Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy.

Myoglobinuria is a frequent complication of metabolic myopathies and may also occur in Duchenne and Becker dystrophies but is not a typical sign of limb-girdle muscular dystrophy. We describe an unusual presentation of alpha-sarcoglycanopathy with myoglobinuria at the onset of the disease. The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics. He was admitted to the hospital and investigated for post-infectious nephritis, but further analysis revealed the presence of myoglobinuria. Immunohistochemistry on muscle tissue revealed absent expression of α-sarcoglycan confirmed by detection of a homozygous mutation in the alpha-sarcoglycan gene. Myoglobinuria has been previously reported four times in sarcoglycanopathies but only once in alpha-sarcoglycanopathy.

The present observation reinforces the idea that the myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy even as the only recognizable sign at the debut of the disease.

    Myoglobinuria
    BIOCHEMICAL

 is a frequent complication of

    metabolic myopathies
    DIAGNOSIS

 and may also occur in

    Duchenne
    DIAGNOSIS

 and

    Becker dystrophies
    DIAGNOSIS

 but is not a typical sign of

    limb-girdle muscular dystrophy
    DIAGNOSIS

. We describe an unusual presentation of

    alpha-sarcoglycanopathy
    DIAGNOSIS

 with

    myoglobinuria
    BIOCHEMICAL

 at the onset of the disease. The

    boy
    GENDER

 presented an

    episode of dark urine
    SYMPTOMS

, identified as

    presence of blood by a urine dipstick
    BIOCHEMICAL

, occurred 10 days after an episode of

    fever
    SYMPTOMS

 and

    sore throat
    SYMPTOMS

 treated with

    antibiotics
    NEG_FINDINGS

.

    He
    GENDER

 was admitted to the hospital and investigated for

    post-infectious nephritis
    DIAGNOSIS

, but further analysis revealed the presence of

    myoglobinuria
    BIOCHEMICAL

.

    Immunohistochemistry on muscle tissue
    PARACLINICAL

 revealed

    absent expression of α-sarcoglycan
    BIOCHEMICAL

 confirmed by detection of a

    homozygous mutation in the alpha-sarcoglycan gene
    GENETICS

.

    Myoglobinuria
    BIOCHEMICAL

 has been previously reported four times in

    sarcoglycanopathies
    DIAGNOSIS

 but only once in

    alpha-sarcoglycanopathy
    DIAGNOSIS

.

The present observation reinforces the idea that the

    myoglobinuria
    BIOCHEMICAL

 should be considered a manifestation of a

    primary sarcoglycanopathy
    DIAGNOSIS

 even as the only recognizable sign at the debut of the disease.

Myoglobinuria
myoglobinuria
presence of blood by a urine dipstick
myoglobinuria
absent expression of α-sarcoglycan
Myoglobinuria
myoglobinuria

metabolic myopathies
Duchenne
Becker dystrophies
limb-girdle muscular dystrophy
alpha-sarcoglycanopathy
post-infectious nephritis
sarcoglycanopathies
alpha-sarcoglycanopathy
primary sarcoglycanopathy


Why short stature is beneficial in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is caused by a genetic defect resulting in absent dystrophin, yet children are able to walk when small and young but lose this ability as they grow. The mdx mouse has absent dystrophin yet does not exhibit significant disability.

Allometric modeling of linearly increasing load per muscle fiber and stress on the sarcolemma with growth and exponential decline associated with loss of muscle fibers correlated with case studies and animal models of DMD.

Smaller species or breeds are predictably less affected than large as follows: mdx mice < small golden retriever muscular dystrophy (GRMD) dogs < large GRMD dogs < humans. Case reports of combined growth hormone and dystrophin deficiency show a relatively benign course of disease.

Future therapeutic trials in DMD might include specific growth inhibitors in combination with standard of care treatments to delay the clinical onset and reduce the severity of disease and disability.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is caused by a

    genetic defect resulting in absent dystrophin
    GENETICS

, yet

    children
    AGE

 are

    able to walk when small and young
    NEG_FINDINGS

 but lose this ability as they grow. The

    mdx
    DIAGNOSIS

 mouse has

    absent dystrophin
    BIOCHEMICAL

 yet does

    not exhibit significant disability
    NEG_FINDINGS

.

    Allometric modeling
    PARACLINICAL

 of

    linearly increasing load per muscle fiber
    SYMPTOMS

 and

    stress on the sarcolemma
    SYMPTOMS

 with growth and

    exponential decline
    SYMPTOMS

 associated with

    loss of muscle fibers
    SYMPTOMS

 correlated with case studies and animal models of

    DMD
    DIAGNOSIS

.

Smaller species or breeds are predictably less affected than large as follows:

    mdx mice
    AGE

 <

    small golden retriever muscular dystrophy (GRMD) dogs
    DIAGNOSIS

 <

    large GRMD
    DIAGNOSIS

 dogs <

    humans
    GENDER

. Case reports of

    combined growth hormone and dystrophin deficiency
    BIOCHEMICAL

 show a relatively

    benign course of disease
    NEG_FINDINGS

.

