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PubMedDate not supplied

[Possibilities and prospects of the use of DNA analysis in the diagnosis and prevention of inherited disease in the Ukraine].

The results from molecular genetic analysis of some mutations in the 10th and 11th exons of cystic fibrosis transmembrane regulator (CFTR) gene as well as of deletions in the 8, 17, 19, 43, 50, 60th exons of dystrophin gene in 61 CF-families and 21 DMD-families from different Ukraine regions are presented. It was shown that delta F508 frequency of CF-patients was 59.2%, the frequencies of S5491, G551D and K533X were about 1%. The frequency of delta F508-carriers analysed among 365 healthy donors from different regions of Ukraine was 1:40. The analyzed deletions of dystrophin gene were revealed only among 6 DMD-patients. The associations of analyzed mutations of CFTR gene and DMD-gene with RELP's in 4 loci of chromosome 7 and 2 loci of X-chromosome, respectively, were found. The results of prenatal diagnosis of cystic fibrosis and DMD are presented.

Chromosomes, Human, Pair 7↗
PubMed1992

[Radioimmunoassay of serum and CSF myelin basic protein and its application to patients with acute cerebrovascular accident].

Myelin basic protein (MBP) was measured in the serum and CSF of patients with acute cerebrovascular disease (CVD, 34 cases), demyelinating disorders (DMD, 30 cases) and other neurological diseases (OND, 26 cases) by using a double antibody radioimmunoassay (RIA). Patients with acute CVD had a mean serum MBP concentration and positivity rate much higher than those with DMD and OND. The differences were significant (P < 0.05). In CSF, MBP levels in patients with acute CVD and patients with DMD were significantly greater than those in OND patients (P < 0.05). The results also show that there was a linear relationship between the CSF MBP levels and the serum MBP levels in patients with acute CVD (r = 0.72, P < 0.01), but no such relationship in patients with DMD and OND. The amount of serum MBP was also significantly correlated to the severity of acute CVD, to the level of consciousness disorder and limb paralysis, and to the extent and site of the cerebral lesion at CT-scan (P < 0.05). This study shows that the measurement of brain specific MBP in serum as a marker of cerebral damage may have clinical value in the diagnosis and prognosis of patients with CVD.

Cerebral Hemorrhage↗
PubMed1992

[Molecular pathology of Duchenne and Becker muscular dystrophy].

Duchenne and Becker muscular dystrophies (DMD and BMD) are two allelic recessive X-linked disorders. Molecular deletions of various regions of the dystrophin gene are the main mutations detected in DMD and BMD patients. Molecular study of DMD and BMD DNA are instrumental to understand the pathological molecular mechanisms and the function of the protein. We describe here dystrophin and its interaction with a glycoprotein complex and we then focus on two particular patients with partial deletions of the dystrophin gene: 1) a typical Becker patient, who shows an intragenic deletion disrupting the reading frame. We describe in this case alternative splicings restoring the reading frame, which might explain the mild clinical phenotype of this patient, 2) a deletion of the distal part of the DMD gene coding for the carboxyterminal domain of the dystrophin in a young patient. The normal localization of dystrophin at the inner face of the plasma membrane in the muscle of this patient suggests that the last domain of this protein is not sufficient to anchor dystrophin at the membrane.

Dystrophin↗
PubMed1992

Multiple products of the Duchenne muscular dystrophy gene.

