed the delineation of the diagnostic criteria of 'classical' proximal SMA and its clinical variability. However, different entities of SMA could be defined that show atypical features and proved to be unlinked to chromosome 5q. Against the background of a longstanding experience of the contributing groups who collected a tremendous material, the diagnostic criteria of SMA 5q were discussed and adapted to current knowledge. The workshop was structured in different molecular and clinical sessions that were briefly reviewed by invited chairpersons (named in brackets). The following summaries cover the essentials of the discussion and consensus achieved. This session was devoted to an overview of mutations [[19]Lefebvre S. Bürglen L. Frézal J. Munnich A. Melki J. The role of the SMN gene in proximal spinal muscular atrophy.Hum Mol Genet. 1998; 7: 1531-1536Crossref PubMed Scopus (129) Google Scholar]. Previous studies have shown that mutations in exon 6 dramatically reduce the self-association capacity of SMN transcripts [[21]Lorson C.L. Strasswimmer J. Yao J-M. et al.SMN oligomerization defect correlates with spinal muscular atrophy severity.Nat Genet. 1998; 19: 63-66Crossref PubMed Scopus (418) Google Scholar]. Spontaneous mutations were first observed in infantile SMA by Melki et al. [[24]Melki J. Lefebvre S. Bürglen L. et al.De novo and inherited deletions of the 5q13 region in spinal muscular atrophies.Science. 2994; 264: 1474-1477Google Scholar] and were found in 2% of isolated cases in a detailed study in Germany, which corresponds to a spontaneous mutation rate of which is close to the expected figure [[38]Wirth B. Schmidt T. Hahnen E. et al.De novo rearrangement found in 2% index patients with spinal muscular atrophy: Mutational mechanisms, parental origin, mutation rate and implications for genetic counselling.Am J Hum Genet. 1997; 61: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. The evolution of a mutation in a family was demonstrated by pulsed field gel electrophoresis (PFGE) analysis (L. Campbell and K. Davies). The copy number of the SMNC gene can be determined by quantitative PCR or PFGE. PFGE data [[7]Campbell L. Potter A. Ignatius J. Dubowitz V. Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype.Am J Hum Genet. 1997; 61: 40-50Abstract Full Text PDF PubMed Scopus (279) Google Scholar] confirmed the PCR data that suggest that the severity of the disease correlates with the copy number of the centromeric gene in the absence of telSMN [6Burghes A.H.M. Spinal muscular atrophy: the importance of being converted.Am J Hum Genet. 1997; 61: 9-15Abstract Full Text PDF PubMed Scopus (239) Google Scholar, 18Lefebvre S. Burlet P. Liu Q. et al.Correlation between severity and SMN protein level in spinal muscular atrophy.Nat Genet. 1997; 16: 265-269Crossref PubMed Scopus (898) Google Scholar]. However, as the assay cannot determine the amount of full length SMN protein produced from these SMNC alleles (and whether they are intact unless the pulsed field assay is used) the correlation of SMNC copy number is not absolute. It is therefore not recommended that SMNC copy number be used for prediction of clinical severity. Data using in situ hybridization to determine copy number were presented by C. Brahe. Overall, it was agreed that even though the inverse correlation between SMNC copy number and severity was very strong, it was not absolute and that other modifying factors must also play a role. Several groups presented data showing the presence of SMN in gems as shown by Liu and Dreyfuss [[20]Liu Q. Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein.EMBO J. 1996; 15: 3555-3565Crossref PubMed Scopus (656) Google Scholar]. The truncated isoforms of SMN (lacking exons 7 and 5) are alternatively spliced SMN products that do not form gems efficiently and do not dimerize sufficiently. No group has yet confirmed the Japanese data on the association of Bcl-2 with SMN [[14]Iwahashi H. Eguchi Y. Yasuhara N. Hanafusa T. Matsuzawa Y. Tsujimoto Y. Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy.Nature. 1997; 390: 413-417Crossref PubMed Scopus (180) Google Scholar]. A. MacKenzie reported protein studies with NAIP and other mediators of apoptosis [[40]Xu D.G. Crocker S.J. Douget J-P. et al.Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus.Nat Med. 1997; 3: 997-1004Crossref PubMed Scopus (224) Google Scholar]. NAIP has shown to be transported only in the ventral and not in the posterior roots of the spinal cord. The discussion on animal models provided insight into the conditional mutants that are being generated but no data are yet available. There is an 82% homology between human and Murine SMN gene. The inactivation of the Murine SMN gene leads to early cell death in mouse embryos [[36]Schrank B. Gotz R. Gunnersen J.M. et al.Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos.Proc Natl Acad Sci USA. 1997; 94: 9920-9925Crossref PubMed Scopus (563) Google Scholar]. A. Burghes discussed the introduction of a human centromeric PAC BamH1 fragment of 36 kB into the mouse as a transgene and crossing against the SMN null mutant mouse [[36]Schrank B. Gotz R. Gunnersen J.M. et al.Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos.Proc Natl Acad Sci USA. 1997; 94: 9920-9925Crossref PubMed Scopus (563) Google Scholar]. Results of these experiments is eagerly awaited. The main part of the discussion of the molecular genetics centered on the approaches to prenatal diagnosis and carrier testing. The following text collates data from many laboratories world-wide. This section outlines the discussion on DNA testing and indicates the policies towards DNA testing. In this regard there is uniformity as regards DNA testing for the diagnosis of SMA but not as concerns carrier status. DNA testing should be performed to confirm the diagnosis of 5q SMA. The absence of the telomeric copy of the survival motor neuron gene (SMNT) in the presence of clinical symptoms of SMA can be regarded as confirmatory of 5q SMA. There are rare cases where the SMNT gene is not detectable but the individual has no clinical symptoms of SMA or extremely mild symptoms. The reason for this is not clear, however it is presumed that the SMN protein is produced in sufficient amounts from the centromeric SMN (SMNC) gene. However, these subjects can transmit an SMA allele to their offspring and therefore it can be considered as variable penetrance and as an error of the specificity of the DNA test. Studies using SMA families that meet the international clinical criteria for 5q SMA have shown that SMNT is not detectable in 95% of type I and II cases and 80% of type III SMAs. It is not unlikely that in the case of type III SMA that a disease that is clinical similar to 5q SMA but is not due to mutation of the SMNT decreased the number of cases which lack SMNT. In the cases of testing potential 5q SMA cases that possess the SMNT gene, Hardy–Weinberg principals predict that the vast majority of these cases would possess only one copy of the SMNT gene. The exception being in consanguineous cases which can be identified by using polymorphic markers in the region. All non-consanguineous SMA 5q patients were found to be compound heterozygous between an SMNT gene lacking exon 7 on one chromosome and a small mutation in the other allele. Thus, cases of SMA that possess two copies of the SMNT gene and where marker studies do not indicate consanguinity should be considered as unlikely to be 5q SMA and should be investigated for other disorders. It is a common experience in most centers that the proportion of SMA 5q cases is small among those referred for genetic testing when not strictly selected according to the diagnostic criteria (below). The presence of one copy of the SMNT gene can indicate either SMA or carrier status. To confirm that these cases are 5q SMA, it is best to identify the mutation in the retained SMNT gene. Testing of SMN protein levels in type I and II cases can also be used to confirm 5q SMA but this is not a routine option at present. Type III SMA cases do not show large alterations in SMN levels in accessible tissues and thus it is not possible to confirm the diagnosis with the protein test. The determination of copy number of SMNT can be used for carrier detection as described by McAndrew et al. [[23]McAndrew P.E. Parsons D.W. Simard L.R. et al.Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNt and SMNc gene copy number.Am J Hum Genet. 