Future therapeutic trials in

    DMD
    DIAGNOSIS

 might include

    specific growth inhibitors in combination with standard of care treatments
    MEDICATION

 to delay the clinical onset and reduce the severity

    of disease and disability
    SYMPTOMS

.

able to walk when small and young
not exhibit significant disability
benign course of disease


Magnetic resonance spectroscopy and molecular studies in ornithine transcarbamylase deficiency novel mutation c.802A>G in exon 8 (p.Met268Val).

Ornithine transcarbamylase (OTC) deficiency, an X-linked, semidominant disorder, is the most common inherited de-fect in ureagenesis, resulting in hyperammonaemia type II. The OTC gene, localised on chromosome X, has been mapp-ed to band Xp21.1, proximate to the Duchenne muscular dystrophy (DMD) gene. More than 350 different mutations, including missense, nonsense, splice-site changes, small de-letions or insertions and gross deletions, have been describ-ed so far. Almost all mutations in consensus splicing sites confer a neonatal phenotype. Most mutations in the OTC gene are 'private' and are distributed throughout the gene with a paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7. They have familial origin or occur de novo. Even with sequencing of the entire reading frame and exon/intron boundaries, only about 80% of the mutations are detected in patients with proven OTC deficiency. The remainder probably occur within the introns or in regulatory domains. The authors present a 4-year-old boy with the unreported missense mutation c.802A>G. The nucleotide transition leads to amino acid substitution Met to Val at codon 268 of the OTC protein.

    Ornithine transcarbamylase (OTC) deficiency
    BIOCHEMICAL

, an

    X-linked
    GENETICS

,

    semidominant disorder
    GENETICS

, is the most common

    inherited
    GENETICS

 de-fect in ureagenesis, resulting in

    hyperammonaemia type II
    BIOCHEMICAL

. The

    OTC gene
    GENETICS

,

    localised on chromosome X
    GENETICS

, has been mapp-ed to

    band Xp21.1, proximate to the Duchenne muscular dystrophy (DMD) gene
    GENETICS

. More than 350 different mutations, including

    missense, nonsense, splice-site changes, small de-letions or insertions and gross deletions
    GENETICS

, have been describ-ed so far. Almost all

    mutations in consensus splicing sites
    GENETICS

 confer a

    neonatal
    AGE

 phenotype. Most

    mutations in the OTC gene are 'private'
    GENETICS

 and are

    distributed throughout the gene
    GENETICS

 with a

    paucity of mutation in the sequence encoding the leader peptide (exon 1 and beginning of exon 2) and in exon 7
    GENETICS

. They have

    familial origin
    GENETICS

 or occur

    de novo
    GENETICS

. Even with

    sequencing of the entire reading frame and exon/intron boundaries
    PARACLINICAL

, only about 80% of the mutations are detected in patients with

    proven OTC deficiency
    BIOCHEMICAL

. The remainder probably occur within the introns or in regulatory domains. The authors present a

    4-year-old
    AGE

    boy
    GENDER

 with the

    unreported missense mutation c.802A>G.
    GENETICS

 The

    nucleotide transition leads to amino acid substitution Met to Val at codon 268 of the OTC protein
    GENETICS

.


Coexistence of peripheral myelin protein 22 and dystrophin mutations in a chinese boy.

We describe a 10-year-old Chinese boy with features of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy (DMD).

Case report.

Weakness and mild sensory loss in the distal extremities, pes cavus, and nerve conduction findings suggested demyelinating neuropathy, while moderate calf pseudohypertrophy, proximal muscle weakness, a myopathic pattern on electromyography, and deficiency of dystrophin immunohistochemical staining on muscle biopsy indicated DMD. Genetic testing revealed a large deletion spanning exon 50 in the gene coding for dystrophin and duplications in the gene coding for peripheral myelin protein 22.

This is an interesting and very rare case of CMT type 1A comorbid with DMD. This results in an unusual phenotype and rapid deterioration of motor function. Usage of both target region capture and next generation sequencing is a powerful tool for predicting precisely the range of the large DNA fragment deletion in DMD.

We describe a

    10-year-old
    AGE

    Chinese
    ETHNICITY

    boy
    GENDER

 with

    features of Charcot-Marie-Tooth disease (CMT)
    SYMPTOMS

 and

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

.

    Weakness and mild sensory loss in the distal extremities
    SYMPTOMS

,

    pes cavus
    SYMPTOMS

, and

    nerve conduction findings
    PARACLINICAL

 suggested

    demyelinating neuropathy
    DIAGNOSIS

, while

    moderate calf pseudohypertrophy
    SYMPTOMS

,

    proximal muscle weakness
    SYMPTOMS

,

    a myopathic pattern
    SYMPTOMS

 on

    electromyography
    PARACLINICAL

, and

    deficiency of dystrophin immunohistochemical staining
    BIOCHEMICAL

 on

    muscle biopsy
    PARACLINICAL

 indicated

    DMD
    DIAGNOSIS

.

