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[Myocardial involvement in carrier states for
Duchenne muscular dystrophy. A rare cause of supraventricular
arrhythmia]
Ruchardt A; Eisenlohr H; Lydtin H
Medizinische Klinik, Krankenhauses des Landkreises
Starnberg.
Dtsch Med Wochenschr (Germany) Jul 31 1998, 123 (31-32)
p930-5
HISTORY AND CLINICAL FINDINGS: Two women, both aged 54
years, were admitted because of supraventricular arrhythmias
of recent onset. Patient 2 was also in heart failure. Male
family members of both patients were known to have Duchenne's
muscular dystrophy, of which one had died.
INVESTIGATIONS: The electrocardiogram of patient 1
demonstrated atrial fibrillation. Patient 2 had a raised serum
creatine kinase concentration and increased pulmonary marking
in the chest radiogram. Patient 1 had normal findings on left
heart catheterization, but immunohistochemical analysis of a
myocardial biopsy revealed dystrophin mosaic with 20%
dystrophin-negative fibres. Patient 2 had a reduced ejection
fraction and 80% dystrophin-negative fibres.
DIAGNOSIS, TREATMENT AND COURSE: Myocardial involvement in
the carrier state for Duchenne's muscular dystrophy having
been demonstrated in both women, patient 1 received
antihypertensive treatment while patient 2, who was in cardiac
failure, was given diuretics, ACE-inhibitor and beta-receptor
blockers.
CONCLUSION: Cardiomyopathy in carriers of Duchenne's
muscular dystrophy is a rare cause of supraventricular
arrhythmias. The cause can be confirmed by immunochemical
analysis of an endomyocardial biopsy.
Nine-year follow-up study of heart rate variability
in patients with Duchenne-type progressive muscular
dystrophy.
Yotsukura M; Fujii K; Katayama A; Tomono Y; Ando H; Sakata K;
Ishihara T; Ishikawa K
The Second Department of Internal Medicine, Kyorin University
School of Medicine, Tokyo, Japan.
Am Heart J (United States) Aug 1998, 136 (2)
p289-96
OBJECTIVES: The purpose of this study was to investigate
the progression of autonomic dysfunction in patients with
Duchenne-type progressive muscular dystrophy (DMD) over time
by using heart rate variability.
BACKGROUND: Although previous studies suggest the presence
of autonomic dysfunction in patients with DMD, the precise
cause is not known. On the other hand, it is well known that
analysis of heart rate variability provides a useful,
noninvasive means of quantifying autonomic activity. High
frequency power is determined predominantly by the
parasympathetic nervous system, whereas low frequency power is
determined by both the parasympathetic and sympathetic nervous
systems.
METHODS AND RESULTS: Frequency and time domain analyses of
heart rate variability during ambulatory electrocardiographic
monitoring were performed in 17 patients with DMD over a
9-year period. At the time of entry, the mean patient age was
11 years and the mean Swinyard-Deaver stage was 4. In the
first year, high frequency power was significantly lower and
the ratio of low frequency to high frequency was significantly
higher in patients with DMD than in the normal control
subjects. These differences become significantly greater as
the disease progressed. At the time of entry, low and high
frequency powers increased at night in both groups. However,
over time, high and low frequency powers at night tended to
decrease. All of the time domain parameters were significantly
lower in the patients with DMD at all time points compared
with the normal control subjects.
CONCLUSIONS: We concluded that DMD patients have either a
decrease in parasympathetic activity, an increase in
sympathetic activity, or both as their disease progresses.
Spinal instrumentation for Duchenne's muscular
dystrophy: experience of hypotensive anaesthesia to minimise
blood loss
Fox HJ; Thomas CH; Thompson AG
Birmingham Orthopaedic Spinal Service, England.
J Pediatr Orthop (United States) Nov-Dec 1997, 17 (6)
p750-3
Nineteen patients with Duchenne's muscular dystrophy
underwent segmental spinal instrumentation and posterior
fusion between 1989 and 1994. The indication for surgery was
loss of the ability to walk and development of scoliosis with
sitting discomfort. Preoperative assessment included
evaluation of pulmonary function. Average age at operation was
12.5 years. Instrumentation and fusion extended from upper
thoracic levels to L-5 or the sacrum. A Hartshill rectangle
was used in all cases, with banked allograft bone. Severe
intraoperative blood loss was avoided by use of hypotensive
anaesthesia. Peroperatively, systolic blood pressure was
maintained between 75 and 85 mm Hg. Average blood loss was
1,246 ml (range, 400-3,100) or 30% of estimated total blood
volume. Average transfusion requirements were 3 units of
packed cells. Postoperative analgesia was provided by infusion
via an epidural catheter. There were no postoperative wound or
chest infections. Three patients required catheterisation for
urinary retention. Postoperatively patients were fitted with a
Neofract jacket to allow early mobilisation and discharge.