1997; 60: 1411-1422Abstract Full Text PDF PubMed Scopus (462) Google Scholar]. The risk for a false negative classification of a carrier was given with 10–15% by A. Burghes based on the American series. They found more than one SMNT copy per chromosome in 3%, a 2% de-novo mutation rate and gave max. 5% due to point mutations. It was agreed that larger samples of proven carriers and non-carriers are required to calculate specificity and sensitivity of the carrier test. In North America, three laboratories (Columbus, Montreal, Philadelphia) currently perform the carrier test. In all cases the cystic fibrosis gene is used as the standard. In Europe the dosage test is performed in Germany (Bonn) using the CF gene as a standard [[39]Wirth B. Herz M. Wetter A. et al.Quantitative analysis of SMN copies: identification of subtle SMNt mutations, genotype-phenotype correlation and implications for genetic counselling.Am J Hum Genet. 1999; (in press)Google Scholar] and in the Netherlands (Groningen) using a modified test that utilizes the RB gene. An adaptation of the original protocols that runs on the automatic sequencer is an assay which shows very good reliability (used in Philadelphia). In all cases, the carrier and non-carrier samples do not show overlap if analysis is performed on the same gel. In addition, all cases analyzed by these groups that were predicted by linkage analysis as non-carriers were confirmed. The test is offered in North America to families who wish testing. The Philadelphia laboratory does not require any prior individual in the family to have an SMNT deletion whereas the other laboratories require one individual in the family to have an SMN deletion (the spouse with no history of SMA will then be tested). In North America current testing policy is similar to DMD carrier testing in that detection of one copy of SMNT is considered as evidence of carrier status. J.-M. Cobben and H. Scheffer (Groningen) reported the results of the heterozygosity test used in 63 carriers and 25 non-carriers identified by linkage studies. The test sensitivity was 97% (61/63), the specificity was 96% (22/23). However, the DNA sample that was determined by linkage analysis to not be a carrier and by the dosage assay to be a carrier (false positive result) was derived from a chorionic villus sample and the state of the DNA sample is known to be critical in this quantitative assay. In Germany, 73 carriers and 42 non-carriers were tested with a modified SMNT dosage test using the CF gene as a standard [[39]Wirth B. Herz M. Wetter A. et al.Quantitative analysis of SMN copies: identification of subtle SMNt mutations, genotype-phenotype correlation and implications for genetic counselling.Am J Hum Genet. 1999; (in press)Google Scholar]. The proportion of carriers carrying at least two SMNT copies per chromosome was 3.8%. In addition, there was an overlapping interval between carriers and non-carriers in 6–7% reducing the validity of the test. These data have important implications for genetic counseling and screening policies. The following points have to be considered when using this quantitative test in SMA.1.The DNA preparation should be undertaken by the same method with control and test DNA.2.The reference marker should preferable be in a region that is not known to undergo somatic mutation or loss, i.e. the cystic fibrosis (CF) gene.3.The test and control sample should be in multiple aliquots on the same gel. It is also preferable to have multiple samples with different amounts of template.4.The amplification efficiency of the test and control samples should be similar. The calculation of copy number should be done relative to the CF gene used as a standard.5.About 3–4% of individuals have more than one copy of SMNT on one chromosome, which gives rise to an individual testing negative but in fact being carrier [23McAndrew P.E. Parsons D.W. Simard L.R. et al.Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNt and SMNc gene copy number.Am J Hum Genet. 1997; 60: 1411-1422Abstract Full Text PDF PubMed Scopus (462) Google Scholar, 39Wirth B. Herz M. Wetter A. et al.Quantitative analysis of SMN copies: identification of subtle SMNt mutations, genotype-phenotype correlation and implications for genetic counselling.Am J Hum Genet. 