    Genetic testing
    PARACLINICAL

 revealed a

    large deletion spanning exon 50 in the gene coding for dystrophin and duplications in the gene coding for peripheral myelin protein 22.
    GENETICS

This is an interesting and very rare case of

    CMT type 1A comorbid with DMD
    DIAGNOSIS

. This results in an unusual phenotype and

    rapid deterioration of motor function
    SYMPTOMS

. Usage of both

    target region capture and next generation sequencing
    PARACLINICAL

 is a powerful tool for predicting precisely the range of the

    large DNA fragment deletion
    GENETICS

 in

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
demyelinating neuropathy
DMD
CMT type 1A comorbid with DMD
DMD


Assessment of a symptomatic Duchenne muscular dystrophy carrier 20 years after myoblast transplantation from her asymptomatic identical twin sister.

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.

Because it is due to a

    mutation on the X-chromosome
    GENETICS

,

    Duchenne muscular dystrophy
    DIAGNOSIS

 rarely affects

    women
    GENDER

, unless there is an

    unequal lyonisation of the X-chromosome containing the normal dystrophin gene
    GENETICS

. We report here the unique situation of a symptomatic

    Duchenne muscular dystrophy
    DIAGNOSIS

    woman
    GENDER

 who was

    transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago
    MEDICATION

.

    Specific dynamometry
    PARACLINICAL

 was performed to possibly detect a long-term effect of this

    cell therapy
    MEDICATION

. Long-term safety of

    myoblast transplantation
    MEDICATION

 was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.

Duchenne muscular dystrophy
Duchenne muscular dystrophy


Analysis using histograms of muscle CT images in patients with Duchenne muscular dystrophy.

We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with Duchenne muscular dystrophy, and this shape of the histogram will employ a new analytical method. CT images of the middle part of the thigh were acquired in a patient with Duchenne muscular dystrophy once a year from 6 to 11 years of age. Regions apparently corresponding to subcutaneous fat, bone and bone marrow were manually excluded, and the CT values were calculated to prepare histograms. His motor disability was also evaluated employing Vignos functional rating scale. A single peak was noted in the muscle CT value range in the histogram at the youngest age. The muscle-to-fat ratio in muscle decreased with the worsening of his disease disability level and the peak of the histogram shifted from the muscle to the fat CT value.

We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

, and this shape of the histogram will employ a new analytical method.

    CT images of the middle part of the thigh
    PARACLINICAL

 were acquired in a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 once a year

    from 6 to 11 years of age
    AGE

. Regions

    apparently corresponding to subcutaneous fat, bone and bone marrow
    SYMPTOMS

 were manually excluded, and the CT values were calculated to prepare histograms. His

    motor disability
    SYMPTOMS

 was also evaluated employing

    Vignos functional rating scale
    PARACLINICAL

. A single peak was noted

    in the muscle CT value range in
    SYMPTOMS

 the histogram at the

    youngest age
    AGE

. The

    muscle-to-fat ratio in muscle
    SYMPTOMS

 decreased with the worsening of his disease disability level and the peak of the histogram shifted from the

    muscle to the fat CT value
    SYMPTOMS

.


Molecular diagnosis of dystrophinopathies using a multi-technique analysis algorithm.

Dystrophinopathies are X-linked recessive neuromuscular diseases caused by mutations in the dystrophin gene. In this study we aimed to detect mutations within the dystrophin gene in DMD patients, to determine the carrier status of women, and to perform a prenatal diagnosis.

We analyzed 17 individuals from 2 unrelated families with a history of DMD. We used multiplex PCR, multiplex ligation-dependent probe amplification (MLPA), and short tandem-repeat (STR) segregation analysis to accurately detect and characterize the mutations and to identify the at-risk haplotype.

The selected methodology allowed for characterization of 2 single-exon out-of-frame deletions in affected patients. Nine of 13 women and a fetus were excluded from being carriers. Three recombination events were found and suggested that germline mosaicism had occurred in both families.

This methodology proved to be efficient for characterizing the disease-causing mutation in affected individuals and for assessing the carrier status in healthy relatives. These findings helped inform precise genetic counseling and contributed to characterization of the disease in the Argentine population.

    Dystrophinopathies
    DIAGNOSIS

 are

    X-linked recessive
    GENETICS

    neuromuscular diseases
    DIAGNOSIS

 caused by

    mutations in the dystrophin gene
    GENETICS

. In this study we aimed to detect

    mutations within the dystrophin gene
    GENETICS

 in

    DMD
    DIAGNOSIS

 patients, to determine the carrier status of

    women
    GENDER

, and to perform a

    prenatal diagnosis
    PARACLINICAL

.

