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[Duchenne's and Becker's muscular dystrophy: analysis of phenotype-genotype correlation in 28 patients] ].

Duchenne's and Becker's muscular dystrophy (DMD & BMD) is a X linked disease caused by mutations in the dystrophic gene. DMD is the malign form of the disease, which significantly shortens the lifetime of the patient, while BMD has late onset with slow progression. Sixty five percent of DMD and BMD cases are caused by deletion of one or more exons in the dystrophic gene, while duplications cause these diseases in 6 to 7% of the cases. There are two hot spots for deletions and duplications. These are exons in the proximal part of the gene (3rd to 18th) and exons of a distal part of the gene (45th to 52nd). The remaining 30% of DMD and BMD cases are caused by point mutations, small deletions or inversions in the dystrophic gene. The correlation between the severity of the disease and the position of deletion shows that most of the out of frame deletions cause DMD phenotype, while in frame deletions result in BMD phenotype. We report on the results of 28 non-related DMD and BMD patients. In 57% of cases deletions were detected and all were found in the distal hot spot of the gene. These results suggest that in most of the cases, out of frame deletions produce DMD phenotype while in frame deletions result in BMD phenotype. This is in compliance with data from literature.

Dystrophin↗

PubMed1992

In vitro and in vivo studies of factors affecting digestion of feeds in synthetic fiber bags.

Dry matter disappearance (DMD) and cellulose disappearance (CD) from alfalfa hay were measured simultaneously in synthetic fiber bags incubated in vitro. In general, DMD, CD, and pH were reduced (P less than .05) inside the bags compared with values in the fermentation flasks. Bags became fully expanded with gas soon after the fermentation started, which seemed to inhibit fluid movement into and out of the bag. By creating a vacuum in the flask, fluid exchange was enhanced, and DMD, CD, and pH increased (P less than .01) inside the bags. Sample size, type of fabric, and fabric pore size affected pH, DMD, and CD. Inoculum source (forage or concentrate diet) did not affect DMD in either bags or flasks. In contrast, DMD in bags incubated in vivo was affected (P less than .01) by animal diet. When bags were incubated in vivo inside a rigid plastic container, both pH and DMD were reduced (P less than .01) compared with bags suspended freely in the rumen. Direct physical action of ruminal contents on the bags apparently enhanced exchange of fluid. Bacterial concentrations in bags suspended freely in the rumen were greater than those in bags incubated inside containers. Synthetic fiber bags may be useful in comparing digestibility between diets; however, caution is needed in evaluating such data in absolute terms.

Animal Feed↗

PubMed2004

[The quantitative analysis of protein particles of erythrocyte membrane from Duchenne muscular dystrophy patients and the gene carriers].

OBJECTIVE: To study the changes of the intramembrane protein particles of erythrocyte from Duchenne muscular dystrophy (DMD) patients and the gene carriers and to explore the pathogenesis of DMD and the diagnostic value of erythrocyte freeze-fracture technology. METHODS: The fixed erythrocyte mass was treated to form replica membrane by means of the freeze-fracture technology. Then the replica membrane was observed and a picture was taken under electron microscope. The protein particles of extracellular face(EF) and protoplasmic face(PF) per square were counted. The statistical comparative analysis was performed. RESULTS: The protein particle counts of EF face and PF face of erythrocyte membrane from DMD patients and DMD carriers decreased obviously in comparison with the normal control group (P<0.001). CONCLUSION: The erythrocyte freeze-fracture electron microscopic technology may serve as a method for accessory examination of diagnosing DMD patients and a method for detecting DMD carriers. This investigation material supplies reliable evidence for the theory of the systemic membrane defect of DMD.

Erythrocyte Membrane↗

PubMed2004

[A probability analysis for HLA matching in adult stem cell transplantation treating nervous genetic diseases].

