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PubMed1996

Urinary dysfunction in Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD), sphincter muscles tend to be clinically spared. However, urinary incontinence is occasionally reported, usually late in the course of the disease. We wished to determine the etiology of urinary dysfunction in patients with DMD. Seven boys with DMD and urinary dysfunction were examined by a neurologist and a urologist followed by urodynamic and electrophysiological assessment. Based on the results of these evaluations, patients were defined as having an upper motor neuron (UMN), lower motor neuron (LMN), or myopathic lesion. Five of the patients had UMN abnormalities consisting of either uninhibited contractions or bladder/sphincter dyssynergy. One patient had a LMN lesion with prolonged duration and high-amplitude motor units. No patient demonstrated myopathic motor units. Five boys had undergone spinal fusion for scoliosis. We conclude that urinary incontinence in DMD is most often due to UMN dysfunction and not due to a severe myopathy of the detrusor or external sphincter. The most likely causes of the UMN abnormalities are severe scoliosis or a complication of spinal fusion surgery.

Adolescent↗
PubMed2001

Coagulation and fibrinolysis disorder in muscular dystrophy.

To investigate whether there are any basic abnormalities of coagulation and fibrinolysis in muscular dystrophy, we measured serum levels of the MM isozyme of creatine kinase (CK-MM), fibrin and fibrinogen degradation products (FDP), plasma levels of fibrinogen, antithrombin (AT), and D-dimer in 36 patients with Duchenne muscular dystrophy (DMD), 11 with Becker muscular dystrophy (BMD), 5 with Fukuyama congenital muscular dystrophy (FCMD), 5 with myotonic dystrophy (MyD), and 5 with spinal muscular atrophy (SMA) type 2. FDP levels were elevated in the patients with DMD, BMD, and FCMD (1.0 to 84.9 microg/ml), but not in the patients with MyD and SMA type 2. In DMD, BMD, and FCMD, FDP levels significantly correlated with CK-MM, but not with age, fibrinogen, AT, D-dimer, and type of dystrophy (multiple regression analysis; r(2) = 0.814, P < 0.0001). These findings suggested that enhanced coagulation and fibrinolysis are associated with muscle degeneration in patients with DMD, BMD, and FCMD.

Adolescent↗
PubMed1982

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

In the absence of an unambiguous test for identifying Duchenne muscular dystrophy (DMD) heterozygotes, methods are needed for combination of the results of individually equivocal tests as effectively and rationally as possible. Tw used logistic discrimination to assess the effectiveness of measurements of serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase alone and in various combinations in identifying DMD carriers. We analyzed 127 serum samples from 63 normal female controls (20-40 years old) and 67 from 38 obligate DMD carriers. The best two tests to use in combination were creatine kinase and hemopexin, and these two, with lactate dehydrogenase, were the best three. t the 95% level (with 5% of controls misclassified), 54% of the carriers were identified by CK alone, whereas 88% were identified by means of the four tests. Although a small proportion of known carriers still cannot be identified, application of the four tests to a group of 45 possible carrier mothers of isolated cases of DMD resolves the population into fairly discrete "normal" and "abnormal" subgroups. Thus, if bias of selection can be eliminated, application of logistic discrimination may permit a direct estimate of the proportion of mothers of affected boys who are homozygous normal.

Adult↗
PubMed1983

Electron spin resonance spin label studies of the erythrocyte membrane in Duchenne muscular dystrophy.

The membrane organisation of erythrocytes from patients with Duchenne muscular dystrophy (DMD) and from asymptomatic carriers was studied by the electron spin resonance (ESR) spin label technique. Following the work of Sato et al [1978], we used 2-(14-carboxytetradecyl)-2-ethyl-4, 4-dimethyl-3-oxazolidinyloxyl as probe. We found no significant difference in lipid fluidity at 30 degrees C, measured by the ratio of the line height at central field to that at high field ho/h-1, in DMD patients or carriers compared to appropriate control persons. Our conclusions for the dystrophic boys differ from those of Sato et al [1978], although our data are consistent with theirs within experimental error. We also studied the variation of the ratio ho/h-1 over the temperature range 5-35 degrees C in these individuals. For normal erythrocytes there is a discontinuity in this plot around 15 degrees C that is absent in the erythrocytes of DMD patients [in agreement with the findings of Sato et al, 1978] and also absent in DMD carriers. We suggest the slope of this logarithmic temperature plot over the range 15-35 degrees C is a more useful empirical parameter as the presence of these discontinuities is sometimes uncertain, and using this parameter, we find a clear separation between carriers and controls.

