Duchenne-like muscular dystrophy in two sisters with normal karyotypes: evidence for autosomal recessive inheritance

Two sisters, products of a consanguineous marriage (with a total of 12 children) showed muscle weakness at ages 7 and 6 yrs, respectively. The symptoms progressed rapidly and the patients were confined to wheelchairs at ages of 12 and 11 yrs, respectively. They had mild facial weakness and pseudohypertrophy of the calves, but neither cardiomyopathy nor mental retardation. Serum CK activities exceeded upper normal limit by 70 to 85-fold. Muscle biopsies were compatible with muscular dystrophy. Both girls had a normal karyotype. The healthy mother had mild CK elevations in two out of three occasions, but the muscle biopsy was normal. Three out of the six unaffected sibs had mild CK elevations. The findings support the concept of severe progressive muscular dystrophy with autosomal recessive inheritance. The condition is clinically indistinguishable from Duchenne muscular dystrophy.     

Preimplantation diagnosis of non-deletion Duchenne muscular dystrophy (DMD) by linkage polymerase chain reaction analysis

The use of preimplantation diagnosis for sex determination and detection of exon deletion means that unaffected babies can be born to parents suffering from Duchenne muscular dystrophy (DMD). However, those who do not have exon deletion should also be considered for further investigation. A new method, known as linkage analysis, has been developed to diagnose the presence of non-deletion DMD in preimplantation embryos. Linkage analysis uses informative intragenic and flanking markers to track the chromosome bearing the mutated gene. The present study reports the analysis of two polymorphic sites, in blastomeres biopsied from embryos from a female carrier of DMD. A single male embryo was obtained who had inherited alternate maternal alleles to the woman's affected surviving son, and this embryo was transferred.      

Genetic heterogeneity of autosomal recessive limbgirdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus

Limb-girdle muscular dystrophy (LGMD) is a hereditary myopathypresenting clinical and genetic hetero geneity. In 1991, a recessiveform (LGMD2A) was linked to chromosome 15q in a genetic isolatefrom the Isle of La Réunion. Confirmation of this localizationwas subsequently reported in Brazilian and northern IndianaAmish pedigrees. Here we report the exclusion of the LGMD2Alocus in six Amish kindreds from southern Indiana that are relatedby multiple consanguineous links to the same northern Indianafamilies in which the involvement of the chromosome 15 locuswas previously demonstrated. These findings indicate unexpectedgenetic hetero geneity of LGMD in an Indiana Amish isolate.Further more, genetic analyses also ruled out the possible involvementof the chromosome 2 locus recently described (LGMD2B), thusdemonstrating that a mutation within at least one additionallocus leads to this condition. Several candidate genes putativelyinvolved in neuromuscular disorders were also excluded.     

Genetic analysis of the Duchenne muscular dystrophy gene

Molecular biology techniques have changed the way in which we now consider a patient with Duchenne muscular dystrophy or Becker muscular dystrophy. Using cDNA probes, it has been shown that approximately 65% of the patients with Duchenne muscular dystrophy or Becker muscular dystrophy have gene deletions. The identification of a deletion allows the disease to be confirmed by noninvasive DNA testing. Furthermore, the identification of the gene defect can help distinguish Becker muscular dystrophy from other clinically similar neuromuscular disorders. Most importantly, the elucidation of the gene defects has resulted in the application of direct carrier and prenatal diagnostics.     

Genetic linkage between the loci for myotonic dystrophy and peptidase D

In a linkage study between myotonic dystrophy and peptidase D it is evident from the lod score values that with high probability θ lies between 0 and 0.1. The data thus support a previous hint of linkage between peptidase D and the Lutheran and secretor loci, which were already known to be linked to myotonic dystrophy.     

Absence of genetic heterogeneity in Duchenne muscular dystrophy shown by a linkage study using two cloned DNA sequences.

A linkage study using two different restriction fragment length polymorphisms (RFLPs) identified with cloned DNA sequences has failed to provide evidence for genetic heterogeneity in Duchenne muscular dystrophy (DMD) when tested against intelligence quotient (IQ). Analysis of data for age of confinement to a wheelchair against IQ gave no evidence for heterogeneity. These results are of a practical as well as theoretical significance, since the existence of multiple loci causing DMD would make it more difficult to apply linkage data to genotype prediction in this disease.     

Genetic linkage between Becker muscular dystrophy and a polymorphic DNA sequence on the short arm of the X chromosome.

A study of DNA restriction fragment polymorphisms and Becker muscular dystrophy has shown eight families informative for the cloned sequence L1.28, which is located on the short arm of the X chromosome between Xp110 and Xp113. Analysis of these families reveals linkage between the two loci, with the maximum likelihood estimate of the genetic distance being 16 centiMorgans (95% confidence limits between 7 and 32 centiMorgans). Since a study of DNA polymorphisms in Duchenne muscular dystrophy has shown a comparable linkage distance with L1.28, our results suggest that the locus for Becker muscular dystrophy, like that for Duchenne dystrophy, is on the short arm of the X chromosome, and further that these two loci may be closely linked or possibly allelic.     

Duchenne muscular dystrophy in Wales: impact of DNA linkage analysis and cDNA deletion screening.

