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Wanda Conte Academy Forum Activities SPINAL MUSCULAR ATROPHY
Abstract The workshop was organized by the World Alliance of Neuromuscular Disorder Associations (WANDA), hosted by the Geatano Conte Academy in Naples and financially supported by the Fondazione Frederica Association (an SMA- parentgroup in Italy). Every two years WANDA brings a focus to a specific NMD. This workshop was the kick-off for SMA and intended to give a brief overall view of the various aspects of SMA, which is the second most common autosomal recessively inherited disease and the most common genetically determined cause of death. The workshop was well attended by a large variety of specialists coming from all continents and disciplines which proved the multifocal character of SMA and the interest of the International scientific community. In the following the main contributions will be summarized. (Klaus
Zerres, Sabine Rudnik-Schöneborn, Marianne de Visser)
The clinical course of SMA type II or chronic childhood SMA or arrested Werdnig-Hoffmann disease is marked by periods of apparent arrest in the clinical progression. The age of onset and presenting signs may be indistinguishable from SMA type I, although median age of onset is generally later (8 months). The children fail to pass motor milestones because of proximal weakness and hypotonia within the first months of life. There is a wide variability of clinical severity, ranging from children who have early difficulties in sitting or rolling over to patients who are able to crawl or walk without support. For practical purposes, this group is defined by the ability to sit independently, as the children never learn to stand or walk unaided. Pronounced weakness of trunk muscles in the non-ambulatory patients causes major problems owing to spine deformities; contractures develop early in all major joints as a result of synergist-antagonists imbalance. Since progression is slow and survival into adulthood is the rule rather than the exception (4), the treatment of scoliosis plays an important role for the preservation of function and quality of life. The effect of spine surgery on the prevention of respiratory problems is still a matter of controversy. Nonetheless, more than 90% of patients survive into the second decade, which has major implications for education and everyday life of the severely handicapped children. A mild form of childhood and juvenile SMA - type III is known as Kugelberg-Welander disease and shows a wide range of clinical onset from the first year of life until the third decade. Patients with SMA type III learn to walk without support, which distinguishes them from those with SMA type II. For prognostic reasons, this group can be separated into IIIa and IIIb; in addition, there is evidence of genetic heterogeneity; especially among the SMA type IIIa patients, which justifies a subdivision on the group. In SMA type IIIa, onset is in the first 3 years of life, the children have early walking difficulties and often fail to pass further motor milestones, for example rising from the floor or climbing steps. Since many patients are non-ambulatory by school age (50% are confined to a wheelchair 14 years after onset), there is a considerable handicap in comparison to those who start with first walking difficulties in adulthood. In SMA type IIIb, first signs of weakness occur between 3 and 30 years and are mainly problems in running, climbing, or sports, with sometimes very slow or even undetectable progression. It has been estimated that about 50% of the SMA type IIIb patients are still ambulatory after a 45-year disease duration (4,10). Life expectancy is not much reduced, the course of the disease is characterized by slow progression with periods of arrest. Depending on the degree of weakness, spine deformities and contractures are frequent complications, mainly in the chairbound patients. Type
IV: While there is a spectrum of manifestations in SMA types I-III, with overlapping features between the subgroups, SMA type IV or adult SMA should be considered a distinct entity. Recently, genetic homogeneity has been reported between childhood-onset and adult-onset autosomal recessive SMA, as identical deletions were discovered in the investigated patients (11). The patients had an age of onset between 20 and 32; we therefore believe that the obtained results do not apply to late-onset types of adult SMA (4). In our material, onset in adult SMA ranges from 30 to 60 years, with pronounced proximal weakness, particularly of the limb girdle and thigh muscles. The condition is relatively benign with slow clinical progression, and a normal life san can be expected (4). (Sabine
Rudnik-Schöneborn, Kristin Bosse, Klaus Zerres)
We therefore asked 169 families (105
patients and 64 parents) with chronic proximal SMA of all types
of severity regarding their attitudes towards expectations and
limitations of future drug trials. 247 study participants were
contacted via postal questionnaires, of whom 68% responded. The
questions were answered by 105 patients over the age of 15 years
and by 64 relatives (parents) in younger children. The study group
was subdivided into SMA type I (n=16), SMA type II (n=69), SMA
type III (n=75), and SMA type IV with an age of onset > 30
years (n=9). A considerable fraction of patients (20-30%) had
principal objections against clinical trials, mainly because these
families coped well with their situation and were therefore critical
regarding potential risks of a future treatment. Parents and patients
of chronic SMA families expressed similar attitudes, although
parents were less likely to tolerate adverse effects or a potential
deterioration of a treatment in comparison to patients. In our
study, the application form had an important impact on the attitude
towards clinical trials, i.e. daily injections were regarded as
too invasive for many families. There was consensus that clinical
trials are not acceptable in early infancy or childhood. Most
participants voted against a clinical trial in small infants (<7
years) or children (7-14 years) if intermediate or serious side
effects were to be expected (figure 1). No objections were seen
for teenagers and adults under the condition of minor side effects.