The aim of this study was to investigate the clinical feasibility of adult stem cell transplantation for lethal mono-gene inherited disease, Duchenne muscular dystrophy (DMD). A total of 30 blood samples from DMD patients were genotyped with HLA-A,-B and -DR alleles by means of polymerase chain reaction-reverse sequence specific oligonucleotide (PCR-RSSO). The HLA gene types in 30 DMD patients were compared with those of 668 unrelated donors from Umbilical Cord Blood Center of Guangdong Province and 34 910 unrelated donors from Chinese Bone Marrow Bank. The results showed that HLA gene of the DMD group was inherited in normal distribution. There was no striking difference of HLA-A, -B and -DR alleles expression between the DMD patients group and control healthy group. 25% of the DMD patients got suitable donors for stem cell transplantation, in which 15 patients found donors with >or= 5/6 HLA match at the Umbilical Cord Blood Center of Guangdong Province, i.e. occupying 50% of the total. Eight patients got 6/6 HLA matching donors at the Chinese Bone Marrow Bank, i.e. occupying 26% of the total. It is concluded that stem cells transplantation therapy for DMD patients is feasible, which will benefit these patients suffered from the lethal neuromuscular disease, and create a new way to treat this tough nervous system disease.

Adolescent↗

PubMed1991

Central benzodiazepine receptors: in vitro efficacies and potencies of 3-substituted 1,4-benzodiazepine stereoisomers.

3-Acyloxy-, 3-methoxy-, and 3-alkyl-substituted derivatives of the benzodiazepine (BZ) agonist desmethyl-diazepam (DMD) were resolved, and the stereochemical properties of binding to central BZ receptors were investigated in synaptosomal membrane preparations of rat brain. Decreasing potency and stereoselectivity of 3-methyl, 3-ethyl, and 3-isopropyl derivatives in displacement of [3H]diazepam binding can be attributed to differential susceptibilities for steric hindrance of 3-axial versus 3-equatorial substituents of the binding conformation M. Chirality in the alpha-methyl-beta-phenyl-propionic acyl moiety of oxazepam, the 3-OH-derivative of DMD, was noncritical in binding, whereas the beta-phenyl substituent selectively increased the binding of the 3S-stereoisomer. Changing the pH from 7.4 to 5.6 significantly increased the IC50 of (3R)-oxazepam acetate but not those of (3R)-methyl-DMD and diazepam. Binding data led to a steric model of the BZ binding site with the postulation of an additional hydrogen-bond-donating moiety, probably histidine in the "ceiling" of the receptor cavity, that binds the 3-carbonyloxy groups and hinders the 3-alkyl ones. In vitro efficacies of 3-substituted BZs were estimated by allosteric binding interactions within the gamma-aminobutyric acidA (GABAA) receptor-ionophore complex. Non-equilibrium enhancement of t-butyl-bicyclophosphoro[35S]thionate binding by the BZ agonist oxazepam was stereoselectively antagonized by (3S)-oxazepam-(S)-alpha-methyl-beta-phenyl-propionate, suggesting a mixed agonist-antagonist character. GABA enhanced the [3H]diazepam-displacing potencies of the 3S-enantiomers of the acetate, hemisuccinate, and (S)-alpha-methyl-beta-phenyl-propionate esters of oxazepam by a factor of about 1.5-1.6, whereas the GABA shifts for 3R-esters were about 1.2. UV affinity labeling with flunitrazepam resulted in a significantly smaller decrease in the displacing potency of (3R)-oxazepam acetate than in that of the 3S-enantiomer. GABA shifts of successively 3-methylated DMD derivatives were also compared. The GABA shifts of DMD and its (3S)-methyl and 3,3-dimethyl derivatives were all characteristic of full agonists (2.4-2.7), whereas that of (3R)-methyl-DMD was 1.5. The 3-methoxy enantiomers of DMD displayed stereoselectivity and GABA shift values intermediate between those of 3-methyl and 3-acetoxy derivatives. These allosteric interactions suggest that 3-carbonyloxy derivatives in general, as well as (3R)-BZ enantiomers bound with axial 3-alkyl and 3-alkyloxy groups, decrease the agonist efficacies of 1,4-BZs to modulate the GABAA receptor complex.