The gene which is defective in Duchenne Muscular Dystrophy (DMD) extends over 2300 kb of the X chromosome. Its product in the muscle is a 14 kb mRNA encoding a 427 kd rod-shaped protein called dystrophin. A 14 kb transcript encoding a very similar isoform of dystrophin is produced in the brain. The brain 14 kb mRNA is transcribed from the same gene but controlled by a different promoter, located at least 75 kb upstream from the muscle dystrophin promoter. The regulation of these promoters is very stringently controlled. The muscle-type but not the brain-type dystrophin mRNA is found in cloned skeletal muscle cells and its presence is correlated with the appearance of multinucleated fibers. The brain type is expressed in neurons, while in glia cells the muscle-type promoter is active. A third DMD gene transcript which is only 6.5 kb long has been identified. It contains the sequence coding for the C-terminal domain and the cysteine-rich domain of dystrophin but not the large region encoding the spectrin-like repeats and the N-terminal domain. The cell type distribution of this transcript is also very different from that of the two 14 kb mRNA isoforms. It is the major product of the DMD gene in many nonmuscle tissues including brain. Using monoclonal antibodies we have identified a 77 Kd protein which seems to be the translation product of this mRNA. As expected from the distribution of the 6.5 Kb mRNA, this protein is the major DMD gene product detectable in brain and many other nonmuscle tissues; it is undetectable in skeletal muscle but is present in the heart and stomach (as is the 6.5 Kb mRNA).

Base Sequence↗
PubMed1992

[Detection of dystrophin with anti-peptide antibodies].

The analysis of dystrophin in skeletal muscles was performed to identify Duchenne and Becker muscular dystrophy (DMD and BMD) by means of immunohistochemical stain and Western blotting with antisera against synthetic dystrophin peptides. The control muscle specimens derived from normal healthy persons, and patients without DMD and BMD revealed clearly continuous stains of dystrophin at surface membrane. A band with 400 kDa of molecular size by Western blotting was positively stained by anti-dystrophin antibodies. The muscle specimens from eleven DMD patients showed no observation both in the band on Western blotting and in the immunohistochemical staining of dystrophin on frozen-thin sections. BMD muscle specimens showed patchy and faint stains, but no detection of any band on Western blotting except a 380 kDa minor band with anti-peptide IX antibody in one patient muscle. The immunohistochemical procedure was found to be more sensitive than Western blotting for the detection of dystrophin. These results indicate that the dystrophin analysis by both methods is an useful tool for the differential diagnosis of patients with DMD and BMD.

Animals↗
PubMed2003

[Adeno-associated virus vector carrying human minidystrophin gene SMCKA3999 effectively ameliorates dystrophic pathology in mdx model mice].

OBJECTIVE: Duchenne muscular dystrophy (DMD) is the most common and letal genetic skeletal muscle disorder, caused by recessive mutations in the dystrophin gene and no treatment is available. The present paper is aimed to study if recombinant adeno-associated virus vector (rAAV) mediated dystrophin minigene SMCKA3999 could effectively ameliorates dystrophic pathology in mdx model mice. METHODS: We used dystrophin minigene SMCKA3999 to construct rAAVSMCKA3999. When injected into the skeletal muscle of mdx mice (DMD model), we adopted methods of immunofluorescent (IF) staining, Evans Blue and electromicroscopy to observe if rAAVSMCKA3999 could effectively ameliorates dystrophic pathology in mdx model mice. RESULTS: rAAVSMCK3999 resulted in efficient and stable expression and restoration of the missing dystrophin onto the plasma membrane. rAAVSMCKA3999 can also protect myofiber membrane integrity. For the first time we prove that rAAVSMCKA3999 can improve ultrastructure changes of DMD. CONCLUSION: We have demonstrated the effectiveness of rAAVSMCKA3999 in correcting pathology changes of skeletal muscle, which offer a promising avenue for DMD gene therapy.

Animals↗
PubMed2003

[Analysis of short tandem repeat polymorphism in a female patient with Duchenne muscular dystrophy].

OBJECTIVE: To understand the mechanism of Duchenne/Becker muscular dystrophy (DMD) in a female patient. METHODS: A multiplex PCR (mPCR) protocol was applied to detect the dystrophin gene of the female DMD patient and her family members, whose haplotypes were analyzed in light of short tandem repeat polymorphism (STR) of five microsatellite markers (located in 5' terminus and introns 44, 45, 49, and 50). RESULTS: No deletion was detected in the affected female patient and her affected son. Examination of the female DMD patient's STR haplotypes identified in the female patient and her affected son the same haplotype inherited from her unaffected mother, who was a likely germinal mosaicism. The female patient has different haplotype from her affected son and her mother as a deletion was identified in the intron 45 of the affected son, and the female patient and her mother were probably heterozygous for this deletion. CONCLUSION: STR haplotype may not be responsible for the pathogenesis of DMD in the female patient and her affected son.

