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PubMed1999

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.

Adult↗
PubMed1998

Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs?

Antiepileptic drugs (AEDs), such as phenytoin (PHT), carbamazepine (CBZ), trimethadione (TMD), and phenobarbital (PB), have all been associated with a similar pattern of malformations, as well as growth retardation and developmental delay. Valproic acid (VPA) has been associated with a different pattern of malformations. Recent studies suggest that PHT's fetal adverse effect is related to its membrane stabilizing pharmacological properties (blockage of voltage-dependent ion channels). During a restricted sensitive period, this results in induction of concentration-dependent bradyarrhythmia in the embryo and episodes of hypoxia/reoxygenation. The aim of this study was to compare the potential of PHT, CBZ, PB, TMD, and dimethadione (DMD; the active metabolite of TMD) to cause bradyarrhythmias. All of these AEDs exert mainly their pharmacological effect via blockage of ion channels. VPA and vigabatrin (VGB), which are pharmacologically active mainly by other mechanisms, were also tested. C57 Bl/6J mouse embryos were cultured in vitro on gestation day 10 in vitro (in 20% rat serum). The drugs were suspended in either water or dimethylsulfoxide and administered into the culture medium in increasing concentrations up to 20 times the human therapeutic plasma concentration. A scoring system was employed in order to rank the drugs based on their potential to cause bradycardia, ventricular arrhythmia, and cardiac arrest in relation to human therapeutic concentrations. Based on this system, the drugs were ranked as follows: DMD = PHT >> PB = CBZ > TMD = VPA >> VGB (no potential). The results correlate well with the available clinical/experimental data of the tested AED's potential to induce hypoxia-related fetal adverse effects, such as oral clefts, distal limb defects, growth retardation, and developmental delay. The results support the idea that adverse fetal effects after in utero exposure to PHT, PB, CBZ, and TMD (via the active metabolite DMD) are initiated via a common pharmacological mechanism: blockage of ion channels in the developing heart in the early embryo resulting in bradyarrhythmias, hemodynamic alterations, and hypoxia/reoxygenation damage.

Abnormalities, Drug-Induced↗
PubMed2000

Regulation and functional significance of utrophin expression at the mammalian neuromuscular synapse.

Duchenne muscular dystrophy (DMD) is caused by the absence of full-length dystrophin molecules in skeletal muscle fibers. In normal muscle, dystrophin is found along the length of the sarcolemma where it links the intracellular actin cytoskeleton to the extracellular matrix, via the dystrophin-associated protein (DAP) complex. Several years ago, an autosomal homologue to dystrophin, termed utrophin, was identified and shown to be expressed in a variety of tissues, including skeletal muscle. However, in contrast to the localization of dystrophin in extrajunctional regions of muscle fibers, utrophin preferentially accumulates at the postsynaptic membrane of the neuromuscular junction in both normal and DMD adult muscle fibers. Since it has recently been suggested that the upregulation of utrophin might functionally compensate for the lack of dystrophin in DMD, considerable interest is now directed toward the elucidation of the various regulatory mechanisms presiding over expression of utrophin in normal and dystrophic skeletal muscle fibers. In this review, we discuss some of the most recent data relevant to our understanding of the impact of myogenic differentiation and innervation on the expression and localization of utrophin in skeletal muscle fibers.

Animals↗
PubMed1996

Rapid death of injected myoblasts in myoblast transfer therapy.

Myoblast transplantation has been proposed as a potential therapy for Duchenne muscular dystrophy (DMD). A Y-chromosome-specific probe was used to track the fate of donor male myoblasts injected into dystrophic muscles of female mdx mice (which are an animal model for DMD). In situ analysis with the Y-probe showed extremely poor survival of isolated normal male (C57B1/10Sn) donor myoblasts after injection into injured or uninjured muscles of dystrophic (mdx) and normal (C57B1/10Sn) female host mice. A decrease in the numbers of donor (male) myoblasts was seen from 2 days and was marked by 7 days after injection: few or no donor myoblasts were detected in host muscles examined at 3-12 months. There was limited movement of the injected donor myoblasts and fusion into host myofibers was rare. The results of this study strongly suggest that the failure of clinical trials of myoblast transplantation in boys with DMD may have been due to rapid and massive death of the donor myoblasts soon after myoblast injection.