Allosteric Regulation↗

PubMed1991

[Analysis of deletion mutations of the dystrophin gene by the multiplex polymerase chain reaction method in the diagnosis of Duchenne muscular dystrophy].

The 33 patients suffering from the Duchenne muscular dystrophy (DMD), 7 healthy donors and a DMD risk family were studied by means of polymerase multiplex chain reaction (MPCR) with 6 oligoprimer pairs for 6 different exons of dystrophin gene. The deletions varying in sizes from 1 to 6 exons were detected in 12 out of 33 DMD patients studied (36.3%). The prenatal diagnosis of DMD was carried out by chorionic villus biopsy on the 1st trimester of pregnancy. Contrary to earlier findings, in elder brother with sever DMD manifestation, no visible deletion was detected in the DNA sample from the male foetus and thus the diagnosis of DMD in foetus was rejected. The perspectives of MPCR in pre and postnatal diagnosis of DMD are discussed.

Chromosome Deletion↗

PubMed1990

Deletion mapping of Aland Island eye disease to Xp21 between DXS67 (B24) and Duchenne muscular dystrophy.

Aland Island Eye Disease (AIED) is an X-linked form of ocular hypopigmentation--also known as Forsius-Eriksson, or type 2, ocular albinism--in which affected males demonstrate subnormal visual acuity, protanomalous red-green colorblindness, axial myopia, astigmatism, hypoplasia of the fovea, and hypopigmentation of the fundus. A patient has previously been described who, in addition to AIED, manifested a contiguous gene syndrome which included congenital adrenal hypoplasia (AHC), glycerol kinase deficiency (GKD), and Duchenne muscular dystrophy (DMD). In the present paper report we report the molecular genetic analysis of his deletion. Initially, multiplex polymerase-chain-reaction amplification was used to screen for a DMD-locus deletion which was then further characterized, using DMD cDNA and genomic probes, via Southern blot analysis. The deletion includes the region encompassed by probes C7 (DXS28) and DMD cDNA 8. Probes B24 (DXS67) and DMD cDNA 5b-7 show normal hybridization patterns and appear to flank the deletion, while the DMD cDNA 8 detects a junction fragment. Molecular genetic techniques have mapped the deletion in this patient to the subbands Xp21.3-21.2, between DXS67 and DMD.

Albinism, Ocular↗

PubMed1989

[Strategy for molecular diagnosis of Duchenne muscular dystrophy: alleles frequency in RFLPs detected with X-linked probes in normal Japanese].

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder. Recently it has been suggested that the protein named "dystrophin" is not produced in the DMD muscle because of their mutant of defective DMD gene. Recent molecular studies using subclones from the DMD-cDNA as probes revealed a DNA deletion in about a half of the DMD patients. Since not all patients showed deletion, segregation analysis with restriction fragment length polymorphisms (RFLPs) is still necessary and important for diagnosis not only patients but female carriers as well. Therefore, we tried to detect RFLPs with the use of many probes localized within and/or flanked with the DMD gene and made a protocol for the diagnosis with our RFLP data. Among 50 normal Japanese females, the frequencies of rare alleles which identified with enzyme/probe combinations in each were as follows (RFLPs practically available for diagnosis are underlined): 0.38 for p782/EcoRI; 0.14 for p99-6/Pst I: 0.45 for pJ66-HI/Pst I: 0.16 for pERT87-30/Bgl II; 0.44 for 87-15/Xmn I: 0.07 for 87-15/Taq I; 0.33 for 87-8/Taq I; 0.44 for 87-1/Xmn I; 0.45 for 87-1/Mva I; 0.43 for Xj-1.1/Taq I; 0.34 for 754-11/EcoR I; 0.41 for 11.28/Taq I. Some of our results were different from the Caucasian both on the allele frequencies and the restriction fragment length. We proposed a diagnostic protocol of DMD and it's carriers in Japan. Firstly, segregation analysis should be performed with five different combinations of double probe/enzyme, such as Yj-1,.1/L1.28/Taq I, ERT87-1/87-15/Xmn I, 87-1/Mva I, J66-HI/99-6/Pst I, and 782/754-11/EcoR I.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1988

Becker and Duchenne muscular dystrophy: a comparative morphological study.