Female↗
PubMedDate not supplied

Altered long chain fatty acids composition in Duchenne muscular dystrophy erythrocytes.

BACKGROUND: Biochemical abnormalities, increased efflux of soluble enzymes and muscle proteins, and altered permeability of muscle membranes imply the presence of a disorganized erythrocyte membrane in Duchenne muscular dystrophy (DMD). The purpose of the present study was to investigate this hypothesis of a generalized membrane defect. MATERIALS AND METHODS: Twenty-five patients with the disease were analyzed for their erythrocyte lipid composition and for alterations in their fatty acid content compared to twenty-five healthy subjects. RESULTS: DMD patients showed a decreased concentration of total phospholipids compared to healthy volunteers, with striking fluctuations in concentrations of erythrocyte long chain fatty acids. Specifically, the unsaturated fatty acids such as oleic, linoleic and arachidonic acids were significantly decreased in the disease, whereas the saturated fatty acid, palmitic acid was increased in DMD patients compared to healthy controls. CONCLUSION: Our findings suggest an abnormal fatty acid composition and disorganization of erythrocyte membrane in patients with DMD associated with possible functional alterations.

Erythrocyte Membrane↗
PubMed2005

[Clinical pathologic studies and genetic analysis of a female Duchenne muscular dystrophy family].

OBJECTIVE: To investigate the clinical features of female Duchenne muscular dystrophy(DMD), and find out the onset mechanism. METHODS: The clinical manifestations of a female DMD family were followed; the immunofluorescence studies on muscle system and the genetic analysis were carried out. RESULTS: The clinical manifestations and results of relevant examinations on the DMD woman in this family were in accordance with the typical characteristics of DMD. The 39-year-old mother of this proband was noted to have a clinical feature resembling that of Becker muscular dystrophy (BMD), and the immunofluorescence analysis revealed that dystrophin positive fibers and negative fibers co-existed in her muscle. The dystrophy genetic analysis of the family indicated non-deletions. The mother's karyotype was found to be normal. CONCLUSION: The 39-year-old female patient's clinical manifestations were similar to BMD, and only one third of her fibers were dystrophin-positive. The present authors assume that the skewed pattern of X inactivation is the likely mechanism, because the karyotype is normal.

Adult↗
PubMed2005

[Allogeneic umbilical cord blood stem cell transplantation in Duchenne muscular dystrophy].

OBJECTIVE: To study the feasibility of treatment of Duchenne muscular dystrophy (DMD) with umbilical cord stem cell transplantation. METHODS: HLA matching was conducted for a 11-year-old DMD boy with family history was underwent umbilical cord blood stem cell transplantation and a sample of umbilical cord stem cells with 5 matched HLA sites was found in the cord blood bank with 27.32 x 10(8) nucleated cells, about 2.6 times that of the treatment dosage for him. After pretreatment with busulfan 14 mg/kg.d, cyclophosphamide 50 mg/kg.d, and rabbit anti-human thymocyte globulin 10 mg/kg.d, the allogeneic cord blood stem cells were transplanted intravenously. Cyclosporin A, methylprednisolone and MMF were used after the transplantation so as to prevent graft versus host reaction. Prostaglandin E1 was used to prevent Budd-Chiari syndrome, and ganciclovir was used to prevent cytomegalovirus infection. At the same time, Gran, granulocytic cell stimulating factor, and gammaglobulin were also used. Biochemistry test, including serum creatine kinase (CK), was conducted. Evidence of reconstruction of blood making, including conversion of blood type, was observed. PCR-STR analysis was used to observe the status of implantation of the donor umbilical cord blood stem cells. RESULTS: (1) 12 days after transplantation, the white blood cells (WBC) of peripheral blood were 0.5 x 10(9)/L, 14 days after, the numbers of WBC and neutrophils were 1.0 x 10(9)/L and 0.6 x 10(9)/L respectively. In 37 days, granulocytic cell stimulating factor was no more used, the peripheral blood WBC fluctuated around 3.34 approximately 12.2 x 10(9)/L. In the 27th day, the number of blood platelets was more than 20 x 10(9)/L and hemoglobin rose to 88 g/L. On the 24th day red blood cells transfusion was stopped. (2) In the 42nd day, the blood type of the patient transformed from type A before transplantation to type AB (the blood type of transplanted stem cells is type B). (3) PCR-STR test of the peripheral blood made 17, 26, and 42 days after transplantation showed that the gene type of the patient was mixed mosaic: The ratio of donor gradually increased from 40% approximately 45% to 55% approximately 65%. (4) In the 38th day I degrees GVHD appeared. (5) serum CK level declined from 6000 U/L to 600 approximately 2200 U/L. (6) In the 42nd day, physical examination revealed obviously improvement in walking, turning the body over, and standing up. CONCLUSION: This is first case of prospective clinical transplantation on DMD by allogeneic cord blood stem cell. Umbilical cord stem cell transplantation helps re-build blood-making function, and improve locomotive function with a mild GVHD reaction. The genotype of rebuilt blood is mosaic but the ratio of gene mosaic gradually turn from recipient gene type > donor gene type to recipient gene type < donor gene type. The serum CK level decreases significantly after transplantation, which may slow down the necrosis of muscle cell. DMD patient will be benefited by stem cell transplantation.

