Chronic childhood spinal muscular atrophy in Germany (West-Thüringen)--an epidemiological study.

This study presents the most extensive epidemiological data on chronic forms of spinal muscular atrophy in childhood (CSMA) in West-Thüringen in Germany. The incidence of CSMA was calculated to be 1 in 9,420 live births. The prevalence was 1.624 in 100,000 of the general population (as of 31 December 1980).

Epidemiological data on Werdnig-Hoffmann disease in Germany (West-Thüringen).

This study contains the largest body of epidemiological data on Werdnig-Hoffmann disease (acute infantile spinal muscular atrophy; ASMA) in West-Thüringen in Germany. The incidence of ASMA was calculated to be 1 in 10,202 live births. The prevalence was 1 in 595,362 of the general population (as of 31 December 1987). The study gives an unexpectedly high incidence rate confirming the suggestion that ASMA in Central and Eastern Europe might be more frequent than in Western Europe. However, we consider that this high incidence rate in West-Thüringen is a result of the almost complete ascertainment made possible because of the well-organised and centralised health system existing in Thüringen over the last few decades.

Population data on acute infantile and chronic childhood spinal muscular atrophy in Warsaw.

This study provides epidemiological data on acute infantile (ASMA) and chronic childhood spinal (CSMA) muscular atrophy in Warsaw for the period 1976-1985. All calculations are based on the assumption that ASMA and CSMA result from mutations at two different gene loci. The incidence of ASMA and CSMA was 1 in 19474 live births with a corresponding gene and carrier frequency of 714 x 10(-5) and 1 in 70, respectively. The prevalence of CSMA for the year 1985 was 1.26 x 10(-5). These figures are higher than in similar studies in other countries. This fact might be connected with the careful ascertainment in this study.

Segregation analysis of 1885 DMD families: significant departure from the expected proportion of sporadic cases.

The proportion of sporadic cases of Duchenne muscular dystrophy has been estimated by classical segregation analysis in a pooled sample of 1885 sibships from 7 different countries. A significant departure from the theoretical expectations based on mutation-selection equilibrium is observed (segregation frequency = 0.439 +/- 0.017; frequency of sporadic cases = 0.229 +/- 0.026, at the maximum likelihood). The occurrence of germinal mosaicism in some of the mothers of Duchenne cases may account for this peculiar finding, although a possible role of inequality of mutation rates in the two sexes cannot be ruled out.

Possibilities and limitation of prenatal diagnosis and carrier determination for Duchenne and Becker muscular dystrophy using cDNA probes.

Two cDNA probes, cf23a and cf56a, identify deletions of selected exons in about 50% of our DMD/BMD patients. We have estimated the most likely order of the 11 exons detectable with both probes with respect to the different extensions of the deletions. In one of our BMD pedigrees, the observed deletion could be traced in the affected males through three generations. This result shows that with the use of cDNA probes detecting deletions, the only risk of error in genomic prenatal diagnosis is the general high frequency of new mutations for DMD/BMD. This is important progress in diagnosis compared to the 2 to 5% risk of misdiagnosis because of crossing over events using conventional linkage analysis with bridging or intragenic probes. The first prenatal diagnosis of an unaffected fetus of a woman who is a DMD carrier according to ultrasound examination is described. In one of our DMD males, the cDNA probe cf56a detects a deletion breakpoint. His sister also shows the altered band and is therefore a DMD carrier, while his mother has a totally normal band pattern. The interpretation of this observation could be either germline mosaicism or two identical new mutations. The identification of deletion breakpoints is a new diagnostic strategy, especially for carrier determination, which excludes misdiagnosis owing to crossing over events and the problems of dosage estimation. It is, however, limited by the low frequency of breakpoints detectable with cDNA probes. Therefore, the generation of new intron probes in this region is an important goal.

Inherited deletion of subband Xp21.13 in a male with Duchenne muscular dystrophy.

The chromosomes of a male patient who suffers from Duchenne muscular dystrophy (DMD) with a molecular deletion were examined with an improved high resolution R type replication banding technique. High resolution cytogenetic analysis of the proband revealed a deletion of the Xp21.13 subband. His healthy mother was heterozygous for the deletion, which is subject to random X inactivation in lymphocytes. The X chromosomes of the proband's grandmother were normal, suggesting that the deletion of the Xp21.13 subband in the mother was a new mutation. The finding of a very small, cytologically visible Xp21.1 deletion in a male DMD patient with a molecular deletion emphasises the importance of resolving the fine structure in the Xp21 region.

Sporadic cases in Duchenne muscular dystrophy. A reappraisal through segregation analysis on 988 sibships.