We analyzed 17 individuals from

    2 unrelated families with a history of DMD
    FAMILY

. We used

    multiplex PCR
    PARACLINICAL

,

    multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

, and

    short tandem-repeat (STR) segregation analysis
    PARACLINICAL

 to accurately detect and characterize the mutations and to identify the

    at-risk haplotype
    GENETICS

.

The selected methodology allowed for characterization of

    2 single-exon out-of-frame deletions
    GENETICS

 in affected patients. Nine of 13

    women
    GENDER

 and a

    fetus were excluded from being carriers
    NEG_FINDINGS

. Three recombination events were found and suggested that

    germline mosaicism had occurred in both families
    FAMILY

.

This methodology proved to be efficient for characterizing the

    disease-causing mutation
    GENETICS

 in affected individuals and for assessing the carrier status in healthy relatives. These findings helped inform

    precise genetic counseling
    MEDICATION

 and contributed to characterization of the disease in the

    Argentine
    ETHNICITY

 population.

Dystrophinopathies
neuromuscular diseases
DMD

X-linked recessive
mutations in the dystrophin gene
mutations within the dystrophin gene
at-risk haplotype
2 single-exon out-of-frame deletions
disease-causing mutation


Cardiac resynchronization therapy in becker muscular dystrophy.

A 44-year-old male patient with known Becker muscular dystrophy and concomitant non-ischemic dilated cardiomyopathy presented to our department because of worsening heart failure and presyncope. Upon admission, the patient was in New York Heart Association functional class III despite optimal pharmacological treatment; his ECG showed sinus rhythm with left bundle branch block and a wide QRS complex. Non-sustained ventricular tachycardia was recorded during 24-hour Holter monitoring. A complete three-dimensional echocardiographic study was performed and documented the dilatation and concomitant hypertrabeculation of the left ventricle (LV), with severely depressed systolic LV performance (ejection fraction 20%), as well as mechanical dyssynchrony--mainly in terms of intraventricular delay. A biventricular cardioverter-defibrillator (CRT-D) was implanted in this patient, with the LV lead in a lateral vein and the right ventricular defibrillating lead in the apical part of the interventricular septum. Echocardiography-guided device programming was performed in order to achieve the optimal atrio-, inter-, and intraventricular resynchronization. The patient's clinical condition was substantially improved within one month after the implantation.

A

    44-year-old
    AGE

    male
    GENDER

 patient with known

    Becker muscular dystrophy
    DIAGNOSIS

 and concomitant

    non-ischemic dilated cardiomyopathy
    SYMPTOMS

 presented to our department because of

    worsening heart failure
    SYMPTOMS

 and

    presyncope
    SYMPTOMS

. Upon admission, the patient was in

    New York Heart Association functional class III
    SYMPTOMS

    despite optimal pharmacological treatment
    NEG_FINDINGS

; his

    ECG
    PARACLINICAL

 showed

    sinus rhythm with left bundle branch block and a wide QRS complex
    SYMPTOMS

.

    Non-sustained ventricular tachycardia
    SYMPTOMS

 was recorded during

    24-hour Holter monitoring
    PARACLINICAL

. A

    complete three-dimensional echocardiographic study
    PARACLINICAL

 was performed and documented the

    dilatation and concomitant hypertrabeculation of the left ventricle (LV)
    SYMPTOMS

, with

    severely depressed systolic LV performance (ejection fraction 20%)
    SYMPTOMS

, as well as

    mechanical dyssynchrony--mainly in terms of intraventricular delay
    SYMPTOMS

. A

    biventricular cardioverter-defibrillator (CRT-D) was implanted
    MEDICATION

 in this patient,

    with the LV lead in a lateral vein and the right ventricular defibrillating lead in the apical part of the interventricular septum
    MEDICATION

.

    Echocardiography-guided device programming
    MEDICATION

 was performed in order to achieve the optimal

    atrio-, inter-, and intraventricular resynchronization
    SYMPTOMS

. The patient's clinical condition was

    substantially improved
    SYMPTOMS

 within one month after the implantation.


Skin biopsy: a new tool to diagnose sarcoglycanopathy.

Muscular dystrophies are progressive, genetic disorders of muscle degeneration. The current gold standard for diagnosis is muscle biopsy or genetic studies. Muscle biopsy is an invasive procedure and genetic testing facilities are available only in a few centers. Thus, a diagnostic test that is easily available, simpler, and less invasive is desirable. Over the past 2 decades, skin biopsy has been evolving as a suitable option. Two cases of sarcoglycanopathy are described here, which have been correctly diagnosed by skin biopsy. Muscle biopsy has been used as the gold-standard diagnostic method. Skin biopsy can substitute for muscle biopsy as the preliminary diagnostic tool directing appropriate molecular testing. However, these results require validation in studies with an adequate sample size. This holds promise for the future when repeated biopsies will be required for evaluating protein rescue in trials of novel treatment options in these disorders.