Adult↗
PubMed1985

Fetal plasma carbonic anhydrase III in prenatal diagnosis of Duchenne muscular dystrophy.

Carbonic anhydrase III (CAIII), a skeletal-muscle-specific enzyme which is elevated in the plasma of Duchenne muscular dystrophy (DMD) patients, was measured by radioimmunoassay in fetal plasma in order to evaluate its application to prenatal diagnosis of DMD. Using fetoscopy, pure fetal blood samples were taken at 17-24 weeks gestation from 25 fetuses at risk for DMD and from 78 control fetuses. Care was taken in the handling and storage of all samples. Normal sons were born in eight cases at risk for DMD. The CAIII levels in the infants were not significantly different from those of the control infants. Pregnancies were terminated in the remaining 17 at-risk cases. The CAIII levels in the fetuses were significantly different (p = 0.0034) from those of the control fetuses, although the distributions overlapped. Based on prior maternal risk, seven affected fetuses were expected in the terminated group; five had CAIII levels at or above the 95th centile of the control range. It is suggested that measurement of CAIII achieves partial discrimination between affected fetuses and their normal at-risk brethren.

Carbonic Anhydrases↗
PubMed1988

Effect of mazindol on growth hormone levels in patients with Duchenne muscular dystrophy.

Human growth hormone (HGH) inhibition may be beneficial in Duchenne muscular dystrophy (DMD) and slow down the rate of progression of the disease. The purposes of the present investigation were: 1) to assess, through pharmacological stimuli (L-dopa test), the HGH response in untreated DMD patients, and 2) to evaluate the inhibitory effect of mazindol on HGH levels as a potential treatment for DMD. In 55 DMD patients, HGH levels were measured through the L-dopa test, and 40 received mazindol. After 1 year, there was wide variability in the individual response to mazindol. An apparent diminution in the mean HGH level was observed in the whole group of patients; this was statistically significant after 3 and 6 months but not after 9 and 12 months of treatment. The results suggest that this drug is not effective for arresting growth or inhibiting HGH secretion for a prolonged period of time.

Adolescent↗
PubMed1989

Echinogenic action of L-alpha-lysophosphatidylcholine in Duchenne muscular dystrophy: a study on carrier detection.

The percentage of echinocytes induced after red cell treatment with L-alpha-lysophosphatidylcholine in the blood of 16 patients affected by Duchenne muscular dystropy (DMD) has been evaluated. Moreover, 15 mothers, 10 sisters, and 15 fathers were also included in the study. We found an increased level of echinocytes in dystrophic patients and in known and possible carriers. Correlations were also evaluated between echinocytes and serum enzymes used in DMD diagnosis, showing an increase of echinocytes also in DMD carriers with normal levels of serum creatine kinase, lactate dehydrogenase, and aldolase. Our results suggest that the sensitivity of erythrocytes to L-alpha-lysophosphatidylcholine in DMD could be used as a diagnostic test for carrier detection.

Adolescent↗
PubMed1989

Duchenne muscular dystrophy in monozygotic twins: deletion of 5' fragments of the gene.