Animals↗
PubMed1998

Alternative dystrophin gene transcripts in golden retriever muscular dystrophy.

Golden retriever muscular dystrophy (GRMD), the canine model of Duchenne muscular dystrophy (DMD), is caused by a splice site mutation in the dystrophin gene. This mutation predicts a premature termination codon in exon 8 and a peptide that is 5% the size of normal dystrophin. Western blot analysis of skeletal muscle from GRMD dogs reveals a slightly truncated 390-kD protein that is approximately 91% the size of normal dystrophin. This 390-kD dystrophin suggests that GRMD dogs, like some DMD patients, employ a mechanism to overcome their predicted frameshift. Reverse-transcriptase polymerase chain reaction on GRMD muscle has revealed two in-frame dystrophin transcripts which lack either exons 3-9 or exons 5-12. Both transcripts could be translated into a dystrophin protein of approximately 390 kD. An understanding of how truncated dystrophin is produced in GRMD may allow this mechanism to be manipulated toward a potential therapy for DMD.

Alternative Splicing↗
PubMed1998

Stiffness of knee extensors in Duchenne muscular dystrophy.

The series elastic component (SEC) of Hill's muscle model is sensitive to a modification in muscle functional demand. In this study, SEC stiffness was quantified from quick-released movements in knee extensors of Duchenne muscular dystrophy (DMD) boys to look for possible modifications with the stage of disease. A SEC stiffness index (SI) was defined and was found significantly lower for controls than for DMD. Moreover, a linear relationship was established between mean SI and knee extensors involvement. This suggests a role for this parameter, together with other functional tests, for following patients with DMD.

Adolescent↗
PubMedDate not supplied

Herpes simplex virus vector-mediated dystrophin gene transfer and expression in MDX mouse skeletal muscle.

BACKGROUND: Duchenne muscular dystrophy (DMD) results from mutations that prevent the expression of functional dystrophin in muscle fibers. Herpes simplex virus type-1 (HSV-1) represents a potentially useful vector for treatment of DMD because it has the capacity to accommodate the 14-kb full-length dystrophin cDNA and can efficiently transduce muscle cells. We have tested the ability of first- and second-generation replication-defective HSV vectors to deliver full-length dystrophin to dystrophin-deficient mdx muscle cells in vitro and in vivo. METHODS: First-generation replication-defective HSV vectors harboring full-length or truncated (Becker) dystrophin expression cassettes and lacking a single viral immediate-early (IE) gene were constructed and tested by immunofluorescence and immunoblotting for their ability to direct dystrophin expression in infected mdx cells in culture. To reduce vector cytotoxicity and safety concerns, a second-generation dystrophin vector missing additional IE genes was constructed and tested in vitro and in vivo. RESULTS: Dystrophin expression was observed in infected mdx myotubes in vitro in all cases. Confocal microscopy showed exclusive localization of full-length dystrophin to the cell membrane whereas the Becker variant was also found abundantly throughout the cytoplasm. Dystrophin expression in mdx mice was restored in muscle cells near the site of vector injection. CONCLUSION: Highly defective HSV-1 vectors which lack the ability to spread systemically and are greatly reduced in toxicity for infected cells, thus removing an impediment to prolonged transgene expression, can direct the delivery and proper expression of full-length dystrophin whose considerable size is compatible with few other modes of delivery. These vectors may offer a legitimate opportunity toward the development of effective gene therapy treatments for DMD.

Animals↗
PubMed1993

Expression of the dystrophin-related protein (utrophin) gene during mouse embryogenesis.

