Genetic basis of adult-onset spinal muscular atrophy.
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Adult↗
Biomedical subjects
B Wirth
Publications and source records attributed to B Wirth.
Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases.
Prenatal prediction in families at risk for autosomal recessive proximal spinal muscular atrophy (SMA) mainly of type I is often requested due to the high incidence and the fetal outcome of the disease. So far, only indirect genotype analysis can be performed in SMA families, since the gene has not yet been identified. We present our experience of 109 prenatal diagnoses obtained in 91 families by use of single- and multi-locus polymorphic microsatellites of the region 5q11.2-q13.3. The marker combinations and specific features of the closest microsatellites are described in detail. From 137 requests for prenatal prediction of SMA between October 1991 and August 1994, 28 families were excluded, mostly because the clinical diagnosis was uncertain or doubtful. Others had to be classified as 'SMA-variants' or showed autosomal dominant transmission of SMA. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at high risk (> 99 per cent) of developing the disease, while in seven additional pregnancies no exact prediction could be made due to a recombination event in one parental haplotype. Altogether, recombinations between closely flanking markers were observed in 14 cases. In 35 cases, the parents decided to terminate the pregnancy. Of the remaining pregnancies, 32 could be followed beyond term. All infants were reported to develop normally without signs of SMA. Two children were born with transverse reduction defects of one hand, which was most likely related to early chorionic villus sampling at 9 and 10 weeks' gestation. No further abnormalities could be detected. The limits of indirect genotype analysis and the problems of diagnostic accuracy and heterogeneity of proximal SMA are discussed.
Alleles↗
Exclusion of the gene locus for spinal muscular atrophy on chromosome 5q in a family with infantile olivopontocerebellar atrophy (OPCA) and anterior horn cell degeneration.
Two sisters with infantile OPCA plus spinal muscular atrophy (SMA) are reported. Both showed severe hypotonia and psychomotor delay from birth, and in addition, nystagmoid eye movements and vision impairment were evident. Cerebellar hypoplasia with cystic dilatation was seen by neuro-imaging methods. Pathoanatomically, a marked cerebellar hypoplasia and neuronal loss in the basal ganglia, brainstem and anterior horns were found in the deceased girl. Linkage studies with polymorphic markers of the region 5q11.2-q13.3 flanking the gene locus for infantile SMA showed identical parental haplotypes in the patients and their older healthy sister. It can be concluded that the gene locus for infantile SMA on chromosome 5q is not responsible for infantile OPCA plus anterior horn cell degeneration in the described family which might apply to this disorder in general.
Chromosome Mapping↗
Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals.
Proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of anterior horn cells in the spinal cord leading to weakness and wasting of voluntary muscles. Here we present the molecular analysis of both SMA candidate genes, the survival motor neuron gene (SMN; exons 7 and 8) and the neuronal apoptosis inhibitory protein gene (NAIP; exons 5, 6 and 13), in 195 patients and 348 parents of SMA families mainly of German origin. The SMN gene is homozygously deleted for both exons 7 and 8 or exon 7 only in 96% of type I SMA, 94% of type II SMA and 82% of type III SMA as well as in 0.3% of SMA parents. The NAIP gene is homozygously deleted in 46% of type I SMA, 17% of type II SMA, 7% of type III SMA and 2% of SMA parents. The frequencies of deletions in patients for both genes, SMN and NAIP, correspond to those for the NAIP gene only. SMA patients of this series who did not show deletions were clinically indistinguishable from deleted patients. In addition to one unaffected mother of a type II SMA patient, we found homozygous deletions of the SMN gene exons 7 and 8 in six further unaffected individuals, all sibs of type II and III patients. These belonged to four families with affected and unaffected sibs who showed identical haplotypes for all SMA flanking markers; therefore, we had regarded these families as chromosome 5 unlinked. All seven unaffected individuals in whom we detected SMA deletions do not show any signs of muscle weakness and are physically inconspicuous. The largest divergence between age at onset of an affected subject and the present age of unaffected deleted sibs is four decades now. The occurrence of SMN deletions in unaffected individuals suggests that other genes or mechanisms may be necessary to produce the SMA phenotype.
Adolescent↗
Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs.