Facing serious adverse effects, more than half of all parents
and patients would not accept a clinical trial in infants, children
or teenagers. Again there was no significant difference in the
attitudes of patients and parents. It was interesting to see that
somatic gene therapy was not considered substantially different
from conventional drug treatment in this well-informed group of
patients. The vast majority of the patients (93%) had no general
objections against gene therapy but had slightly higher expectations
as regards the therapeutic success and the accompanying risks
in comparison to conventional therapy. The question „Would you
personally take part in a clinical trial?„ was set as a summary
of the problems raised in the previous questions. Eventually,
70% of patients and parents would participate in clinical trials
while only a small percentage (2-5%) would agree to either conventional
or gene therapy (figure 2). There was broad consensus among patients
and parents.
(Eduardo Tizzano) Molecular
pathology of the SMN1 gene: Approximately 90% of patients suffering
from different forms of SMA show absence of the two copies of
the SMN1 gene exons 7 and 8. This gene was identified in 1995
and is located in the 5q13 chromosome region. SMN2, its high homologous
copy, differs only by five nucleotide changes and is present in
all patients (13) (figure 3). A small number of SMA patients show
homozygous deletions of SMN 1 exon 7 but not exon 8. In these
patients hybrid genes were characterized. These hybrid genes result
from the fusion of exon 7 of SMN2 with exon 8 of SMN1. In the
SMA cases where the SMN1 gene is present, subtle mutations have
been detected, indicating that the SMN1 gene is the determining
gene. In the Spanish population, a 4 bp deletion in exon 3 was
detected in approximately 2.5% of the SMA cases (14). SMN1 absence
was associated to a wide spectrum of manifestations from congenital
disease to asymptomatic cases and this could be the result of
modifier factors, particularly the number of copies of the SMN2.
Analysis of patients with type II and III forms has shown that
these individuals have on average a larger number of SMN2 copies
than type I patients (15). These findings indicate that the homozygous
absence of SMN1 is the result of a true deletion in type I cases
and a gene conversion in type II or III cases (figure 3). Based
on the high frequency of homozygous absence of SMN1 observed in
SMA patients and in accordance with the Hardy–Weinberg equilibrium,
99.7% of all SMA patients must carry at least one SMN1 deletion
on one chromosome (16). The availability of a useful molecular
test for SMA has facilitated the diagnosis of the disease. Relatives
who are at risk of being carriers usually request molecular studies.
Given that the normal copy of the gene masks the deletion, carrier
diagnosis in relatives relies on gene tracking with polymorphic
markers (i.e. C212 and C272/Ag1-CA of the 5´end of both SMN genes).
To study cases with heterozygous absence of the SMN1 (a deletion
in one chromosome and a subtle mutation in the other) various
quantitative methods to analyse the exon 7 of the SMN1 gene have
been developed with an adequate sensitivity and specificity (17-19).
However, it must be taken into account that approximately 4% of
carriers have two SMN1 copies in one chromosome and a null allele
in the other. In our experience, these methods are useful to determine
a single SMN1 dose in affected cases without homozygous deletion
and to test individuals without a family history of the disease
(partners of known carriers). Moreover, these methods allow the
dosimetric analysis of SMN2 copies.  The SMN protein is a 38 kDa polypeptide
which bears no significant sequence similar to any other protein.