1999; (in press)Google Scholar].6.There is a method dependent risk for overlapping results between carriers and non-carriers which reduces the validity of the test.7.In about 2% of SMA patients a spontaneous mutation can be detected, which has to be taken into account depending on the specific question. In order to resolve the current issues in testing it has been agreed to exchange a set of test samples to try and resolve the differences that exist. It will also be advantageous to exchange information on SMNC copy number. This is currently being organized [[26]Muscular Dystrophy Association USA Internet Homepage/Research. http://www. mdausa.org/research/ct-smagab.htmlGoogle Scholar]. The pathoanatomic spectrum of Werdnig–Hoffmann disease has been controversially discussed in the past 20 years. Previous studies showed that neuronal loss is not limited to the anterior horn cells but can affect other parts of the CNS and the spinal cord in a similar way [[37]Towfighi J. Young R.S.K. Ward R.M. Is Werdnig-Hoffmann disease a pure lower motor neuron disorder?.Acta Neuropathol. 1985; 65: 270-280Crossref PubMed Scopus (53) Google Scholar]. Based on molecular genetic findings, there is now strong evidence that a 'congenital' type of infantile SMA exists, which so far has usually not been classified as infantile SMA due to atypical findings or evidence of peripheral neuropathy [11Devriendt K. Lammens M. Schollen E. et al.Clinical and molecular genetic features of congenital spinal muscular atrophy.Ann Neurol. 1996; 40: 731-738Crossref PubMed Scopus (56) Google Scholar, 17Korinthenberg R. Sauer M. Ketelsen U.P. et al.Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region.Ann Neurol. 1997; 42: 364-368Crossref PubMed Scopus (88) Google Scholar]. Major findings of congenital SMA can include severe neonatal onset with respiratory insufficiency, congenital contractures, external ophthalmoplegia and severe axonal involvement. Life span is short with death within the first weeks of life. While the patients clinically do not exhibit signs of sensory disturbances, electrophysiological investigations reveal a lack of sensory and motor nerve excitability [17Korinthenberg R. Sauer M. Ketelsen U.P. et al.Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region.Ann Neurol. 1997; 42: 364-368Crossref PubMed Scopus (88) Google Scholar, 28Omran H. Ketelsen U.P. Heinen F. et al.Axonal neuropathy and predominance in type II myofibres in SMA 1.J Child Neurol. 1998; 13: 327-331Crossref PubMed Scopus (40) Google Scholar]. Morphologically (upon sural nerve biopsies), there are typical signs of axonal degeneration, including reduction of myelinated fibers and dystrophic axons with shrunken and condensed axon structures. Fiber density of myelinated nerve fibers is below the lower limit. In addition, a similar loss of myelinated fibers is present in the spinal cord, both anterior and posterior roots. Cerebral atrophy was documented in some cases. The demonstration of less pronounced sural nerve pathology of less severe cases, which are clinically indistinguishable from classical type I SMA, has important implications with regard to the primary affected structures in SMA. Of great importance for the understanding of the pathogenetic pathway is the observation that the number of motor neurons in the spinal cord in these neonatal forms was not markedly reduced in contrast to the severe clinical manifestation [[17]Korinthenberg R. Sauer M. Ketelsen U.P. et al.Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region.Ann Neurol. 1997; 42: 364-368Crossref PubMed Scopus (88) Google Scholar]. This finding is of interest indicating that the severity of clinical manifestation does not correlate with the extent of alpha motor neuron loss in spinal cord or that a morphologically typical pattern does not develop in congenital SMA. The molecular analysis shows a large deletion, including SMNT and NAIP genes as well as the multicopy markers C212 and Ag1-CA, on one chromosome in combination with a single copy of these markers on the second chromosome, giving evidence of an extended deletion of the SMA region in most families with congenital or atypical SMA. The systematic analysis of the SMN gene in cases with a severe axonal neuropathy/hypomyelinization seems to be justified. The following SMA plus phenotypes, as defined previously at the 35th ENMC workshop on SMA, are now regarded as separate entities definitely not linked to chromosome 5q markers. In none of the tested families, absence of SMNT deletion could be detected [[42]Zerres K. Wirth B. Rudnik-Schöneborn S. Spinal muscular atrophy – clinical and genetic correlations.Neuromusc Disord. 