Mean postoperative length of stay was 16 days. Posterior
spinal fusion by using the Hartshill rectangle provided good
correction and fixation. Hypotensive anaesthesia permitted
surgery to be performed rapidly in a relatively dry field and
avoided the complications of severe intraoperative blood loss
and massive transfusion.
Duchenne muscular dystrophy: a model for studying
the contribution of muscle to energy and protein
metabolism.
Hankard R
Centre d'investigation clinique, Hopital Robert-Debre, Paris,
France.
regis.hankard@rdb.ap-hop-paris.fr
Reprod Nutr Dev (France) Mar-Apr 1998, 38 (2)
p181-6
Duchenne muscular dystrophy (DMD) is associated with a
dramatic muscle mass loss. We hypothesized that DMD would be
associated with significant changes in both energy and protein
metabolism. We studied the resting energy expenditure (REE) in
DMD and control children using indirect calorimetry, and their
protein metabolism using an intravenous infusion of leucine
and glutamine labeled with stable isotopes. In spite of a 75%
muscle mass loss in the DMD children, the REE only decreased
by 10%. DMD was associated with increased leucine oxidation
but neither protein degradation nor protein synthesis were
different from that of the controls. In contrast, whole body
turnover of glutamine, an amino acid mainly synthesized in the
muscle, was significantly decreased. These studies emphasized
the quantitatively poor contribution of muscle to energy and
protein metabolism in children. The qualitative impact of
muscle mass loss on amino acid metabolism (glutamine) offers a
fascinating field of research for the next few years and has
therapeutic potential. (24 Refs.)
The molecular basis of activity-induced muscle
injury in Duchenne muscular dystrophy.
Petrof BJ
Department of Medicine, Royal Victoria Hospital, McGill
University, Montreal, Quebec, Canada.
Mol Cell Biochem (Netherlands) Feb 1998, 179 (1-2)
p111-23
Duchenne muscular dystrophy (DMD) is the most common of the
human muscular dystrophies, affecting approximately 1 in 3500
boys. Most DMD patients die in their late teens or early
twenties due to involvement of the diaphragm and other
respiratory muscles by the disease. The primary abnormality in
DMD is an absence of dystrophin, a 427 kd protein normally
found at the cytoplasmic face of the muscle cell surface
membrane. Based upon the predicted structure and location of
the protein, it has been proposed that dystrophin plays an
important role in providing mechanical reinforcement to the
sarcolemmal membrane of muscle fibers. Therefore, dystrophin
could help to protect muscle fibers from potentially damaging
tissue stresses developed during muscle contraction. In the
present paper, the nature of mechanical stresses placed upon
myofibers during various forms of muscle contraction are
reviewed, along with current lines of evidence supporting a
critical role for dystrophin as a subsarcolemmal
membrane-stabilizing protein in this setting. In addition, the
implications of these findings for exercise programs and other
potential forms of therapy in DMD are discussed. (93
Refs.)
Social adjustment in adult males affected with
progressive muscular dystrophy.
Eggers S; Zatz M
Centro de Miopatias, Departamento de Biologia, Universidade
de Sao Paulo, Brazil
saeggers@usp.br
Am J Med Genet (United States) Feb 7 1998, 81 (1)
p4-12
Adult male patients affected with Becker (BMD, N = 22),
limb girdle (LGMD, N = 22) and facioscapulohumeral (FSHMD, N =
18) muscular dystrophy were interviewed to assess for the
first time how the disease's severity and recurrence risk (RR)
magnitude alter their social adjustment. BMD (X-linked
recessive) is the severest form and confers an intermediate RR
because all daughters will be carriers, LGMD
(autosomal-recessive) is moderately severe with a low RR in
the absence of consanguineous marriage, and FSHMD
(autosomal-dominant) is clinically the mildest of these three
forms of MD but with the highest RR, of 50%. Results of the
semistructured questionnaire [WHO (1988): Psychiatric
Disability Assessment Schedule] showed no significant
difference between the three clinical groups, but more
severely handicapped patients as well as patients belonging to
lower socioeconomic levels from all clinical groups showed
poorer social adjustment. Taken together, myopathic patients
displayed intermediate social dysfunction compared to controls
and schizophrenics studied by Jablensky [1988: WHO Psychiatric
Disability Assessment Schedule]. Since the items of major
dysfunction proportion among myopathic patients concern
intimate relationships (70%), interest in working among those
unemployed (67%), and social isolation (53%), emotional
support and social and legal assistance should concentrate on
these aspects. Interestingly, the results of this study also
suggest that high RRs do not affect relationships to the
opposite sex.