Child↗
PubMed2004

Utility of dystrophin and utrophin staining in childhood muscular dystrophy.

To determine the utility of dystrophin and utrophin staining in the differential diagnosis of childhood muscular dystrophy. Fifty muscle biopsies of histologically confirmed cases of childhood muscular dystrophy, below 16 years of age, were stained immunohistochemically for dystrophin and utrophin. All the 30 muscle biopsies of patients with Duchenne muscular dystrophy (DMD) showed all or majority of muscle fibers deficient for dystrophin and positive for utrophin. In the 4 female DMD carriers there was mosaic pattern of staining for dystrophin and reciprocal positivity for utrophin. All the muscle biopsies of patients with other childhood onset muscular dystrophies were positive for dystrophin and negative for utrophin. This study shows that dystrophin staining differentiates DMD and DMD carriers from other childhood muscular dystrophies and utrophin staining is of no added value. Utrophin up-regulation may compensate for structural deficiency in dystrophic muscle.

Adolescent↗
PubMed2005

[Regenerative medicine of skeletal muscle].

In the dystrophin-deficient mdx mice, an animal model of Duchenne muscular dystrophy (DMD), damaged skeletal muscles are efficiently regenerated and thus the animals thrive. The phenotypic differences between DMD patients and mdx mice suggest the existence of factors that modulate the muscle wasting in the mdx mice. To identify these factors, we searched for mRNAs affected by the mdx mutation using cDNA microarrays with newly established skeletal muscle cell lines derived from mdx and normal mice. We found that genes encoding thymosin beta4, frizzled related protein 2 (FRP2), and regeneration-associated muscle protease (RAMP) are up-regulated in skeletal muscle of mdx mice. Thymosin beta4 was induced in both regenerating muscle fibers and inflammatory cells after muscle injury. It stimulated migration and chemotaxis of myoblasts. FRP2 was dramatically induced upon muscle injury. RNA interference-mediated knockdown of FRP2 mRNA in myoblasts resulted in a massive cell death. Thus FRP2 may enhance the survival rate of myoblasts in the regenerative regions. RAMP mRNA was specifically induced in the regenerating areas of injured skeletal muscle. Expression of RAMP and FRP2 was much lower in individual muscle cell lines derived from biopsy specimens from several DMD patients compared to in a normal muscle cell line. Above results suggest that thymosin beta4, FRP2, and RAMP may play roles in the regeneration of skeletal muscle and that down-regulation of these molecules could be involved in the progression of DMD in humans.

Animals↗
PubMed2005

Rescue of dystrophin mRNA of Duchenne muscular dystrophy by inducing exon skipping.

Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease, and its victims usually succumb in their twenties. Many studies, including investigations into gene-replacement therapy, have been conducted in a search for a treatment for DMD, and the most promising treatment to date is rescue of mutant dystrophin mRNA by induction of exon skipping. On the basis of results from the molecular analysis of dystrophin Kobe, we propose a treatment for DMD in which antisense oligonucleotides induce exon skipping to edit out-of-frame dystrophin mRNA into in-frame, thereby converting severe DMD to a milder form. Here we review the progress of development of this alternative treatment, with a special focus on dystrophin Kobe.

Dystrophin↗
PubMed2005

Major clinical and histopathological characteristics of canine X-linked muscular dystrophy in Japan, CXMDJ.

Canine X-linked muscular dystrophy (CXMD), which was found in a colony of golden retriever, is caused by a mutation in the dystrophin gene and it is a useful model of Duchenne muscular dystrophy (DMD). To investigate the pathogenesis and to develop therapy of DMD, we have established a beagle-based CXMD colony in Japan (CXMDJ) and examined their phenotypes. The mortality by 3 days of age in the third generation (G3) of CXMDJ dogs, 32.3%, was considerably higher than that in normal G3 littermates, 13.3%. Serum creatine kinase (CK) levels of G3 CXMDJ were significantly higher than that of normal male dogs with two peaks: at shortly after birth and around 2 months of age. Diaphragm muscle involvement occurred shortly after birth and was more severe than that of limb muscles. Stress during whelping might be associated with the neonatal death and respiratory muscle involvement. Gait disturbance was also noticed after 2 months of age. The involvement of limb and temporal muscles was observed from 2 months of age, which corresponded with the second peak of serum CK. Macroglossia, dysphagia, drooling and jaw joint contracture were overt from 4 months of age. We noticed severe macroglossia and hypertrophy of the sublingual muscles at the age of 12 months, and these were important features of this model, because dysphagia is one of major symptoms in older DMD patients. Overall, the phenotypes of CXMDJ were roughly identical to those of CXMD dogs in the literature. Beagle-based CXMDJ is smaller and easier to handle than golden retriever, therefore they are a useful model for DMD.

Animals↗
PubMed2006

[A stress model for parents of children with duchenne muscular dystrophy].

This study explored the problems encountered by parents in caring for children with Duchenne muscular dystrophy (DMD). Open questionnaires (N=21) designed to identify and gauge stress factors were used to collect study data. Results showed that key elements of the care stress model in parents of DMD children prior to joining a support group included: (1) recognition of the factors underlying the changes in their child's health condition (incomprehension, inference, rationalization, and acceptance of mutation and sexual heredity); (2) special assistance needs such as barrier-free facilities, government/social assistance (role substitution, coordination, and long-term care) and medical information (on treating disease causes, psychological adjustment, rehabilitation, and the welfare system); and (3) strains (physical, psychological, sleep disturbances, and feelings of powerlessness). Once families of DMD children began participating in DMD support groups, it is important to note the information exchanged, particularly with regard to medical, rehabilitation, psychological adjustment, role substitution, and welfare benefit information.

Adult↗
PubMed2006

[Desensitization of dust mite drops on antigen-specific asthmatic reaction in guinea pigs].

AIM: To establish an antigen-specific asthmatic model of guinea pig induced by protein antigen extracted from Dermatophagoides farinae (Der f), and study the desensitization of dust mite drops (DMD, extracted from Der f) in a dose progressive manner and long-term sublingual administration. METHODS: To sensitize the guinea pigs, the protein antigen emulsified in aluminium hydroxide gel was subcutaneously and intraperitoneally injected. To observe early-phase reaction of asthma, lung resistance (R(L)) and lung dynamic compliance (Cdyn) in the sensitized guinea pigs were determined by intravenously injecting antigen. To observe late-phase reaction of asthma, the sensitized guinea pigs were challenged with aerosolized antigen for 7 days. Subsequently, methacholine (Mch) in a cumulative dose-manner induced-airway hyperreactivity (AHR), inflammatory cells numbers in bronchoalveolar lavage fluid (BALF) and pathological changes of lung tissue were measured in the model. From the first day of sensitization, the guinea pigs in treatment group sublingually received DMD in a dose progressive manner. The model group sublingually received equivalent saline. The normal control group did not receive any treatment. RESULTS: The guinea pigs in model group showed a significant increase in R(L) and decrease in Cdyn, and developed a marked AHR to Mch. The number of total leukocytes and eosinophils increased significantly in BALF. Serious infiltration of eosinophils was observed in pathological section of lung tissue. Compared with model group, DMD treatment group exhibited a significant amelioration for early-phase and late-phase reaction of asthma. CONCLUSION: DMD in a dose progressive manner and long-term sublingual administration displays a significant desensitization on Der f antigen-specific asthmatic reaction. The results provided experimental evidence for clinical therapy.