The utrophin (UTRN) locus is the autosomal homologue of the DMD (Duchenne muscular dystrophy) gene and encodes a protein, utrophin which is thought to be upregulated in the absence of dystrophin. In this study the spatial and temporal expression of the UTRN gene has been examined during mouse embryogenesis and compared with that of the DMD gene. The patterns of expression of these two genes are very different. Whilst DMD is expressed largely in mesodermal derivatives such as cardiac and striated muscle, UTRN shows a more widespread distribution and is expressed in neural tube, tissues which originate from neural crest and a variety of other sites of non-neural origin. In early embryos UTRN transcripts initially accumulate in the mid-neural plate and thereafter in the caudal neural tube. UTRN mRNA then becomes abundant in a subset of neural crest cell derived tissues, in particular the spinal and facial ganglia and ossifying facial cartilages. UTRN is also expressed in a variety of other sites and organs such as the tendon primordia in the digits, the pituitary, thyroid and adrenal glands, cardiac muscle, kidney and lung, follicles of the vibrissae and the outflow tract of the heart. Several patterns of UTRN expression are apparent and we discuss the possibility that these can be ascribed to a family of mRNAs transcribed from the UTRN gene using alternative promoters.

Animals↗
PubMed1981

Duchenne muscular dystrophy carrier detection using logistic discrimination: serum creatine kinase and hemopexin in combination.

Creatine kinase (CK) activity and hemopexin concentration were measured in 208 serum samples from 104 normal females and 22 obligate carriers of Duchenne muscular dystrophy (DMD) 20-40 years old. Logistic discrimination was used to assess the effectiveness of the parameters alone or in combination in identifying DMD carriers. In this approach, a serum sample with particular CK, hemopexin, or a combination of CK and hemopexin values is given a probability that if drawn at random from a defined mixture of controls and carriers, it comes from a carrier. The carrier probability based on the biochemical tests can be directly combined with the carrier probability determined from a woman's pedigree to yield a final posterior probability that she is a carrier. When CK and hemopexin were considered individually, 65 and 27% of the carriers, respectively, could be distinguished from 95% of the controls. When the two tests were used in combination, 82% of the carriers could be distinguished from 95% of the controls. When the two-test method was applied to 93 possible carriers, 35 women were classified as carriers, whereas only 29 were identified using CK alone. This method can be extended to include other variables in order to further improve the identification of DMD carriers. It can also be applied to carrier detection in other genetic disorders.

Adolescent↗
PubMed1986

Treatment of Duchenne muscular dystrophy with growth hormone inhibitors.

A controlled, double-blind therapeutic trial with the drug mazindol, a growth hormone inhibitor, was performed in a pair of 7 1/2 year-old monozygotic twins, with Duchenne muscular dystrophy (DMD). The rationale for this trial was based on a patient (reported previously) affected simultaneously with DMD and growth hormone (GH) deficiency, who is showing a benign course of the dystrophic process and is still walking at 18 years. One of the twins received 2 mg of mazindol daily, while the other received a placebo. The assessment, repeated every 2 months, included weight and height measurements, functional and motor ability tests, ergometry and determinations of serum enzymes and GH levels. After one year of trial the code was broken and it was seen that the twin under placebo treatment was strikingly worse than his brother, the progression of whose condition was practically arrested. These results strongly suggest that treatment with a GH inhibitor is beneficial for DMD patients.

Body Height↗
PubMed1986

DUCHEN: an interactive computer program for calculating heterozygosity (carrier) risks in X-linked recessive lethal diseases, and its application in Duchenne muscular dystrophy.