    Muscular dystrophies
    DIAGNOSIS

 are

    progressive, genetic disorders of muscle degeneration
    DIAGNOSIS

. The current gold standard for diagnosis is

    muscle biopsy
    PARACLINICAL

 or

    genetic studies
    PARACLINICAL

.

    Muscle biopsy
    PARACLINICAL

 is an invasive procedure and genetic testing facilities are available only in a few centers. Thus, a diagnostic test that is easily available, simpler, and less invasive is desirable. Over the past 2 decades,

    skin biopsy
    PARACLINICAL

 has been evolving as a suitable option. Two cases of

    sarcoglycanopathy
    DIAGNOSIS

 are described here, which have been correctly diagnosed by

    skin biopsy
    PARACLINICAL

.

    Muscle biopsy
    PARACLINICAL

 has been used as the gold-standard diagnostic method.

    Skin biopsy
    PARACLINICAL

 can substitute for

    muscle biopsy
    PARACLINICAL

 as the preliminary diagnostic tool directing appropriate

    molecular testing
    PARACLINICAL

. However, these results require validation in studies with an adequate sample size. This holds promise for the future when repeated biopsies will be required for evaluating protein rescue in trials of novel treatment options in these disorders.


Ultra-widefield imaging of Duchenne muscular dystrophy-associated proliferative retinal vasculopathy improved with panretinal laser photocoagulation alone.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder whose ophthalmic associations most commonly consist of pigmentary fundus changes and scotopic electroretinogram abnormalities. A 23-year-old man with advanced DMD and associated cardiopulmonary compromise complaining of floaters presented with a striking retinal vasculopathy characterized by vitreous hemorrhage, neovascularization, capillary drop-out, and prominent saccular venular aneurysms diffusely throughout the fundus of both eyes. This vasculopathy was promptly treated with panretinal phocoagulation with marked improvement to at least 1 year. This report suggests that early identification and prompt treatment of DMD may be important in managing this condition.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked recessive genetic disorder
    GENETICS

 whose ophthalmic associations most commonly consist of

    pigmentary fundus changes
    SYMPTOMS

 and

    scotopic electroretinogram abnormalities
    SYMPTOMS

. A

    23-year-old
    AGE

    man
    GENDER

 with

    advanced DMD
    DIAGNOSIS

 and

    associated cardiopulmonary compromise
    SYMPTOMS

 complaining of

    floaters
    SYMPTOMS

 presented with a

    striking retinal vasculopathy
    SYMPTOMS

 characterized by

    vitreous hemorrhage
    SYMPTOMS

,

    neovascularization
    SYMPTOMS

,

    capillary drop-out
    SYMPTOMS

, and

    prominent saccular venular aneurysms diffusely throughout the fundus of both eyes
    SYMPTOMS

. This

    vasculopathy
    DIAGNOSIS

 was promptly treated with

    panretinal phocoagulation
    MEDICATION

 with

    marked improvement to at least 1 year
    SYMPTOMS

. This report suggests that early identification and

    prompt treatment
    MEDICATION

 of

    DMD
    DIAGNOSIS

 may be important in managing this condition.

Duchenne muscular dystrophy (DMD)
advanced DMD
vasculopathy
DMD

panretinal phocoagulation
prompt treatment


Dissecting the structure and mechanism of a complex duplication-triplication rearrangement in the DMD gene.

Pathogenic complex genomic rearrangements are being increasingly characterized at the nucleotide level, providing unprecedented opportunities to evaluate the complexities of mutational mechanisms. Here, we report the molecular characterization of a complex duplication-triplication rearrangement involving exons 45-60 of the DMD gene. Inverted repeats facilitated this complex rearrangement, which shares common genomic organization with the recently described duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) events; specifically, a 690-kb region comprising DMD exons from 45 to 60 was duplicated in tandem, and another 46-kb segment containing exon 51 was inserted inversely in between them. Taking into consideration (1) the presence of a predicted PRDM9 binding site in the near vicinity of the junction involving two inverted L1 elements and (2) the inherent properties of X-Y chromosome recombination during male meiosis, we proposed an alternative two-step model for the generation of this X-linked DMD DUP-TRP/INV-DUP event.

    Pathogenic complex genomic rearrangements
    GENETICS

 are being increasingly characterized at the nucleotide level, providing unprecedented opportunities to evaluate the complexities of mutational mechanisms. Here, we report the molecular characterization of a

    complex duplication-triplication rearrangement involving exons 45-60 of the DMD gene
    GENETICS

.