1997; 7: 202-207Abstract Full Text PDF PubMed Scopus (95) Google Scholar]. This entity is usually characterized by initial respiratory insufficiency due to diaphragmatic palsy often followed by a distally pronounced weakness and wasting [[1]Bertini E. Gadisseux J.L. Palmieri G. Ricci E. DiCapua M. Ferriere G. Lyon G. Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy.Am J Med Genet. 1989; 33: 328-335Crossref PubMed Scopus (59) Google Scholar]. The prognosis is usually poor with early death, survival up to several years has been reported only under assisted ventilation. Muscle biopsy shows features of general atrophy of all fibers, while signs of reinnervation may not be present. Linkage studies did exclude 5q linkage [[27]Novelli G. Capon F. Tamisari L. Grandi E. et al.Neonatal spinal muscular atrophy with diaphragmatic paralysis is unlinked to 5q11.2-q13.Neuromusc Disord. 1995; 2: 423-428Google Scholar]. In patients with olivopontocerebellar atrophy and anterior horn cell involvement, a profound floppiness at birth can be seen which is followed by mental retardation and cerebellar signs (vision impairment, nystagmus, ataxia). EMG and muscle biopsy are clearly neurogenic leading to diagnostic difficulties, unless a cerebellar atrophy can be seen at neuroimaging methods. Post-mortem examinations disclose cerebellar atrophy and extended neuronal loss in the anterior horns of the spinal cord, basal ganglia, and brain stem, suggesting a more widespread neuronal degeneration [[8]Chou S.M. Gilbert E.F. Chun R.W.M. et al.Infantile olivopontocerebellar atrophy with spinal muscular atrophy (infantile OPCA + SMA).Clin Neuropathol. 1990; 9: 21-32PubMed Google Scholar]. Linkage studies excluded 5q linkage in some families [12Dubowitz V. Daniels R.J. Davies K.E. Olivopontocerebellar hypoplasia with anterior horn cell involvement (SMA) does not localize to chromosome 5q.Neuromusc Disord. 1995; 5: 25-29Abstract Full Text PDF PubMed Scopus (30) Google Scholar, 33Rudnik-Schöneborn S. Wirth B. Röhrig D. Saule H. Zerres K. Exclusion of the gene locus for spinal muscular atrophy on chromosome 5q in a family with olivopontocerebellar atrophy (OPCA) and anterior horn cell degeneration.Neuromusc Disord. 1995; 5: 19-23Abstract Full Text PDF PubMed Scopus (26) Google Scholar]. Arthrogryposis is a heterogeneous group of neuromuscular disorders. A neurogenic type is caused by anterior horn cell degeneration and leads to severe muscle weakness similar to SMA type I and congenital contractures. While the majority of patients with arthrogryposis is believed to be non-progressive and non-familial, there are patients with more complex pathology which follow autosomal recessive [[3]Borochowitz Z. Glick B. Blazer S. Infantile spinal muscular atrophy (SMA) and multiple congenital bone fractures in sibs: a lethal new syndrome.J Med Genet. 1991; 28: 345-348Crossref PubMed Scopus (34) Google Scholar] or X-linked inheritance [[13]Greenberg F. Fenolio K.R. Hejtmancik J.F. et al.X-linked infantile spinal muscular atrophy.Am J Dis Child. 1988; 142: 217-219PubMed Google Scholar]. In the latter families, the disease was mapped to Xp11.3-q11.2 [[16]Kobayashi H. Baumbach L. Matise T.C. Schiavi A. Greenberg F. Hoffman E.P. A gene for a severe lethal form of X-linked arthrogryposis (X-linked spinal muscular atrophy) maps to chromosome Xp11.3-q11.2.Hum Mol Genet. 1995; 4: 1213-1216Crossref PubMed Scopus (68) Google Scholar]. There is a male predominance indicating a considerable proportion of cases with X-linked inheritance. In some families with autosomal recessive inheritance, chromosome 5q was excluded as the responsible gene locus [[22]Lunt P.W. Mathew C. Clark S. et al.Can prenatal diagnosis be offered in neonatally lethal spinal muscular atrophy (SMA) with arthrogryposis and fractures?.J Med Genet. 