It is important to be able to clearly differentiate between Duchenne (DMD) and Becker (BMD) muscular dystrophies in early childhood in order to offer more accurate prognostic information to parents. In response to this need, biopsies from BMD and DMD patients were compared to see which features, if any, allowed a differentiation to be made. Fifteen biopsies of vastus lateralis muscle from boys with the mild (BMD) X-linked muscular dystrophy were compared with 19 biopsies from patients with the severe (DMD) form using a variety of histochemical and morphometric parameters. Both forms showed many similarities including increases in fibre variation, percentages of Type 1 fibres, internal nuclei counts, split and fragmented fibres and groups of fibres attempting regeneration. Hypercontracted and necrotic fibres, interstitial inflammatory cells and endomysial connective tissue were more commonly increased in DMD. Fibre hypertrophy was initially prominent, particularly in DMD boys until 5 years of age and in BMD patients until approximately 10 years, thereafter the mean fibre sizes became smaller than normal. Type 2B deficiency was again common in DMD as well as occurring in some BMD cases. Nuclear aggregates and small group atrophy were more likely to be found in BMD. In the absence of morphological criteria to accurately discriminate between DMD and BMD, classification of young affected males with muscular dystrophy into one or other groups, remains a difficulty in the first decade of life.

Adolescent↗

PubMed1980

Duchenne muscular dystrophy: systematic neonatal screening and earlier detection of carriers.

Systematic neonatal screening programme for DMD has been set up since June 1975. Constant and specific SCK increase in DMD newborn can be found on whole dried blood between the 5th and 8th day after birth. The amount of false positives is small : 1,6%. At the first control, DMD diagnosis is very probable and is made certain by EMG and muscle microscopic observations. For a period of 3 years and 6 months, we have achieved 138 579 screening tests, and 12 DMD were found, among 71 091 boys (1/5 929 male births). Genealogical data from 11 families out of the 12 lead to identify 93 women relatives as possible carriers; 23 of them are menstruating women who benefit by recognition and receive genetic information several years before the DMD clinical diagnosis in the first family's proband could have been done. Systematic neonatal screening programme for DMD seems to be a means to reduce the incidence of DMD to the theoretical mutation cases.

Female↗

PubMed1998

Nutritional aspects of neuromuscular diseases.

Evidence suggests that individuals with DMD have reduced skeletal development, including decreased linear growth and bone mineral density, compared to normal subjects. Despite their reduced muscle mass, a high percentage of DMD patients are overweight. Body composition measurements can assist with monitoring changes in fat mass and skeletal muscle mass as the disease progresses. Weight management in overweight DMD patients is indicated because excess adiposity burdens mobility and breathing, but only one study in two DMD patients has documented that weight reduction can be done safely. In the latter stages of the disease most DMD subjects become underweight because of an acceleration in skeletal muscle protein degradation relative to its synthesis. Studies of energy, protein and branched chain amino acid supplementation in DMD have yielded promising but inconclusive results, and more well-designed studies are needed in this area. Although there is currently no cure for DMD, studies on the role of nutritional therapy in increasing the quality of life in these patients are urgently needed. Studies in adults with various SP-NMDs indicate a reduction in fat-free mass and an increase in fat mass relative to controls. The newly developed method of air displacement plethysmography for measuring body composition is ideally suited for SP-NMD subjects because it requires very little effort and the measurement procedure is relatively fast. Dual energy x-ray absorptiometry technology has been proposed for distinguishing myogenic from neurogenic SP-NMDs from calculation of the fat-to-lean soft tissue ratio, which is higher in patients with myogenic muscular atrophy. Studies on the energy metabolism of ambulatory SP-NMD subjects indicate that their basal metabolic rate is either similar to or slightly lower than controls, but 24-hour energy expenditure is about 25% lower than controls. This reduction in 24-hour energy expenditure is due to a reduction in physical activity in SP-NMD. Studies examining the roles of energy expenditure, physical activity, and diet in the development of adiposity and risk for secondary chronic diseases in SP-NMD subjects are currently underway.