    Inverted repeats
    GENETICS

 facilitated this complex rearrangement, which shares common genomic organization with the recently described

    duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) events
    GENETICS

; specifically,

    a 690-kb region comprising DMD exons from 45 to 60 was duplicated in tandem, and another 46-kb segment containing exon 51 was inserted inversely in between them
    GENETICS

. Taking into consideration (1) the presence of a

    predicted PRDM9 binding site in the near vicinity of the junction involving two inverted L1 elements
    GENETICS

 and (2) the inherent properties of

    X-Y chromosome recombination
    GENETICS

 during

    male meiosis
    GENETICS

, we proposed an alternative two-step model for the generation of this

    X-linked DMD DUP-TRP/INV-DUP event
    GENETICS

.


[Two cases of Duchenne muscular dystrophy over 40 years after onset].

We report two 45 year old men with Duchenne muscular dystrophy. Case 1 showed a deleted exon 50 of the dystrophin gene by MLPA analysis, and Case 2 showed deleted exons 46-52. Both patients presented with severe weakness of the skeletal muscles and respiratory dysfunction, while cardiac involvement was mild and cognitive function was almost normal. The patients are able to shop at a mall, participate in activities, and attend hobbies, although they are bedridden with artificial respiration through tracheotomy. With the progress of the respiratory care and cardiac protective therapy, the prognosis of Duchenne muscular dystrophy has improved remarkably. At present, it is possible to survive over 40 years with maintenance of quality of life, if cardiac damage is not severe.

We report two

    45 year old
    AGE

    men
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

. Case 1 showed a

    deleted exon 50 of the dystrophin gene
    GENETICS

 by

    MLPA analysis
    PARACLINICAL

, and Case 2 showed

    deleted exons 46-52
    GENETICS

. Both patients presented with

    severe weakness of the skeletal muscles
    SYMPTOMS

 and

    respiratory dysfunction
    SYMPTOMS

, while

    cardiac involvement
    SYMPTOMS

    was mild
    NEG_FINDINGS

 and

    cognitive function was almost normal
    NEG_FINDINGS

. The patients are able to

    shop at a mall
    MEDICATION

,

    participate in activities
    MEDICATION

, and

    attend hobbies
    MEDICATION

, although they are

    bedridden
    MEDICATION

 with

    artificial respiration through tracheotomy
    MEDICATION

. With the progress of the

    respiratory care
    MEDICATION

 and

    cardiac protective therapy
    MEDICATION

, the prognosis of

    Duchenne muscular dystrophy
    DIAGNOSIS

 has improved remarkably. At present, it is possible to survive over 40 years with

    maintenance of quality of life
    SYMPTOMS

, if

    cardiac damage
    SYMPTOMS

 is not severe.

deleted exon 50 of the dystrophin gene
deleted exons 46-52

severe weakness of the skeletal muscles
respiratory dysfunction
cardiac involvement
maintenance of quality of life
cardiac damage

was mild
cognitive function was almost normal


A family with fragile X syndrome, Duchenne muscular dystrophy and ichthyosis transmitted by an asymptomatic carrier.

The human X chromosome carries regions prone to genomic instability: deletions in the Xp22.31 region, involving the steroid sulfatase gene (STS) cause X-linked ichthyosis; rearrangements in the Xp21.2 region are associated with Duchenne or Becker muscular dystrophies (DMD or BMD); and the Xq27.3 unstable region, containing the (CGG)n repeat expansion in the FMR1 gene is associated with fragile X syndrome. We report on a family with two affected boys, the elder diagnosed with fragile X syndrome, the younger with DMD, and both suffering from severe ichthyosis. The family was analyzed by polymerase chain reaction, multiplex ligation-dependent probe amplification and haplotype analysis. The mother proved to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the DMD gene and a FMR1 expansion. To the best of our knowledge, this is the first description of an asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on both long and short arms of the X chromosomes. The boy with fragile X syndrome has inherited a triple recombinant maternal X chromosome, this way inheriting the FMR1 expansion and ichthyosis, originating most probably from different maternal Xes and excluding the DMD gene deletion. The transmission of these extremely defective maternal chromosomes to the next generation involved several recombinations.

The

    human X chromosome
    GENETICS

 carries regions prone to

    genomic instability
    GENETICS

:

    deletions in the Xp22.31 region, involving the steroid sulfatase gene (STS)
    GENETICS

 cause

    X-linked ichthyosis
    DIAGNOSIS

;

    rearrangements in the Xp21.2 region
    GENETICS

 are associated with

    Duchenne or Becker muscular dystrophies (DMD or BMD)
    DIAGNOSIS

; and the

    Xq27.3 unstable region, containing the (CGG)n repeat expansion in the FMR1 gene
    GENETICS

 is associated with

    fragile X syndrome
    DIAGNOSIS

. We report on a

    family with two affected boys
    FAMILY

, the

    elder diagnosed with fragile X syndrome
    FAMILY

,

    the younger with DMD
    FAMILY

, and both suffering from

    severe ichthyosis
    SYMPTOMS

. The family was analyzed by

    polymerase chain reaction
    PARACLINICAL

,

    multiplex ligation-dependent probe amplification
    PARACLINICAL

 and

    haplotype analysis
    PARACLINICAL

. The

    mother proved to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the DMD gene and a FMR1 expansion
    FAMILY