A tight correlation between the level of SMN protein and the severity
of disease has been observed in tissues and cells derived from
SMA patients. This protein has been located by immunohistochemistry
within a novel structure named "gems", which
are more commonly associated
with coiled bodies. Ramon y Cajal described the coiled bodies
in 1903, and there is, at present, considerable evidence that
both structures are involved in RNA metabolism. Gems are present
in almost all cell populations and SMN mRNA and protein are detected
in different neuronal populations and tissues (15,20,21). Recent
studies have demonstrated that there is an interaction between
the SMN protein and the different components of the spliceosomal
complex suggesting that the role of SMN appears related at least
with two essential cellular processes such as the biogenesis of
spliceosomal U snRNPs and in pre-mRNA splicing (22,23). If SMN
is only necessary in large amounts in motor neurons, it could
either play an alternative role in these cells or just require
a high quantity for splicing factors. The SMN gene is not duplicated in mouse
and homozygous inactivation of the Smn gene in mice leads to massive
cell death in early blastocyst stage, a period that corresponds
with the initiation of embryonic RNA transcription (24). In humans,
there is evidence that the SMN2 expresses protein in the absence
of the SMN1 and that an increase in the copy number of SMN2 may
correlate with a decrease in disease severity. These observations
were confirmed by the developing of SMN-deficient mice models
that mimic human SMA. In transgenic mice (Smn-/-) with different
number of copies of human SMN2, lethality has been rescued (25,26).
Moreover, the phenotype of these mice was in correlation with
the number of copies of SMN2. Given that SMA patients retain at
least one SMN2 copy, these observations open an alternative approach
to therapy by overexpression or activation of SMN2. Views
of patients and parents
(Ysbrand Poortman) Parents and adult patients living with the consequences of SMA, have many questions and problems. They expect science to work for the answers and for the solutions. A collection of wishes, questions and problems was presented (see survey) which was drawn from the Dutch SMA- group. Parents and patients learn about the progress in science. They read in the papers about genomics, proteomics, farmaco-genetics, bio-informatics and also about neurotrophic agents, about recovery of dying motorneurons, about gene therapy. They hear about revolutionary breakthroughs leading to new drugs. They wonder about the opportunities for them. They wonder if there is a worldwide, systematised approach, using the current range of opportunities for identification and development of new drugs and treatments. Now that clinical and molecular efforts come closer to therapeutic options in SMA, there is an increased necessity for all stakeholders to have good communication about and understanding of the opportunities, of the challenges and of what is holding back progress. WANDA will contribute to such an approach on the global level and from a strategic point of view. And this in good cooperation with all parties involved and more specifically in coordination with the European Neurmomuscular Centre (ENMC).
The SMA- patient groups from all over the world communicate together and meet every year. They want to do from their side what is possible to facilitate an accelerate research for early detection and more accurate diagnosis, for prognosis and genetic counselling, for treatment and the alleviation of the burden of disease. SMA diagnosis· Standardized protocol for early recognition. · International standardization and implementation of diagnostic criteria, for all SMA subtypes.
Living with SMA· Advice on lifestyle issues such as active versus passive life (energy management), nutrition. · Information on pregnancy-associated risks for women with SMA. · Information on late-stage consequences of chronic SMA types. · Guidelines for relevant information for medical alert cards
SMA treatment· Standardized protocols for disease management and therapeutical trials. · Guidelines for indication for spinal surgery and mechanical ventilation. · Information on the relationship between SMA and other specific diseases.
SMA research· Why is research so fragmented? · Why is there no globally coordinated effort in research leading to drug/therapy development? · We would like systematic, comprehensive, and periodic review of research results in lay language. · How can we, patients and patients´organsations, contribute to more and better research? · How can we ensure that no stone will be left unturned, in testing novel medical technologies (e.g. gene therapy) towards treating SMA? Outlook
Although an effective therapy of SMA
is not yet available, the progress in SMA research during the
last decade is impressive. Further insights can be expected in
the near future. The contribution of the self support groups to
this success was essential in the past and will a major driving
force in the future. The opinion and demands of the patients describe
stress, however, that we nevertheless are just at the beginning
on the long way to an effective therapy of SMA. Acknowledgments We thank Professor Giovanni Nigro,
the Gaetano Conte Academy and the Fondazione Frederica Association
for their active support. This
work was supported by the Deutsche Gesellschaft für Muskelkranke,
the Deutsche Forschungsgemeinschaft (K.Z. and S. R.-S.) and FIS
00-0481, Marató TV3 and Premi Ferrer Salat (F. T.). References:
1. Dubowitz V.: Chaos in classification of spinal muscular atrophies in childhood, editorial, Neuromusc. Disord. 1991; 1: 77-80.
2. International SMA coLLaboration: Workshop report, Neuromusc. Disord. 1991; 1: 81.
3. Russman B.S., Iannacone S.T., Buncher C.R. et al.: Spinal muscular atrophy: new thoughts on the pathogenesis and classification schema. J. Child. Neurol. 1992; 7: 347-353.