[Genetic diagnosis of Duchenne/Becker muscular
dystrophy; clinical application and problems]
Takeshima Y
Department of Pediatrics, Kobe University School of
Medicine.
No To Hattatsu (Japan) Mar 1998, 30 (2) p141-7
Duchenne/Becker muscular dystrophies (DMD/BMD) are the most
common inherited muscular disease and caused by mutations in
the dystrophin gene. A half to two-thirds of DMD and BMD
patients carry deletions (usually of several kilobases of
genomic DNA). The clinical progression in DMD and BMD patients
with deletions can be predicted in 92% of cases based on
whether the deletion maintains or disrupts the translational
reading frame (frame-shift hypothesis). However, some
exceptional cases have been reported in which some
posttranscriptional modifications were suggested, such as
alternative splicing and reinitiation of translation. Splicing
mutation is one kind of mutations of dystrophin gene, and
usually induced by a small mutation of exon-intron boundary
sequence. However, intraexonal small mutation also induces
exon skipping, due to disruption of an exon recognition
sequence, which is an intraexonal sequence and necessary for
splicing of the upstream intron. Carrier diagnosis is one of
the important clinical application of genetic diagnosis. In
the case of DMD/BMD with deletions of the dystrophin gene,
carrier diagnosis is difficult because of the existence of
normal X chromosome. In these cases a linkage analysis is
useful, and in some cases non-carriers can be directly
diagnosed on the basis of microsattelite polymorphism detected
in deleted region of patient. For the molecular diagnosis of
DMD/BMD it is important to analyze not only at the genomic DNA
level, but also at the mRNA, protein, and clinical levels. And
the relationship between the molecular abnormality and
clinical phenotype should be examined, especially
extramuscular symptoms such as heart failure and mental
retardation.
[Detection of mutation in dystrophin gene in
Duchenne muscular dystrophy--multiplex PCR and Southern blot
analysis]
Kawamura J
Department of Internal Medicine, National Higasisaitama
Hospital.
Nippon Rinsho (Japan) Dec 1997, 55 (12) p3126-30
The genetic defect responsible for Duchenne muscular
dystrophy (DMD) can be identified as a partial deletion of the
dystrophin gene in 50% of cases, or as a partial duplication
in a further 10%. Multiplex PCR has been applied to screening
of mutations in dystrophin gene, and it can identify 98% of
deletions detected by Southern blot analysis. However, PCR
cannot be available for quantifying DNA, so that detection of
carrier status or duplication cannot be identified by
multiplex PCR. Quantitative analysis of Southern blot
hybridization is the most widely used and reliable method for
detection of carrier and duplication mutation in dystrophin
gene, but this method is a technically demanding procedure.
(10 Refs.)
Scoliosis in Duchenne muscular dystrophy : aspects
of orthotic treatment.
Heller KD; Forst R; Forst J; Hengstler K
Orthopaedic Department, University Clinic RWTH Aachen,
Germany.
Prosthet Orthot Int (Denmark) Dec 1997, 21 (3)
p202-9
The x-linked Duchenne muscular dystrophy (DMD) is the most
frequent generalized muscle disorder arising from a lack of
the sarcolemmic protein "dystrophin". Patients with DMD
develop in the majority a progressive scoliosis when they
cease walking and/or standing at the age of 10 years and
become confined to a wheelchair. Increasing muscle weakness
leads to a progression of the curvature, the pelvic tilt and
problems in sitting. Together with the simultaneous
progressive weakness of the respiratory muscles a restrictive
pulmonary insufficiency will occur. Surgical stabilization of
the spine (> 20 degrees Cobb, forced vital capacity >
35%) by an adequate multisegmental instrumentation enabling
early mobilization is now the treatment of choice. However,
orthotic treatment may offer an acceptable compromise in
exceptional cases, if the patient rejects surgical
intervention or is in the late (inoperable) stages of the
disease. Such a treatment is superior to a primary sitting
support provision with insufficient possibilities of
correction. The authors' experiences with 48 scoliosis
orthoses made for 28 patients with DMD are reported. A "double
plaster" cast has emerged as the best method to optimize
adaption, especially in severe curvatures and the time taken
for manufacturing the orthosis. A great deal of experience,
patience and the consideration of the patients' individual
demands are inevitable for a successful orthotic
treatment.