. To the best of our knowledge, this is the first description of an

    asymptomatic
    DIAGNOSIS

 carrier of three different

    X-linked disorders
    GENETICS

, involving

    severe genetic rearrangements on both long and short arms of the X chromosomes
    GENETICS

. The

    boy
    GENDER

 with

    fragile X syndrome
    DIAGNOSIS

    has inherited a triple recombinant maternal X chromosome
    FAMILY

, this way

    inheriting the FMR1 expansion
    GENETICS

 and

    ichthyosis
    SYMPTOMS

    , originating most probably from different maternal Xes
    FAMILY

 and

    excluding the DMD gene deletion
    GENETICS

. The

    transmission of these extremely defective maternal chromosomes to the
    FAMILY

 next generation involved several recombinations.


Intraoperative airway obstruction in a Duchenne muscular dystrophy patient.

To report a complication of airway obstruction during spinal deformity correction surgery in Duchenne muscular dystrophy (DMD) patient, due to lordoscoliosis, airway malacia, and prone surgical positioning, which was rectified by changing the position of the patient and surgery was successfully completed.

A 15-year-old boy was diagnosed with DMD and admitted for surgical treatment of thoracolumbar scoliosis. The patient's preoperative Cobb's angle was 79° and the kyphotic angle was -19°. During the initial period of surgery, while in the prone position, peak inspiratory pressure (PIP) suddenly increased from 20-21 to 38-41 cmH2O, wheezing sounds were heard on auscultation of both lungs, and his blood pressure began to fall. Under suspicion of airway problem, intraoperative fiberoptic bronchoscopy was performed which confirmed airway obstruction. Attributing patient's prone position as the cause of airway obstruction, the surgical position of the patient was changed from prone to semi-lateral. After this change, the PIP stabilized to within normal limits (20-23 cmH2O). The surgical correction was successfully completed with a posterior-only pedicle screw by the free-hand technique, with the patient in the semi-lateral position for the rest of surgery.

Lordoscoliosis and airway malacia in a patient with DMD can lead to occlusion of the tracheobronchial lumen when the patient is in the prone position. Changing the patient's position from prone to semi-lateral can be of help to reverse this airway obstruction and complete the surgery. Pedicular screw insertion can be safely and effectively carried out in this position using free-hand technique.

To report a complication of

    airway obstruction
    SYMPTOMS

 during

    spinal deformity correction surgery
    MEDICATION

 in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patient, due to

    lordoscoliosis
    SYMPTOMS

,

    airway malacia
    SYMPTOMS

, and

    prone surgical positioning
    MEDICATION

, which was rectified by changing the position of the patient and

    surgery
    MEDICATION

 was successfully completed.

A

    15-year-old
    AGE

    boy
    GENDER

 was diagnosed with

    DMD
    DIAGNOSIS

 and admitted for

    surgical treatment of thoracolumbar scoliosis
    MEDICATION

. The patient's preoperative Cobb's angle was 79° and the

    kyphotic angle was -19°
    SYMPTOMS

. During the initial period of

    surgery
    MEDICATION

, while in the prone position,

    peak inspiratory pressure (PIP) suddenly increased from 20-21 to 38-41 cmH2O
    SYMPTOMS

,

    wheezing sounds were heard on auscultation of both lungs
    SYMPTOMS

, and his

    blood pressure began to fall
    SYMPTOMS

. Under suspicion of

    airway problem
    SYMPTOMS

,

    intraoperative fiberoptic bronchoscopy
    PARACLINICAL

 was performed which confirmed

    airway obstruction
    SYMPTOMS

. Attributing patient's prone position as the cause of

    airway obstruction
    SYMPTOMS

, the

    surgical position of the patient was changed from prone to semi-lateral
    MEDICATION

. After this change, the

    PIP stabilized to within normal limits (20-23 cmH2O)
    BIOCHEMICAL

. The

    surgical correction
    MEDICATION

 was successfully

    completed with a posterior-only pedicle screw by the free-hand technique
    MEDICATION

, with the

    patient in the semi-lateral position for the rest of surgery
    MEDICATION

.

    Lordoscoliosis
    SYMPTOMS

 and

    airway malacia
    SYMPTOMS

 in a patient with

    DMD
    DIAGNOSIS

 can lead to

    occlusion of the tracheobronchial lumen
    SYMPTOMS

 when the patient is in the prone position. Changing the patient's position from prone

    to semi-lateral
    MEDICATION

 can be of help to reverse this

    airway obstruction
    SYMPTOMS

 and

    complete the surgery
    MEDICATION

.