Administration, Sublingual↗
PubMed1991

[The low-amplitude elements of the ECG in diabetic patients].

To estimate the rate of changes in low-amplitude elements of the ECG (P wave greater than or equal to 120 ms, distance between its bifurcate peaks greater than 30 ms, P of the terminal index greater than 1.5 microV/s, corrected according to Bazett's formula, PQ interval greater than 200.0 ms, T-U segment displaced downwards from the isoline, negative, biphasic U wave), the additionally enhanced ECGs (1 mV = 50 mm) were recorded in 137 patients suffering from type I diabetes mellitus (DM) without the clinical signs of heart damage (CSHD), in 35 patients with type II DM, in 83 with diabetic myocardiodystrophy (DMD) associated with type I DM and 115 in association with type II DM, in 19 patients with coronary heart disease (CHD) in the presence of type I DM, and in 83 patients suffering from CHD and type II DM. It has been established that changes in low-amplitude elements of the ECG may occur in 55-60% of patients suffering from DM without CSHD, 79-80% of patients with DMD, and in 90-100% of patients with CHD in the presence of DM versus 18.2% in the control group of normals (110 test subjects). In most cases, the changes in the atrial complex of the ECG are not coupled with those seen in the TU-U complex in patients suffering from DM without CSHD and DMD and may be coupled in patients suffering from CHD and DM. The increasing rate of the changes in the P complex together with those in TU-U was ascertained in patients suffering from DM without CSHD, DMD, CHD in the presence of both type I and type II DM. The DM type did not exert any appreciable effect on the characteristics or the rate of changes in low-amplitude elements of the ECG.

Cardiomyopathies↗
PubMed1991

Domiciliary investigation of sleep-related hypoxaemia in Duchenne muscular dystrophy.

In Duchenne muscular dystrophy (DMD) nocturnal oxygen desaturation occurs during rapid eye movement (REM) sleep. Polysomnography, which requires hospital admission, will detect sleep-related breathing abnormalities. In order to avoid the inconvenience of hospital admission for the disabled patient, we investigated overnight oxygenation in ten boys with DMD by domiciliary oximetry. In four boys the results of oximetry were compared with those of a polysomnographic recording. The "repeatability" of domiciliary oximetry was assessed in six boys by performing oximetry on two non-consecutive nights. Older boys with DMD may develop a cardiomyopathy. In order to assess cardiac rhythm and ST segment changes we performed simultaneous Holter monitoring and oximetry in seven boys with overnight hypoxaemia. Six of the initial ten boys studied demonstrated episodic nocturnal hypoxaemia and there was a strong correlation between minimum oxygen saturation overnight and daytime arterial oxygen and carbon dioxide tensions (PaO2 r = 0.89; PaCO2 r = -0.87). Despite adequate REM time during polysomnography, greater oxygen desaturation was found during domiciliary oximetry. No difference was found in the severity of desaturation recorded in the boys who were studied on two separate occasions. Five boys demonstrated marked heart rate variation during hypoxaemic episodes and more serious arrhythmias occurred overnight in the three most hypoxaemic boys. Domiciliary oximetry is a simple, repeatable method of assessing overnight oxygenation and compares well with polysomnography. In boys with advanced DMD and severe nocturnal hypoxaemia, 24 h electrocardiographic monitoring may detect potentially life-threatening arrhythmias.

Adolescent↗