The program DUCHEN calculates the probability that a woman is a carrier of an X-linked, lethal recessive disease on the basis of information in the woman's family and any available biochemical data. It is easily used by persons without computer knowledge or experience. The present version can accommodate families consisting of up to 100 people in seven generations. Risks may be estimated on the basis of pedigree information only, or with the inclusion of one or more types of biochemical test results. Biochemical data are incorporated with pedigree information into final risks using the powerful statistical technique of logistic discrimination, a procedure particularly suited for the separation of non-normal populations on the basis of overlapping quantitative characteristics. Mutation rates are specified separately for males and females. DUCHEN is available in FORTRAN 77, IBM BASIC, and Applesoft BASIC, and may be used on a variety of mainframe or microcomputers. The model was used to calculate risks for 375 girls and women in 46 families with Duchenne muscular dystrophy (DMD); serum creatine kinase tests had been carried out on 167 of these subjects who were of reproductive age. Carrier probabilities equal to or lower than the population risk (0.0004) were obtained for 21% of the aunts and 43% of the cousins of affected boys from families with an isolated case of DMD and for 14% of the cousins of affected boys from families with a known DMD history. DUCHEN should assist counsellors in determining which members of large families should be further examined using either standard biochemical carrier detection methods or DNA marker studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatine Kinase↗
PubMed1986

Evaluation of carrier detection rates for Duchenne and Becker muscular dystrophies using serum creatine-kinase (CK) and pyruvate-kinase (PK) through discriminant analysis.

Serum pyruvate-kinase (PK) and creatine-kinase (CK) determinations have been carried out in a sample of 100 obligate carriers for the Duchenne muscular dystrophy (DMD) gene, 23 obligate carriers for the Becker muscular dystrophy (BMD) gene, and 50 normal adult control women. Blood samples were collected from all subjects three times on three independent occasions and the means of these three determinations were considered for both PK and CK activities in the statistical analysis. Discriminant analysis has shown that, in the group of carriers for the DMD gene, the estimated misclassification frequencies (M.F.) using either serum CK, PK, or both enzymes were: 26.5% for CK alone, 19.5% for PK alone, and 19% for both enzymes. In the group of carriers for the BMD gene, the estimated proportions of M.F. were: 31.7% for CK alone, 23.8% for PK alone, and 20.4% for both enzymes. It is concluded that, although a proportion of carries still remains undetected, the use of serum PK determinations enhances the capability of detecting carriers of both DMD and BMD mainly when compared with serum CK alone.

Biometry↗
PubMed1986

Duchenne muscular dystrophy in a girl with an (X;15) translocation.

This is a report of a girl with Duchenne muscular dystrophy (DMD) associated with an 46,X,t (X;15) (p21; q 26) chromosome constitution. Although in the eight published cases of girls with DMD and a t(X;aut) different autosomes were involved in the translocation, the breakpoint was always at Xp21. The present case supports the hypothesis that the DMD gene must be located at Xp21. In this study, involvement of the father's chromosomes in the translocation was detected.

Child↗
PubMed1986

Duchenne muscular dystrophy in a girl with a 45,X/46,XX/47,XXX chromosome constitution.

We report on a 4-year-old girl with Duchenne muscular dystrophy (DMD). One of her sisters had grossly elevated serum creatine-kinase and pyruvate-kinase levels, and one of her maternal great uncles was presumptively affected by DMD. Cytogenetic analysis showed a 45,X/46,XX/47,XXX chromosome constitution. The maternally inherited DMD gene is presumed to be present on the single X of the 45,X cell line.

Child, Preschool↗
PubMed1988

Relation between height and clinical course in Duchenne muscular dystrophy.

We have evaluated the relation between height and rate of clinical progression in boys with Duchenne muscular dystrophy (DMD). In all, 111 DMD patients with age ranging from 2 to 23 years (mean 8.2 +/- 3.4 years) were assessed; of these patients, 92 had their height measured. Clinical course was determined through Vignos scale of functional disability, motor ability, and timed functional tests. All patients had grossly elevated serum creatine-kinase (CK) and pyruvate-kinase (PK) levels. When height was adjusted for patients' age, a statistically significant correlation was found between height and clinical course (positive with Vignos scale and negative with motor ability), suggesting that smaller boys have a better clinical course than taller patients of comparable age. These results support our previous hypothesis and suggest that growth inhibition seems to be effective in diminishing the progression of DMD.