A recombinant DNA study for deletion evaluation was performed in a 4 generation family with Duchenne muscular dystrophy (DMD) in twins. The patients were 6 years old, had a history of progressive difficulty in walking since age 4, and showed weak gluteals, iliopsoas, latissimus dorsi, rhomboids, lower trapezius, sternocleidomastoids, pseudohypertrophic calves, and tight heelcords. Both patients had high serum creatine kinase of 19,000 and 11,000 IU, respectively, and the muscle biopsy of the left vastus lateralis showed dystrophic alterations. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing also detected the same antigens in both twins: A2, B44, DR4, and DR5. Cytogenetic studies were consistent with 46, XY male individuals with normal banding pattern. By cDNA probes the entire DMD gene was surveyed for missing or abnormal-sized restriction fragments. Both twin boys showed absence of 8.5, 8.0, 4.6, 4.2, and 3.1 kb fragments on Hind III blots and absence of 13.5, 3.7, 2.9, and 1.4 kb fragments on Bgl II blots both hybridized with cDNA 1-2a corresponding to most 5' region of the DMD gene. The mother and other relatives of the patient did not show deletion. These findings strongly suggest that the deletion in the DMD monozygotic twins represents a new mutation.

Child, Preschool↗
PubMed1991

Three years' experience with neonatal screening for Duchenne/Becker muscular dystrophy: gene analysis, gene expression, and phenotype prediction.

Neonatal screening for Duchenne/Becker Muscular dystrophy (DMD/BMD) was begun as a pilot program on January 1, 1986. The aim of this program was to reduce the incidence of this X-linked recessive degenerative neuromuscular disease. The neonatal detection of a boy with DMD allows early identification of carriers and genetic counselling. This may avert the birth of other affected males born prior to clinical diagnosis of DMD in the propositus at about age 5 years. Between January 1, 1986, and December 31, 1988, we identified and characterized a cohort of 8 asymptomatic infant boys with grossly elevated levels of creatine kinase, an active primary dystrophic process of muscle and complete dystrophin deficiency. Five of 8 males have detectable DNA alterations involving the DMD/BMD locus. Based on current hypotheses, characterization of dystrophin expression of this cohort allows us to predict a DMD phenotype in all 8 boys. To date, no additional males with DMD have been born in these families. Prospective follow-up will allow us to test the validity of dystrophin testing in predicting the clinical course and impact of this program on reproductive decision making in these families.

Cohort Studies↗
PubMed1993

In utero fetal muscle biopsy for the diagnosis of Duchenne muscular dystrophy in a female fetus "suddenly at risk".

DNA methods to diagnose Duchenne muscular dystrophy (DMD) are not always informative, and we have published previously the first instance of in utero muscle biopsy to assess dystrophin in a male fetus having the same "X" as an affected sib. We present here a female fetus with a de novo X,1 translocation with breakpoint at Xp21, detected on amniocentesis for advanced maternal age. The translocation breakpoint placed her at high risk for DMD. In utero muscle biopsy at 20 weeks of gestation produced a specimen positive for dystrophin immunofluorescence indicating a likely normal fetus. The pregnancy was continued, and at term the baby girl was found to have normal serum creatine kinase levels, and was therefore unaffected with DMD. Our experiences add de novo Xp21 translocation to the indications for in utero muscle biopsy for diagnosis of DMD.

Adult↗
PubMed1995

Absence of correlation between utrophin localization and quantity and the clinical severity in Duchenne/Becker dystrophies.

While present in the surface membrane of embryonic muscle fibers, in adult normal muscle fibers, utrophin is restricted to the motor endplate and cells of blood vessel walls. However, the observation that utrophin is maintained in the extrajunctional plasma membrane in Duchenne (DMD) and in mdx muscle fibers has led to the suggestion that excess utrophin might compensate for dystrophin deficiency in the Xp21 muscular dystrophies. In order to detect an inverse correlation of utrophin presence and clinical severity, we have assessed utrophin distribution and quantity in DMD and Becker (BMD) patients of different ages and stages of clinical severity. All patients showed a positive discontinuous immunolabeling of utrophin on the sarcolemma, staining equally small and large muscle fibers, indicating that immature characteristics are maintained in such fibers. On Western blot, utrophin bands with concentrations 2- to 10-fold greater than in normal controls were detected in all DMD/BMD patients. However, no negative correlation was found between the amount of utrophin and the severity of clinical course, implying that the detectable utrophin levels in these patients did not compensate for dystrophin deficiency. In a DMD patient with growth hormone (GH) deficiency and a BMD-like clinical course, utrophin levels were comparable to the other typical DMD cases, which reinforces the hypothesis that the observed increase in utrophin is apparently not responsible for a milder clinical course in some patients with Xp21 muscular dystrophies.