1992; 29: 282Google Scholar]. Autosomal dominant forms of arthrogryposis in combination with lower motor neuron disease of milder course are also reported. Although contractures in classical (5q) SMA are usually mild or develop over time, some cases present with arthrogryposis, especially those rare 'congenital' manifestations [2Bingham P.M. Shen N. Rennert H. et al.Arthrogryposis due to infantile neuronal degeneration associated with deletion of the SMNT gene.Neurology. 1997; 49: 848-851Crossref PubMed Scopus (50) Google Scholar, 5Bürglen L. Amiel J. Viollet L. et al.Survival motor neuron gene deletion in the arthrogryposis multiplex congenita-spinal muscular atrophy association.J Clin Invest. 1996; 98: 1130-1132Crossref PubMed Scopus (81) Google Scholar]. There is apparent heterogeneity, as other patients are clinically indistinguishable and do not show SMNT alterations [[42]Zerres K. Wirth B. Rudnik-Schöneborn S. Spinal muscular atrophy – clinical and genetic correlations.Neuromusc Disord. 1997; 7: 202-207Abstract Full Text PDF PubMed Scopus (95) Google Scholar]. It has been mentioned that the chest development in arthrogryposis patients not linked to 5q is considerable better than in classical SMA (F. Muntoni). It has been pointed our that some patients with severe congenital arthrogryposis turned out to have amyoplasia which is associated with a good prognosis (J. Ignatius). Progress in understanding the pathophysiological mechanisms behind anterior horn cell degeneration in ALS has been accelerating during the 1990s and this has stimulated the planning of therapeutical trials even in SMA. Several drugs like neurotrophic factors have been considered to be worth a trial [[15]Jennekens F.G. Medical therapy in spinal muscular atrophy: a realistic expectation?.Clin Neurol Neurosurg. 1992; 94: S89-S92Abstract Full Text PDF PubMed Scopus (1) Google Scholar] and since 1994, the ENMC workshop on spinal muscular atrophy have been very much focused on the development of study protocols for therapeutical trials in SMA. Special attention has been paid for the ethical issues related to this topic. Separate protocols for SMA Type I and Types II-III were finalized at the 38th ENMC workshop (December 1995, Naarden, The Netherlands). Although planned, however, no clinical trials have hitherto been conducted under the guidance of ENMC. A summary of known efforts mainly from the USA was given. Data on therapeutic trials by other groups are scanty. An unpublished phase I trial using ciliary neurotrophic factor (CNTF) and another using brain-derived growth factor (BDTF) on SMA Type I patients have been attempted but both trials apparently have been stopped because the patients developed antibodies to these drugs [31Perez G. Perez M. Conference summary of Families of SMA 1997.Conference Direction (Families of SMA Newsletter). 1997; 10: 1Google Scholar, 35Samaha F. CNTF and spinal muscular atrophy. Direction (Families of SMA Newsletter) 1994/95;9 (1):1-2.Google Scholar]. No information is available on trials with insulin-like growth factor (IGF-1) and its use in children may be difficult because of side-effects. In November 1997, a one-year multicenter phase II trial using glutamate inhibitor gabapentin (Neurontin, Parke-Davis) was begun in USA and Canada [[25]Miller R.G. Drug study update.Direction (Families of SMA Newsletter). 1997; 10: 8Google Scholar]. This on-going study includes 84 adult SMA type II or III patients aged 18–60 (42 on drug and 42 taking placebo). The principal investigator is Dr Robert Miller, San Francisco, CA, eight other centers are participating. Only preliminary information is available on a clinical trial of riluzole in type I SMA to begin Spring 1998 and initially intended to test safety of this drug in children [[24]Melki J. Lefebvre S. Bürglen L. et al.De novo and inherited deletions of the 5q13 region in spinal muscular atrophies.Science. 2994; 264: 1474-1477Google Scholar]. Riluzole, a drug used in ALS patients is thought to have neuroprotective properties although the precise molecular mechanism is unknown. Gene therapy with known genes (SMNC, NAIP) have been only theoretically discussed. There was consensus that practical steps cannot be expected within the near future. During discussions it was agreed that an effective therapy should be started at an early stage in order to prevent further destruction of motor neurons. An increasing number of patients with adult onset proximal SMA [[30]Pearn J. Hudgson P. Walton J.N. A clinical and genetic study of adult-onset spinal muscular atrophy: the autosomal recessive form as a discrete disease entity.Brain. 