4. Zerres K., Rudnik-Schöneborn S.: Natural history in proximal spinal muscular atrophy (SMA): clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch. Neurol. 1995; 52: 518-523.
5. INTERNATIONAL SMA CONSORTIUM: Spinal muscular atrophies: recent progress and diagnostic criteria. Neuromusc. Disord. 1999; 9: 272-278.
6. Pearn J.: Fetal movements and Werdnig-Hoffmann disease. J. Neurol. Sci. 1973; 18: 373-379
7. Thomas N.H., Dubowitz V.: The natural history of severe spinal muscular atrophy. Neuromusc. Disord. 1994; 5/6: 497-502.
8. Ignatius J.: The natural history of severe spinal muscular atrophy - further evidence for clinical subtypes. Neuromusc. Disord. 1994; 5/6: 527-528.
9. Zerres K., Wirth B., Rudnik-Schöneborn S.: Spinal muscular atrophy – clinical and genetic correlations. Neuromusc. Disord. 1997; 7: 202-207.
10. Zerres K., Rudnik-Schöneborn S., Forkert R. et. al.: Genetic basis of adult-onset spinal muscular atrophy. Lancet 1995; 346: 741-742.
11. Brahe C., Servidei S., Zappata S. et al.: Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 1995; 346: 9741-742.
12.
Lefebvre S., Bürglen L., Beboullet S. et
al.: Identification and
characterization of a spinal muscular atrophy-determining gene.
Cell 1995; 80: 155-165.
13.
Bussaglia E., Clermont O., Tizzano E.
et al.: A frameshift deletion
in the survival motor neuron gene in Spanish spinal muscular atrophy
patients. Nat. Genet. 1995; 11: 335-337.
14.
Coovert D.D., Le T.T., McAndrew P. et
al.: The survival motor
neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 1997; 6: 1205-1214.
15.
Wirth B.: An update of the mutation spectrum of the survival motor neuron gene (SMN1)
in autosomal recessive spinal muscular atrophy. Hum. Mutat.
2000; 15: 228-237.
16.
Mc Andrew 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: 1411-1422.
17.
Wirth B., Herz M., Wetter A., et
al.: Quantitative analysis
of survival motor neuron copies: identification of subtle SMN1
mutations in patients with spinal muscular atrophy, genotype-phenotype
correlation, and implications for genetic counseling. Am. J. Hum. Genet. 1999; 64: 1340-1356.
18.
Scheffer H., Cobben J.M., Mensink R.G.J. et
al.: SMA carrier testing-validation
of hemizygous SMN exon 7 deletion test for the identification
of proximal spinal muscular atrophy carriers and patients with
a single allele deletion. Eur. J. Hum. Genet.
2000; 8: 79-86.
19.
Lefebvre S., Burlet P., Liu Q. et
al.: Correlation between
severity and SMN protein level
in spinal muscular atrophy. Nat. Genet. 1997; 16: 265-269.
20.
Tizzano E., Cabot C., Baiget M.
Cell-specific survival motor
neuron gene expression during human development of the central
nervous system. Implications for the pathogenesis of spinal muscular
atrophy. Am. J. Pathol. 1998; 153: 355-361.
21.
Fischer U., Liu Q., Dreyfuss G.
The SMN-SIP1 complex has an essential role in spliceosomal snRNP
biogenesis.
Cell 1997; 90: 1023-1029.
22.
Pellizoni L., Katoaka N., Charroux B. et
al.: A novel function for
SMN, the spinal muscular atrophy disease gene product in pre-mRNA
splicing. Cell 1998; 95: 615-624.
23.
Schrank B, Götz R, Gunnersen J, Ure JM, Toyka KV, Smith
AG, Sendtner 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: 9920-9925.
24.
Monani U., Sendtner M., Coovert D.D. et al. The human centromeric survival motor
neuron gene (SMN2) rescues embryonic lethality in SMN-/- mice
and results in a mouse with spinal muscular atrophy. Hum. Mol. Genet. 2000;
9: 333-339.
25.
Hsieh-Li H.M., Chang J.G., Jong Y.J. et al. A mouse model for spinal muscular atrophy. Nat. Genet. 2000; 24: 66-70. Classification of proximal muscular spinal atrophy modified according to the International SMA*
*
According to ref. 4 and 5. For more details data see Zerres and
Rudnik-Schöneborn, 1995 (4).
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