Adolescent↗
PubMed1995

Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: deletion detection and familial diagnosis.

Deletion studies were performed in 26 Duchenne muscular dystrophy (DMD) patients through amplification of nine different exons by multiplex polymerase chain reaction (PCR). DNA from paraffin-embedded muscle biopsies was analyzed in 12 of the 26 patients studied. Optimization of this technique is of great utility because it enables analysis of material stored in pathology archives. PCR deletion detection, useful in DMD-affected boys, is problematic in determining the carrier state in female relatives. For this reason, to perform familial linkage diagnosis, we made use of a dinucleotide repeat polymorphism (STRP, or short tandem repeat polymorphism) located in intron 49 of the gene. We designed a new pair of primers that enabled the detection of 22 different alleles in relatives in the 14 DMD families studied. The use of this marker allowed familial diagnosis in 11 of the 14 DMD families and detection of de novo deletions in 3 of the probands.

Alleles↗
PubMed2005

Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort.

Mutations in the DMD gene result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Readily available clinical tests detect only deletions of one exon or greater, which are found in approximately 60% of cases. Mutational analysis of other types of DMD mutations, such as premature stop codons and small frameshifting insertions or deletions, has historically been hampered by the large size of the gene. We have recently reported a method that allows the rapid and economical sequencing of the entire coding region of the DMD gene, and that is more sensitive than methods based on single-strand conformational polymorphism (SSCP) screening or other preliminary screening steps. Here we use single condition amplification/internal primer (SCAIP) sequencing analysis, in combination with multiplex amplifiable probe hybridization (MAPH) analysis of duplications, to report the frequency of mutations in a large cohort of unselected dystrophinopathy patients from a single clinic. Our results indicate that 7% of dystrophinopathy patients do not have coding region mutations, suggesting that intronic mutations are not uncommon. The availability of rapid and thorough mutation analysis from peripheral blood samples, along with an improved estimate of the percentage of non-coding region mutations, will be of benefit for improved genetic counseling and in identification of cohorts for clinical trials.

Codon, Nonsense↗
PubMedDate not supplied

On the chemiluminescence in the oxidation of tetravalent uranium to the uranyl ion by dimethyldioxirane.

The reaction of the tetravalent uranium [U(IV)] with dimethyldioxirane (DMD) in strongly acidic water-acetone solutions is accompanied by chemiluminescence (CL) in the visible (Vis) and infra-red (IR) regions. At least three independent reaction pathways are involved in the U(IV)-DMD oxidation: the first entails the non-chemiluminescent oxidation of U(IV) to the uranyl ion (UO(2) (2+)); the second involves the catalytic decomposition of DMD by U(IV) to afford singlet oxygen, as manifested by its characteristic IR-CL; and in the third process, slow Vis-CL (510-540 nm) is emitted, following DMD consumption.

Epoxy Compounds↗
PubMed1994

Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations.

The past few years have seen a rapid increase in our knowledge of naturally occurring mutations in the dystrophin gene. Although earlier studies were limited to gross rearrangement mutations, we are now in a position to draw lessons on the molecular etiology of the remaining one-third of cases of Duchenne and Becker muscular dystrophy (DMD, BMD) which are associated with small mutations. This paper reviews 70 published and unpublished small mutations in the dystrophin gene and asks what we can learn about their nature, their distribution, and approaches to their characterisation. Strikingly for such a well-conserved gene, missense mutations are extremely rare, and the vast majority of DMD point mutations, like the gross rearrangements, result in premature translational termination. It seems increasingly likely that almost all cases of DMD arise solely as a result of a reduction in the level of dystrophin transcripts, and we argue that > 95% of DMD mutations contribute nothing to the functional dissection of the dystrophin protein. Most of the few BMD point mutations presented here are missense mutations in the N-terminal or C-terminal domains or are splice-site mutations that probably act, like BMD deletions, via the production of in-frame, interstitially deleted transcripts.