1978; 101: 591-606Crossref PubMed Scopus (63) Google Scholar] have been reported. The genetic basis is obviously heterogeneous with some patients demonstrating the SMNT deletion [4Brahe C. Servidei S. Zappata S. et al.Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy.Lancet. 1995; 346: 741-742Abstract PubMed Google Scholar, 9Clermont O. Burlet P. Lefebvre S. Bürglen L. Munnich A. Melki J. SMN gene deletions in adult-onset spinal muscular atrophy.Lancet. 1995; 346: 1712-1713Abstract PubMed Google Scholar] and those not being deleted [[41]Zerres K. Rudnik-Schöneborn S. Forkert R. Wirth B. Genetic basis of adult-onset autosomal recessive spinal muscular atrophy.Lancet. 1995; 346: 741-742Crossref PubMed Scopus (53) Google Scholar]. It seems that there is a correlation between age of onset and the proportion of non-deleted cases. In addition to earlier published cases, a further six patients with an onset between 27 and 45 years of age were presented who did not show a deletion of the SMNT gene, neither did any of these cases give evidence of a heterozygous state in the quantitative PCR test. The molecular basis has to be elucidated. A systematic collection of cases has been planned with the aim to systematically analyze adult onset cases. So far only very few cases fulfilling the diagnostic criteria did not give evidence for linkage to chromosome 5q [[10]Cobben J.M. Scheffer H. De Visser M. et al.Apparent SMA I unlinked to 5q.J Med Genet. 1994; 31: 242-244Crossref PubMed Scopus (11) Google Scholar]. There was consensus that these cases are exceptional. According to the literature at least two types of childhood and adult onset have to be distinguished [[29]Pearn J. Autosomal dominant spinal muscular atrophy.J Neurol Sci. 1978; 38: 263-275Abstract Full Text PDF PubMed Scopus (51) Google Scholar]. In contrast to earlier reports, it has been shown that intrafamilial variability of age of onset and progression is much broader [[32]Rietschel M. Rudnik-Schöneborn S. Zerres K. Clinical variability of autosomal dominant spinal muscular atrophy.J Neurol Sci. 1992; 107: 65-73Abstract Full Text PDF PubMed Scopus (22) Google Scholar]. A selection of pedigrees has been discussed with some of them presenting with additional features not typical for proximal SMA (such as muscle cramps, later distal involvement, evidence of peripheral neuropathy). Since the gene locus for dominant proximal SMA is still unknown, collaborative efforts regarding future genome scan attempts were discussed. SMN gene deletion screening was considered important to exclude pseudodominant pedigrees [[34]Rudnik-Schöneborn S. Zerres K. Hahnen E. et al.Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations.Am J Hum Genet. 1996; 59: 1163-1165PubMed Google Scholar]. It was noted that other entities like facioscapulohumeral muscular dystrophy or autosomal dominant types of limb girdle muscular dystrophy can be difficult to distinguish from SMA. Therefore a re-evaluation of clinical features and muscle biopsy findings was thought to be required prior to inclusion of appropriate families for linkage studies. The participants agreed in constituting a separate meeting of experts discussing the necessary clinical criteria for autosomal dominant SMA in order to initiate future linkage studies. On the background of growing knowledge about the variability of proximal spinal muscular atrophy and the delineation of SMA plus forms, there was agreement to update the clinical diagnostic criteria. Although the diagnosis is today usually confirmed by demonstration of a homozygous absence of the SMNT gene or, in rare cases, of a small mutation, the criteria are still of importance defining the clinical manifestation and course. They are formulated in the format of the diagnostic criteria for neuromuscular disorders published by the European Neuro Muscular Center (ENMC). (I, inclusion criteria; E, exclusion criteria; C, comment). •In SMA type I (severe form) onset ranges from prenatal period to age of 6 months;•In SMA type II (intermediate form) onset before the age of 18 months;•In SMA type III (mild form) onset is usually after the age of 18 months. I, Muscle weakness