The candidate region for spinal muscular atrophy (SMA) has been defined as a 750 kb interval on 5q13. In this study, we performed allelic association studies in 154 German SMA families with the multicopy markers Ag1-CA (D5S1556); C212 (D5F149S1/S2) and correlated genotype data with deletion of candidate genes. Both multicopy markers recognize 0-3 alleles pro chromosome. Deletions were detected for all copies of the markers Ag1-CA (C272) and C212 in 13 of 88 (15%) type I SMA patients and three of 48 (6%) type II patients. In all informative cases, the deletion was inherited from one parent. In two further cases (one type I and one type III SMA), de novo deletions of only one copy of Ag1-CA and C212 were found. In both cases the patients were homozygously deleted for the survival motor neuron (SMN) gene (exons 7 and 8) but only the type I SMA patient was deleted for the neuronal apoptosis inhibitory protein (NAIP) gene (exons 5 and 6). A third case (type II SMA) showed de novo deletion of SMN, but not of Ag1-CA, C212 and NAIP. Specific alleles of Ag1-CA and C212 showed significant association with SMA, particularly in type I SMA. When the number of marker copies defines genotypes, 1,1 (one allele on each chromosome) is found to be increased in type I SMA (50%) and 1,2 (one allele on one chromosome and two alleles on the other one) in type II SMA (60%). The 2,2 genotype (two alleles on each chromosome) was found in 4% of type I and II patients. By comparison, pooled normal genotype frequencies were 20, 44 and 36%, respectively. These results suggest a strong correlation between genotype and severity of disease. Based on these data we propose a model which indicates that type I SMA patients are composed of two severe alleles, type II of a mild and a severe, and type III of two mild alleles. Correlation of Ag1-CA genotype with deletion of the XS2G3/NAIP genes indicates that most patients with a deletion have a 1,1 genotype. Owing to the physical proximity of these markers, we propose that a large deletion occurs on type I SMA chromosomes that removes DNA between C212 and XS2G3/NAIP and that type II SMA results from compound heterozygosity for mild (small deletion) and severe mutations.
Alleles↗
Mapping of the spinal muscular atrophy (SMA) gene to a 750-kb interval flanked by two new microsatellites.
The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped between D5S629 and D5S557. We report here a new single-locus microsatellite A31 (D5S823) and two multicopy microsatellites 97T-CA and 95/23-CA. The marker A31 maps to the region of overlap between YACs y116, y55 and y122, distal to D5S629; 97T-CA originates from a cosmid corresponding to the STS 97T, localized distally to A31, while 95/23-CA derives from a cosmid corresponding to the STS 97U, localized proximally to D5S557. We tested all our key recombinant families with these markers. In one type I/II SMA family, a recombinant was found that placed the SMA locus distal to D5S823. Homozygosity mapping in a consanguineous type I SMA family indicates that the SMA gene lies proximal to 95/23-CA. Thus, the two new markers, A31 and 95/23-CA further refine the SMA gene to an approximately 750-kb interval.
Base Sequence↗
[Improvement of interstitial brachytherapy for localized prostate neoplasms with a new implantation technique].
PURPOSE: The success of an interstitial brachytherapy treatment is based on the correct implantation geometry. Frequently, deviations of top needle vs. template coordinates were observed by transrectal sonography of 358 high-dose-rate (HDR) implantations for prostate cancer. PATIENTS AND METHODS: In cooperation with the companies BIP GmbH and Isotopen-Technik Dr. Sauerwein GmbH we developed a high-speed implantation machine, which was tested by 22 interstitial prostate applications. We compared the manual needle positioning method to the high-speed machine and observed the sequence of needle deviation as well as the acute postoperative side effects (hematoma, macroscopic hematuria, pain and urin stop). RESULTS: Using the manual implantation method (n = 12) 43.8% of all implanted needles (42 out of 96, mean 3.5) showed a deviation vs. 3.6% (3 out of 83, mean 0.3) by the use of the high-speed device (n = 10). Acute postoperative side effects according to the implantation were: urin stop (3 vs. 0), macroscopic hematuria (3 vs. 1), and pain (4 vs. 1), respectively. CONCLUSION: The use of a modified high-speed biopsy device for the interstitial brachytherapy results in a higher accuracy in the needle positioning and in reproducing pretreatment implantation plans. Because of the good clinical experience we introduced the high-speed implantation device into our clinical routine.
Brachytherapy↗
Autosomal recessive proximal spinal muscular atrophy in 101 sibs out of 48 families: clinical picture, influence of gender, and genetic implications.
We analysed the clinical picture of 101 sibs (43 sib pairs, 5 triplets) with autosomal recessive proximal spinal muscular atrophy (SMA). Linkage data of 20 sibships, which were available for analysis, were in agreement with chromosome 5q linkage. The patients were classified according to the motor development into SMA I (never sat), SMA II (sitting without support), and SMA III (walking without aids). Three sibs with adult onset (> 30 years = SMA IV) were discussed as a separate entity. Age-of-onset of the 101 patients showed a wide spectrum (prenatal to 47 years). Among sib pairs with SMA I and SMA II the ages-of-onset appeared to be very similar except of one atypically discordant sib pair. With regard to SMA III, 3 out of 13 sibships (23%) showed a marked variation in age-of-onset ranging from 5-15 years within a family. Concerning acquired motor development (ability to sit and walk), 7 sibships (15%) belonged to different SMA types. Ages of death in 29 sib pairs in whom at least one sib had died before the age of 20 years were strikingly discordant. Neither the degree of disability nor the respiratory deficits are reliable predictors of life expectancy. Although a predominance of males can be observed, no significant effect of gender has been established in familial cases. The existence of multiple allelism seems to be the most suitable explanation for the high interfamilial variability considering the clinical concordance in most affected sib pairs.