A new estimation of the proportion of sporadic cases in Duchenne muscular dystrophy was attempted by means of segregation analysis in a sample of 988 sibships collected on a world-wide scale by different authors. Maximum likelihood estimates of ascertainment probability (pi), segregation frequency (p), and frequency of sporadic cases (x) were calculated by Morton's equations under different hypotheses. The best fit was found for p = 0.454 +/- 0.024 and x = 0.235 +/- 0.034. The possibility that the proportion of sporadic cases might be lower than the expected 1/3 is suggested.

Atypical form of X-linked proximal pseudohypertrophic muscular dystrophy.

A series of 95 families, consisting of 317 patients with severe and mild X-linked proximal pseudohypertrophic muscular dystrophy (MD), was analysed by the use of two different and rigid clinical criteria based on the age when the patient became chairbound. Using these criteria the families from Erfurt and Warsaw could be clearly separated into classical Duchenne (DMD) and classical Becker (BMD) type patients. A third group of patients was found with atypical clinical course, who could not be identified as neither Duchenne nor Becker cases. Statistically highly significant differences were found between the groups of classical DMD and atypical MD cases on the one hand and between the groups of atypical MD and classical BMD cases on the other, especially with respect to age when chairbound and age at death. The comparisons of progression of the disease, life expectancy and of fertility between the three groups of X-linked MD show that classical DMD and atypical MD may be considered as separate types of severe X-linked proximal pseudohypertrophic MD. On the basis of these findings the authors offer conclusions for the general practice of neurology, paediatrics and genetic counseling.

Possibilities and problems in genomic diagnosis of Duchenne muscular dystrophy with molecular probes.

Selected families affected with Duchenne muscular dystrophy from an extensive pedigree analysis with linked restriction fragment length polymorphisms and creatine kinase estimations are compiled to demonstrate the various counselling situations for carrier determination and prenatal diagnosis. The creatine kinase determination suffers from approximately 30% false negative values in carrier determination. The DNA analysis is limited by the uninformativity of the DNA markers and the occurrence of meiotic crossovers between the particular restriction fragment length polymorphism pattern and the Duchenne muscular dystrophy locus. The use of markers bridging the Duchenne muscular dystrophy locus, such as 754 and C7, is presently best suited for this purpose but is applicable to only a relatively small number of cases. The use of the physically closer probe, pERT 87, is much more informative althrough it too recombines with the Duchenne muscular dystrophy locus. DNA analysis allows prenatal diagnosis for unaffected boys from the restriction fragment length polymorphism pattern confined to the healthy grandpaternal X-chromosome in cases where the carrier status of the mother is established or in doubt. As in the case of carrier determination, crossover events and uninformativity of restriction fragment length polymorphisms limit the feasibility of this approach.

Human X chromosome markers and Duchenne muscular dystrophy.

Two DNA markers, a random DNA fragment 754 and the cDNA sequence encoding the gene for ornithine transcarbamylase (OTC) have been studied in kindreds segregating for Duchenne muscular dystrophy. 754 and OTC are located close physically to the mutation in the region Xp21 below the breakpoints in two Duchenne females. The genetic distance was found to be approximately 10cM between 754 and DMD (two crossovers in 26 meioses) and to be approximately 10cM between OTC and DMD (two crossovers in 26 meioses). Physical data suggest the order DMD-754-OTC. The frequency of recombination compared to physical distance between these markers and DMD suggests that there may be a hot spot of recombination. The relevance of these observations for the isolation of the DMD mutation and clinical use of these probes is discussed.

Becker muscular dystrophy: carrier detection by real-time ultrasound.

The applicability was tested of real-time ultrasound imaging to the high musculature for the carrier detection of Becker muscular dystrophy (BMD). A total of 17 obligate carriers were examined. Ultrasound images in 3 patients, aged between 46 and 59 years, showed moderate differences compared with the controls. In 3 other obligate carriers, aged between 46 and 71 years, only doubtfully abnormal findings could be made; ultrasound images showed no differences in 11 BMD carriers aged between 10 and 47 years. In women aged over 40 years, compared with adequate controls of the same body type, real-time ultrasound imaging may provide additional evidence and thus help in the detection of BMD carriers.

Carrier detection in X-linked Becker muscular dystrophy by muscle provocation test (MPT).

The muscle provocation test (MPT: 40 min of strenuous exercise on a bicycle ergometer) is a sensitive method for the detection of carriers of Duchenne muscular dystrophy. The diagnostic applicability of MPT for carrier detection in X-linked Becker muscular dystrophy is demonstrated. Obligate carriers with mean creatine kinase (CK) values on repeated determination within the normal range showed a greater CK elevation after MGP than control subjects. Three of seven daughters of obligate carriers with normal resting CK activity had increased CK activity after MPT. These data suggest that the use of MPT may enhance the capability to discriminate carriers for these X-linked recessive genes.