DNA↗
PubMed2004

IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1.

IL1RAPL1 (interleukin-1 receptor accessory protein-like, gene 1) has recently been shown to be mutated in patients with X-linked mental retardation. Clinical experience has suggested that patients with the contiguous gene syndrome, complex glycerol kinase deficiency (cGKD), will have mental retardation (MR) if they have deletions extending from the GK gene into the DMD gene and/or involving a significant extension telomeric from DAX1. We examined cell lines from patients with cGKD whose clinical features would be informative and would allow us to determine if IL1RAPL1 deletions can help to explain the MR in patients with deletions extending telomeric from DAX1. Our results showed that nearly all patients with deletions involving DAX1, but not DMD, had MR if IL1RAPL1 was deleted. If ILIRAPLI and DMD were intact, the patients with DAX1 deletions only rarely had normal development. Deletions in DNA from patients with cGKD who exhibited MR and had normal IL1RAPL1 all involved the GK and DMD genes. Our data are consistent with the association of IL1RAPL1 gene deletion and MR in the majority of patients with cGKD and deletions extending telomeric from DAX1.

Adrenal Glands↗
PubMed1991

PCR analysis of dystrophin gene mutation and expression.

Duchenne muscular dystrophy (DMD) is caused by mutations that impair normal production of dystrophin in muscle and brain tissues. The dystrophin gene is expressed at extremely low levels in both humans and mice, which makes analysis of the 14kb mRNA a difficult task. In addition, 30% of all cases of DMD (and the genetic lesion in all three known mdx mouse models for DMD) are thought to arise from single base mutations, yet methods are not available to routinely identify and analyze these mutations and their effects on disease progression. We have been using the polymerase chain reaction (PCR) to analyze the expression of the murine dystrophin gene. A simple assay is described that distinguishes the murine dystrophin transcripts expressed from either the muscle or brain promoter. In addition, amplification of overlapping segments from the 5' end of the murine transcript has enabled the identification of DNA sequence variations between wild-type and mdx mice. These results demonstrate that the mutation in the original strain of mdx mice is distinct from those in two newer mdx isolates and that three independently isolated mdx mutants are available for study of DMD.

Animals↗
PubMed1981

Patients with myotonic dystrophy, a possible segmental progeroid syndrome, and Duchenne muscular dystrophy have fibroblasts with normal limits for in vitro lifespan and growth characteristics.

Myotonic dystrophy (MyD) has been suggested to be a segmental progeroid syndrome in man, as this syndrome has some clinical manifestations of premature aging. Fibroblasts from patients with other progeroid syndromes have been shown to have diminished in vitro lifespans or growth characteristics; therefore, it was of interest to study cellular senescence in fibroblasts from patients with MyD. Fibroblast cultures from patients with Duchenne muscular dystrophy (DMD) were used as additional controls, as premature aging is not associated with this genetic disorder. Primary skin fibroblast cultures obtained from patients with MyD or DMD and from age-sex matched controls were grown in DMEM plus 10% FBS. The in vitro lifespan was determined by either a 1:4 split ratio or with a constant initial inoculum of 1 times 10(4) cells/cm2, followed by determination of the final density at weekly intervals. Our results demonstrate that there is no difference in the limits of the in vitro lifespan for either the MyD or DMD fibroblast strains compared to the controls. Likewise, no difference could be detected in the growth characteristics of these cells. The only observable difference was that the pooled age-matched controls and MyD cultures had a shorter in vitro lifespan than the DMD group and their pooled controls, a finding expected because of the age of the patients in each group. Unlike the other progeroid syndromes, MyD fibroblasts have normal limits for in vitro lifespan. MyD is probably not closely related to the other premature aging syndromes, although there is an increasing phenotypic expression as a function of age.

Adolescent↗