Challenges in Duchenne muscular dystrophy.
Davies KE
Department of Biochemistry, University of Oxford, UK.
kdavies@bioch.ox.ac.uk
Neuromuscul Disord (England) Dec 1997, 7 (8)
p482-6
The last seven years has witnessed an explosion in our
understanding of the muscular dystrophies. In the early 1980s,
prenatal diagnosis of Duchenne muscular dystrophy was
developed. The cloning of the gene, in 1996, resulted in a
better understanding of the disease process and led to the
identification of a novel complex at the membrane. This
information led to the cloning of other genes responsible for
the autosomally inherited dystrophies. As we approach the
millenium, the challenge is shifting to the development of
therapy of these diseases. This review, in honour of Professor
Alan Emery, explains how these advances have an impact in the
clinical management of patients and head the promise the
progress holds for the future. (47 Refs.)
Problems and potential for gene therapy in Duchenne
muscular dystrophy.
Kakulas BA
Australian Neuromuscular Research Institute, Perth,
Australia.
Neuromuscul Disord (England) Jul 1997, 7 (5)
p319-24
Hopes ran high that a cure for Duchenne muscular dystrophy
(DMD) would quickly follow the discovery of dystrophin by Lou
Kunkel and his group in the 1980's. Myoblast transplantation,
the favoured method of gene 'complementation', unfortunately
did not progress beyond the experimental stage. A more sober
approach to gene therapy followed using a variety of
transfection or direct methods to introduce the normal gene.
In view of these advances it is timely for the potential of
gene therapy for DMD to be considered in the light of the
disease process. It may be assumed that if dystrophin is
replaced muscle fibre necrosis will cease. For this purpose
expression of the gene should be continuous and expressed
throughout the body well before there are irreversible
changes. It would seem that gene therapy would not be
particularly helpful if this occurs when the muscle lesions
are near the end stage. If our objective is to retain
ambulation dystrophin must be replaced well before the end
stage. It should be kept in mind that even when the disorder
first becomes clinically apparent at the age of about 5 years,
muscle lesions are very advanced in the limb girdle groups.
Therefore, the best that may be hoped to achieve by gene
therapy at the age of 5 years would be to arrest the process
at that stage of involvement with the patient having permanent
but static weakness. Cardiac lesions are probably minimal at
this time. To improve life expectancy, the respiratory muscles
would need to be preserved. The enormous size of the gene is
another difficulty so that some thought has been given to the
introduction of a 'minigene' converting the clinical phenotype
from DMD to the more benign Becker phenotype with improved
life expectancy.
Improved adenoviral vectors for gene therapy of
Duchenne muscular dystrophy.
Hauser MA; Amalfitano A; Kumar-Singh R; Hauschka SD;
Chamberlain JS
Department of Human Genetics, University of Michigan Medical
School, Ann Arbor 48109-0618, USA.
Neuromuscul Disord (England) Jul 1997, 7 (5)
p277-83
We have been exploring the feasibility of gene therapy for
Duchenne muscular dystrophy by characterizing parameters
important for the design of therapeutic protocols. These
studies have used transgenic mice to analyze expression
patterns of multiple dystrophin vectors, and have been
accompanied by the development of viral vectors for gene
transfer to dystrophic mdx mouse muscle. Analysis of
transgenic mdx mice indicates that greater than 50% of the
fibers in a muscle group must express dystrophin to prevent
development of a significant dystrophy, and that low-level
expression of truncated dystrophins can function very well.
These results suggest that gene therapy of DMD will require
methods to transduce the majority of fibers in critical muscle
groups with vectors that express moderate levels of dystrophin
proteins. Strategies for the development of viral vectors able
to deliver dystrophin genes to muscle include the use of
muscle specific regulatory sequences coupled with deletion of
viral gene sequences to limit virus-induced immune rejection
of transduced tissues. These strategies should enable
production of adenoviral vectors expressing full-length
dystrophin proteins in muscle.
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