Adolescent↗

PubMed2023

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons-DMD exons 45, 51, and 53-which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

AAV↗

PubMed2024

Identifying inversions with breakpoints in the Dystrophin gene through long-read sequencing: report of two cases.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, with large deletions being the most common type of mutation. Inversions involving the DMD gene are a less frequent cause of the disorder, largely because they often evade detection by standard diagnostic methods such as multiplex ligation probe amplification (MLPA) and whole exome sequencing (WES). CASE PRESENTATION: Our research identified two intrachromosomal inversions involving the dystrophin gene in two unrelated families through Long-read sequencing (LRS). These variants were subsequently confirmed via Sanger sequencing. The first case involved a pericentric inversion extending from DMD intron 47 to Xq27.3. The second case featured a paracentric inversion between DMD intron 42 and Xp21.1, inherited from the mother. In both cases, simple repeat sequences (SRS) were present at the breakpoints of these inversions. CONCLUSIONS: Our findings demonstrate that LRS is an effective tool for detecting atypical mutations. The identification of SRS at the breakpoints in DMD patients enhances our understanding of the mechanisms underlying structural variations, thereby facilitating the exploration of potential treatments.

Humans↗

PubMed1998

Paternal inheritance or different mutations in maternally related patients occur in about 3% of Duchenne familial cases.

Duchenne dystrophy (DMD) is an X-linked lethal condition which affects 1 in 3,500 boys. The DMD gene is deleted in about 60-65% of patients while in the remaining 35-40% the condition is caused by point mutations, small insertions, or duplications. We have ascertained 967 DMD families (680 isolated and 287 familial cases). Screening for deletions showed a molecular deletion in 383 among 615 (62.3%) analyzed cases. However, 10 families were unusual: In 7 of them, 2 or more DMD patients were related through paternal lines while in 3 others, affected boys related through maternal lines carried different mutations or originated through independent new mutation events. The finding of 10 atypical genealogies, which represent about 1% of the sample (10/967) or about 3% of familial cases (10/287) is higher than we would expect by chance. Even so, it is an underestimate because screening of mutations in all the affected DMD relatives from each genealogy is not done in many of the familial cases. It suggests that other mechanisms (such as transposon-like elements, for example) could be responsible for a higher genomic instability leading to novel mutations as reported previously by us and others in DMD and in other genetic disorders such as hemophilia and inherited peripheral neuropathies. On the other hand, it shows the importance of testing all affected patients within each genealogy to prevent possible mistakes in carrier detection, genetic counseling, and prenatal diagnosis.

Child↗

PubMed2006

Screening for conditions that do not meet the Wilson and Jungner criteria: the case of Duchenne muscular dystrophy.

In this manuscript, I examine four overlapping policy and ethical issues regarding screening newborns (and infants) for Duchenne muscular dystrophy (DMD). First, what are the risks and benefits of expanding newborn screening (NBS) to include DMD? Second, if NBS were to expand to include DMD, should it require informed consent? Third, should NBS for DMD be limited to boys? Why or why not? Fourth, when is the ideal timing for screening (prenatal, newborn, or later in infancy) and what factors influence this determination? I argue that decisions about when, how, and whom to test reflect a tension between maximizing uptake and diagnosis versus maximizing autonomy and choice with respect to genetic information. I conclude that screening for DMD is a valid moral option, but not as part of the mandatory NBS population program. Rather, I propose that screening for DMD should be offered only on a voluntary basis beyond the newborn period. I support offering this screening to families of young boys and girls to ensure that all children and their families can benefit from early diagnosis and its reproductive implications. A rigorous consent process will be necessary to ensure that the decision whether or not to test is a voluntary and informed choice.