Age Factors↗
PubMed1988

Direct method for prenatal diagnosis and carrier detection in Duchenne/Becker muscular dystrophy using the entire dystrophin cDNA.

DNA sequence polymorphisms (RFLPs) have been widely used as genetic markers for identification of the X chromosome that carries the mutation for Duchenne muscular dystrophy (DMD) in affected families, but serious limitations and pitfalls are associated with this approach [Darras et al., 1987]. The complementary DNA (cDNA) of the DMD gene has recently been isolated and shown to detect partial gene deletions in a large proportion of patients [Koenig et al., 1987]. Two prenatal studies are presented to illustrate how the unambiguous identification of deletion mutations by cDNA probes permits direct DNA-based diagnoses with high accuracy and in otherwise uninformative families. In a single proband family, DNA marker analysis had determined that the Xp21 chromosomal region present in the affected male was also carried by a male fetus in a subsequent pregnancy. Analysis of this family's DNA with probes covering the entire 14 kb cDNA revealed a small deletion in the affected male that was not present in the fetus nor in the mother. In the second family the fetus was a female deletion carrier identified by comparing intensities of restriction fragments. Since 1/3 of all DMD patients are thought to result from new mutations and most families have only single affected males, the cloned cDNA probes now available are likely to revolutionize DNA-based diagnostic studies in this disorder. More reliable, more rapid and less expensive than linkage studies with DNA polymorphisms, this method will be informative in the more than 50% of DMD/BMD cases that have deletion mutations.

Chromosome Deletion↗
PubMed1988

Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.

Five male Japanese patients with complex glycerol kinase deficiency (CGKD) and their relatives were studied clinically, cytogenetically, and molecular-genetically. All patients had muscular dystrophy or muscle weakness, mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency. High-resolution GTG-banded chromosomes showed a microdeletion in the Xp21 region in all four patients examined and in all five mothers. Southern hybridizations, after digestions by restriction endonucleases, with various cloned DNAs (D2, 99-6, B24, C7, L1-4, cDMD13-14, J66-HI, P20, J-Bir, ERT87-30, ERT87-15, ERT87-8, ERT87-1, XJ-1.1, 754, cx5.7, and OTC-1) that are located around Xp21 also showed a deletion in the genome of all patients and mothers. Although the deletion differed in size among patients, a segment commonly absent was located between the genomic sequences corresponding to L1-4 and cDMD13-14. This finding indicated that the gene coding for glycerol kinase (GK) is located within this segment. A comparison of the clinical manifestations of the present five patients and reported CGKD or Duchenne muscular dystrophy (DMD) patients with DNA deletion suggests the existence of a certain gene responsible for gonadotropin deficiency (GTD). The result of the present study and results of previous studies suggest that genes for ornithine transcarbamylase (OTC), DMD, and GK and putative genes responsible for congenital adrenal hypoplasia (AHC) and GTD are arranged from telomere to centromere as pter--GTD--AHC--GK--DMD--OTC--cen.

Adolescent↗
PubMed1989

Estimate of the proportion of Duchenne muscular dystrophy with autosomal recessive inheritance.

The aim of the present report was to estimate the proportion of autosomal recessive (AR) inheritance among families with affected males diagnosed as Duchenne muscular dystrophy (DMD) in which X-linked inheritance could not be confirmed. A total of 470 families was studied: 20 with at least one affected girl with "Duchenne-like" phenotype and 450 with only affected boys. Based on the number of families with at least one affected girl and the number of patients per sibship among these pedigrees, the proportion of families with DMD inherited as an AR trait was estimated at 6.8%. It is also estimated that 2.5-4% of male isolated patients diagnosed as DMD may have the AR form, which could be one possible explanation for the inconsistent results between clinical diagnosis and dystrophin assessment in one case recently reported.

Child↗