Adolescent↗
Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3.
The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507- D5S6-D5S125-D5S680-D5S435-SMA-D5S557- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable.
Base Sequence↗
Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy.
The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has been mapped to an 850-kb interval on 5q11.2-q13.3, between the centromeric D5S823 and telomeric D5S557 markers. We report a new complex marker, Ag1-CA, that lies in this interval, whose primers produce one, two, or rarely three amplification-fragment-length variants (AFLVs) per allele. Class I chromosomes are those which amplify a single AFLV allele, and class II chromosomes are those which amplify an allele with two or three AFLVs. Ag1-CA shows highly significant allelic association with type I SMA in both the French Canadian (Hôpital Sainte-Justine [HSJ]) and American (Ohio State University [OSU]) populations (P < .0001). Significant association between the Ag1-CA genotype and disease severity was also observed. Type I patients were predominantly homozygous for class I chromosomes (P = .0003 OSU; P = .0012 HSJ), whereas the majority of type II patients were heterozygous for class I and II chromosomes (P = .0014 OSU; P = .001 HSJ). There was no significant difference in Ag1-CA genotype frequencies between type III patients (P = .5 OSU; P = .25 HSJ) and the paired normal chromosomes from both carrier parents. Our results indicate that Ag1-CA is the most closely linked marker to SMA and defines the critical candidate-gene region. Finally, we have proposed a model that should be taken into consideration when screening candidate SMA genes.
Alleles↗
Refining the map and defining flanking markers of the gene for autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12.
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Base Sequence↗
Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy.
Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explantation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (P = .09 +/- .06 for onset at 10-36 mo and .13 +/- .07 for onset at > 36 mo; and P = .09 +/- .07 for SMA IIIa and .12 +/- .07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given.
Adolescent↗
Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies.
The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene, which allowed us to narrow the SMA region to about 4 cM and to define a new proximal genetic border by the locus D5S125 (EF(TG/AG)n. Based on haplotype analysis and specific recombination events, the following order of the loci was determined: 5cen-D5S76-D5S6-D5S125-SMA-(5'MAP-1B-3'MAP- 1B)/D5S112-JK53CA1/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5S125 and MAP-1B is further supported by multipoint linkage analysis.
Cell Line, Transformed↗
Dinucleotide repeat polymorphism at the D12S371 locus.
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Base Sequence↗
Dinucleotide repeat polymorphism at the D5S214 locus.
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Base Sequence↗
Twenty different alleles at the locus D5S683 on 5q23-31.
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Alleles↗
Efficiency of various strategies and materials to generate new markers: saturating the region 5q11.2-q13.3 with 30 new randomly distributed clones.
Several different strategies and materials were used for saturating the region 5q11.2-q13.3 with new, randomly distributed markers: isolation of human clones from three chromosome-5-specific libraries (a BssHII endclone phage library from the somatic cell hybrid H64 and two total genomic phage libraries from radiation hybrids IH12 and IH132), as well as Alu-PCR from chromosome-5-specific radiation hybrids with overlapping fragments in the region around the spinal muscular atrophy locus, followed either by direct isolation of Alu-PCR products or hybridization of Alu-PCR products to chromosome-5-gridded cosmid libraries. 253 human phage and cosmid clones were mapped to various parts of chromosome 5 by deletion mapping to somatic cell hybrid panels. 30 of these clones were mapped into the region 5q11.2-q13.3, 9 of which are flanking rate cutting BssHII-sites, known to be, often, starting points for genes. They represent excellent starting material for the development of new polymorphic markers and sequence-tagged sites, for YAC screening and building of contigs, as well as for direct isolation of genes.
Animals↗
[Spinal muscular atrophy in childhood. Possibilities and limits of clinical and molecular genetic diagnosis].
The proximal spinal muscular atrophies (SMA) are a clinically and genetically heterogeneous group of neuromuscular disorders which are characterized by selective degeneration of motor neurons in the spine and brainstem. The clinical features resemble other muscle diseases, the diagnostic criteria of proximal SMA have recently been defined by the International SMA Consortium. The classification of the clinical picture in different subgroups is still a focus of discussion. At present it seems likely that childhood onset SMA represents a broad spectrum of various ages of onset and different degrees of disability. Apart from different modes of inheritance, there is further evidence of heterogeneity in proximal SMA. The autosomal recessive forms represent the second frequent recessive disorder after cystic fibrosis, whereas autosomal dominant inheritance is an exception in childhood onset SMA. There are no convincing reports of X-linked SMA hitherto. With mapping of acute and chronic forms of childhood SMA to chromosome 5q11.2-13.3 diagnosis by use of DNA markers in affected families has become available. The current possibilities but also problems and limitations of genotype analysis are discussed, with special regard to the application of prenatal diagnosis. We report on the first experiences with prenatal diagnosis in 37 SMA families.
Adolescent↗