Genetic Testing↗

PubMed1983

Abnormalities of erythrocytes in Duchenne muscular dystrophy.

Erythrocytes from patients with Duchenne muscular dystrophy (DMD) were studied in relation to the extracellular calcium ion concentration. The shape of fresh erythrocytes in DMD was normal and not affected by Ca++. When DMD erythrocytes were stored in buffer solution with Ca++, however, the rate of the shape change over time was enhanced compared with that of cells from normal controls. The calcium content of DMD erythrocytes stored in buffer solution with Ca++ and dextrose was also two and one-half times that of control cells. In contrast, when DMD erythrocytes were stored in buffer solution with dextrose but without Ca++, no differences from controls were observed. The adenosine triphosphate content of DMD erythrocytes stored in the buffer solution was not affected by Ca++ concentration.

Adenosine Triphosphate↗

PubMed1978

Doxepin kinetics.

The kinetics of doxepin (DOX) hydrochloride were studied in 7 volunteers after the oral administration of 75 mg. Peak plasma concentrations of DOX ranged from 8.8 to 45.8 ng/ml and were reached within 4 hr. The disappearance of DOX was biphasic and followed first-order kinetics. The mean DOX half life (t1/2) was 16.8 hr and in individuals ranged from 8.2 to 24.5 hr. The mean apparent volume of distribution was 20.2 L/kg and ranged from 9.1 to 33.3 L/kg. The estimated first-pass metabolism of DOX ranged from 55% to 87% of the oral dose assuming complete absorption. Significant quantities of the metabolite desmethyldoxepin (DMD) were produced. Peak levels of DMD ranged from 4.8 to 14.5 ng/ml and were reached between 2 and 10 hr after administration. The mean t1/2 of DMD was 51.3 hr and in individuals ranged from 33.2 to 80.7 hr. There was no correlation between the DOX and DMD t1/2s. The amount of DMD produced correlated with the plasma concentration of DOX and appears to explain the correlation between the steady-state concentrations of DOX and DMD in patients given DOX.

Adult↗

PubMed2002

Altered regional brain glucose metabolism in Duchenne muscular dystrophy: a pet study.

The basis for cognitive impairment in Duchenne muscular dystrophy (DMD) is not well understood but may be related to abnormal expression of dystrophin in brain. The aim of this study was to determine whether regional brain glucose metabolism is altered in children with DMD and whether such metabolic disturbances are localized to regions shown to be normally rich in dystrophin expression. Ten boys (mean age, 11.8 years) with DMD and 17 normal adults as a control group (mean age, 27.6 years) underwent 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography (PET) and neuropsychological evaluation. The PET data were analyzed by statistical parametric mapping (SPM). The SPM analysis showed five clusters of decreased glucose metabolism in children with DMD, including the medial temporal structures and cerebellum bilaterally and the sensorimotor and lateral temporal cortex on the right side. At the voxel level, significant glucose hypometabolism was found in the right postcentral and middle temporal gyri, uncus, and VIIIB cerebellar lobule, as well as in the left hippocampal gyrus and cerebellar lobule. The neuropsychological profile of the DMD group revealed borderline nonverbal intellectual functioning, impaired manual dexterity bilaterally, borderline cognitive functioning, and internalizing behavioral difficulties. Our findings demonstrate region-specific hypometabolism, as well as cognitive and behavioral deficits in DMD children. As the regions showing hypometabolism on PET include those normally rich in dystrophin expression, it will be important to determine whether the hypometabolic regions also show cytoarchitectural abnormalities related to the lack of dystrophin.

Adolescent↗