of the trunk and limbs (proximal more than distal;lower limbs weaker than upper).I, SymmetricalE, Weakness of extra-ocular muscles, diaphragm and the myocardium, or marked facial weakness.C, There are rare congenital-onset cases of SMA whose clinical picture also includes external ophthalmoplegia, facial diplegia, and early respiratory insufficiency.C, Wasting if often not conspicuous in SMA type I. I, Fasciculations of tongue and tremor of hands.C, Tremor of the hands is frequently observed in SMA types II and III.E, Sensory disturbances.E, Central nervous system dysfunction.C, Arthrogryposis of the major joints is a rare finding in a severe form of SMA type I. In SMA type I some mild limitation of abduction of the hips or extension of the knees or elbows is common.E, Involvement of other neurological systems or organs, i.e. hearing or vision. I, In SMA type I and II there is an arrest of development of motor milestones. Children with SMA type I are never able to sit without support.Children with SMA type II are unable to stand or walk without aid.In SMA type III the ability to walk will be achieved.I, In SMA type I the majority of patients have a life expectancy < 2 years.In SMA type II survival into adolescence or adulthood is common.In SMA type III life expectancy is most likely normal.C, There will be certain patients who do not clearly fit any one category. I, The homozygous absence/mutation of the telomeric SMN gene (SMNT) in the presence of clinical symptoms is diagnostic.C, In cases with absence/mutation of the telomeric SMN gene further diagnostic procedures such as EMG and muscle biopsy are no longer needed.C, The presence of both copies of SMNT argues strongly against the diagnosis. C, CK usually < 5 times the upper limit of normal. I, Abnormal spontaneous activity, e.g. fibrillations, positive sharp waves and fasciculations by EMG.I, Increased mean duration and amplitude of motor unit action potientials by EMG.E, In SMA types II and III reduction of motor nerve conduction velocities (MNCVs) < 70% of lower limit.C, MNCVs may be markedly reduced in SMA type I.E, Abnormal sensory nerve action potentials (SNAPs) in SMA types II and III.C, There is a rare congenital-onset SMA with death within the first weeks of life in which MNCVs are very long and SNAPs are absent. Characteristic features are the following:I, Groups of atrophic fibers of both types.Hypertrophic fibers of type I.Type grouping (chronic cases).C, In early-onset cases of SMA type I these characteristic features may not be present.Instead there are small fibers of both types. In SMA III there may be a concomitant myopathic pattern. Dr. Christine Brahe, Rome, Italy Dr. Arthur Burghes, Columbus, OH, USA Dr. Louise Campbell, Oxford, UK Dr. Jan-Maarten Cobben, Groningen, The Netherlands Professor Kay Davies, Oxford, UK Professor Hans Goebel, Mainz, Germany Professor Irena Hausmanowa-Petrusewicz, Warsaw, Poland Dr. Jaakko Ignatius, Espoo, Finland Dr. Vesa Juvonen, Turku, Finland Dr. Susie Lefebvre, Paris, France Dr. Alex Mac Kenzie, Ottawa, Ontario, Canada Dr. Judith Melki, Strasbourg, France Dr. Fancesco Muntoni, London, UK Dr. Sabine Rudnik-Schöneborn, Bonn, Germany Dr. Hans Scheffer, Groningen, The Netherlands Professor Marianne de Visser, Amsterdam, The Netherlands Dr. Brunhilde Wirth, Bonn, Germany Professor Klaus Zerres, Bonn, Germany In attendance: Ms. Jenny Versnel, Cambridge, UK This workshop report was written with the help of Dr. Sabine Rudnik-Schöneborn, Bonn, Germany. We thank Professor A.E. Emery for his scientific advice and Michael Rutgers and Janine de Vries for their organizational help. This workshop was made possible thanks to the financial support of the European Neuromuscular Center (ENMC) and ENMC main sponsors: Association Francaise contre les Myopathies (France) Italian Teleton Committee (Italy) Muscular Dystrophy Group of Great Britain and Northern Ireland (UK) Vereniging Spierziekten Nedeland (The Netherlands) Muskelsvindfonden (Denmark) Deutsche Gesellschaft für Muskelkranke (Germany) Schweizerische Gesellschaft für die Erforschung der Muskelrkankheiten (Swizerland) and ENMC associate members: Unione Italiana Lotta alle Distrofia Muscolare Muscular Dystrophy Association of Finland
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