A register of families with Duchenne muscular dystrophy (DMD) has been maintained in Wales since 1973. Since 1986 we have attempted to refine carrier status, and when necessary offer prenatal diagnosis, for those at significant risk by using intragenic probes. cDNA probes were included from the beginning of 1988. Thirty-four (30%) of the 115 women tested were assigned a risk of carrying the DMD gene of less than 5%. Thirty-three (29%) of the women at 5% or greater risk are now able to have prenatal diagnosis using a molecular deletion; such deletions were detected in 50% of affected boys. The remaining women could have prenatal diagnosis using a linked intragenic probe with an error rate varying between 0.25% and 9%. In 19 cases DNA samples from DMD boys who were dead at the time of analysis were used, indicating that it is essential to bank DNA from all males affected by DMD. We conclude that a large proportion of women at risk of carrying the DMD gene can now be helped by DNA studies.     

Fukuyama-type congenital muscular dystrophy (FCMD) and oc-dystroglycanopathy

ABSTRACT  Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein 0-linked mannose pi, 2-N-acetylglucosaminy ltransferase (POMGnTl), respectively. Recent studies have revealed that posttranslational modification of oc-dystro-glycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with a-dystroglycan are discussed.     

The value of deletion analysis for carrier detection in Duchenne muscular dystrophy (DMD)

We performed genetic analysis for carrier detection for several at-risk females in a four-generation Duchenne muscular dystrophy (DMD) pedigree using deletion analysis. We demonstrated that dosage analysis is a suitable alternative method to determine the carrier status of female relatives of DMD patients shown to have a deletion within the DMD gene. Subsequently, we diagnosed an affected male fetus for an at-risk female shown to be a DMD carrier by deletion analysis. The usefulness of deletion and linkage analysis are compared. In this family, linkage analysis was complicated by the unavailability of key family members, two recombination events and by previously undisclosed nonpaternity. We found that dosage analysis was more efficient than linkage for carrier evaluation in this family.     

Evidence of genetic heterogeneity in the autosomal recessive adult forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families.

The autosomal recessive limb-girdle muscular dystrophies (LGMD) represent a heterogeneous group of diseases which may be characterised by one or more autosomal loci. A gene at 15q has recently been found to be responsible for a mild form of LGMD in a group of families from the isolated island of Réunion, now classified as LGMD2. Based on results of eight out of 11 large Brazilian LGMD families of different racial background (which were informative for the closest available probe to the LGMD2 gene), we confirmed linkage to the LGMD2 gene at 15q in two of these families and exclusion in six others. These data provide the first evidence of genetic heterogeneity for the autosomal recessive limb-girdle muscular dystrophies.     

No evidence of genetic heterogeneity in Brazilian facioscapulohumeral muscular dystrophy familes (FSHD) with 4q markers

The gene responsible for facioscapulohuineral muscular dystrophy(FSHD), an autosomal dominant neuromuscular condition, has beenmapped to chromosome 4. Until recently, the two closest availablemarkers were D4S139 and D4S163 but a new marker (p13E-11) whichrecognizes de novo rearrangements in isolated cases of FSHDcharacterized by shorter EcoRI fragments has been now identified.Linkage analysis In FSHD families with pl3E4l shows that usuallya smaller fragment segregates with the disease gene among theaffected individuals from each genealogy. In the present paper,we report the results from linkage analysis with the markerloci D4S163 and D4S139 in 6 FSHID families and with pl3E-11in these and In 6 other additional Brazilian families (totalof 12). The results from such analysis do not suggest geneticheterogeneity for FSHD in our population. In 11 out of the 12families studied with pl3E-11, a shorter specific EcoRI bandwas found to segregate In all affected patients from each genealogy.In one family, the normal Individuals had a smaller EcoRI fragmentthan the affected ones. The size of the EcoRI fragments detectedwith pl3E-11 varied from 13.5 to 29 kb but was constant withineach genealogy. Our results suggest that the use of the markerpl3E-11 for predlinical and prenatal diagnosis should be doneonly in families in which it is possible to identify the fragmentssegregating among the affected individuals.     

Genetic counseling for childless women at risk for Duchenne muscular dystrophy.

The aim of the present study was to assess the impact of genetic counseling in young women at risk to have Duchenne muscular dystrophy (DMD) children prior to childbearing. A total of 263 potential DMD carriers, who had had genetic counseling and were given different genetic risks, were included in this investigation. Their reproductive outcome and future plans as well as their requests for DNA tests (for carrier detection and prenatal diagnosis) were analyzed according to genetic risk magnitude, comprehension of genetic counseling is- sues, family and personal history, socio-educational level, and subjective opinion about selective abortion. We noted that genetic risk magnitude had no significant influence on reproductive plans or outcome nor on the request for additional DNA testing, even considering only those clients with good comprehension and retention of issues discussed during genetic counseling. On the other hand, counselees who had more than one affected or at least one deceased DMD case in their family understood genetic counseling significantly better, suggesting that "learning with life" has a stronger impact than genetic counseling.     

Genetic linkage for Darier disease (keratosis follicularis)

Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23–24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Z_max) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general. © 1995 Wiley-Liss, Inc.