    Pedicular screw insertion
    MEDICATION

 can be safely and effectively carried out in this position using

    free-hand technique
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
DMD
DMD


First successful pregnancy in Switzerland after prospective sex determination of the embryo through the separation of X-chromosome bearing spermatozoa.

The feasibility and the potential advantages of separating X-chromosome bearing spermatozoa for the prevention of a severe X-chromosome linked disorder with the use of intracytoplasmic sperm injection are presented.

A carrier of muscular dystrophy type Becker was treated with intracytoplasmic sperm injection, using spermatozoa previously stained with the Hoechst dye 33342 and sorted with flow cytometry.

After transfer of one single blastocyst, an intrauterine pregnancy arose. In the ninth week of gestation, the female sex of the embryo was confirmed with proof of absence of the SRY gene of the Y-chromosome. After normal pregnancy, the patient delivered a healthy daughter.

The staining of spermatozoa with specific markers and sorting with flow cytometry provides a means of preventing significant disease in the offspring and may help in reducing the number of surplus embryos needed for preimplantation genetic diagnosis.

The feasibility and the potential advantages of

    separating X-chromosome bearing spermatozoa
    MICROSCOPIC

 for the prevention of a

    severe X-chromosome linked disorder
    GENETICS

 with the use of

    intracytoplasmic sperm injection
    MEDICATION

 are presented.

A carrier of

    muscular dystrophy type Becker
    DIAGNOSIS

 was treated with

    intracytoplasmic sperm injection
    MEDICATION

, using spermatozoa previously stained with the

    Hoechst dye 33342
    PARACLINICAL

 and sorted with

    flow cytometry
    PARACLINICAL

.

After

    transfer of one single blastocyst
    MEDICATION

, an

    intrauterine pregnancy
    DIAGNOSIS

 arose. In the

    ninth week of gestation
    AGE

, the

    female sex of the embryo
    GENETICS

 was confirmed with proof of

    absence of the SRY gene of the Y-chromosome
    GENETICS

. After

    normal pregnancy
    SYMPTOMS

, the patient delivered a healthy daughter.

The

    staining of spermatozoa
    PARACLINICAL

 with specific markers and

    sorting with flow cytometry
    PARACLINICAL

 provides a means of preventing

    significant disease in the offspring
    SYMPTOMS

 and may help in reducing the number

    of surplus embryos needed for preimplantation genetic diagnosis
    MEDICATION

.

muscular dystrophy type Becker
intrauterine pregnancy

normal pregnancy
significant disease in the offspring


Detrusor overactivity in Becker muscular dystrophy.

A 20-year-old man with normal motor milestones as an infant but subsequent progressive difficulty in walking in childhood, was genetically confirmed to have Becker muscular dystrophy (BMD) at age 13. He was independent in ambulation and activities of daily living. He was referred to the Department of Uro-neurology for a 5-year history of urinary urgency and incontinence. He would visit the toilet 10 times in the daytime and experience urinary urgency daily, often associated with incontinence. He did not report difficulties initiating voiding, stress incontinence, pain, or hematuria. There was no history of urinary tract infections.

A

    20-year-old
    AGE

    man
    GENDER

 with

    normal motor milestones
    NEG_FINDINGS

 as an

    infant
    AGE

 but subsequent

    progressive difficulty in walking
    SYMPTOMS

 in

    childhood
    AGE

, was genetically confirmed to have

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 at

    age 13
    AGE

.

    He
    GENDER

 was

    independent in ambulation
    NEG_FINDINGS

    and activities of daily living
    SYMPTOMS

.

    He
    GENDER

 was referred to the Department of

    Uro-neurology
    PARACLINICAL

 for a 5-year history of

    urinary urgency
    SYMPTOMS

 and

    incontinence
    SYMPTOMS

.

    He
    GENDER

 would

    visit the toilet
    MEDICATION

 10 times in the daytime and experience

    urinary urgency daily
    SYMPTOMS

, often associated with

    incontinence
    SYMPTOMS

.

    He
    GENDER

    did not report difficulties initiating voiding, stress incontinence, pain, or hematuria
    NEG_FINDINGS

. There was

    no history of urinary tract infections
    NEG_FINDINGS

.

progressive difficulty in walking
and activities of daily living
urinary urgency
incontinence
urinary urgency daily
incontinence


NGS identifies TAZ mutation in a family with X-linked dilated cardiomyopathy.

We reported a family with two male siblings affected with infantile dilated cardiomyopathy (DCM). Extensive evaluation failed to identify the underlying cause for the DCM. Next generation sequencing (NGS) with targeted enrichment identified a hemizygous variant c.718G>C (p.Gly240Arg) in the TAZ gene. This variant has been reported in three other families with X linked infantile DCM and is therefore likely pathogenic. NGS allows efficient screening of a large number of uncommon genes in complex disorders like DCM, in which there is substantial genetic and phenotypic heterogeneity. The identification of TAZ mutation has major impact on their medical care as the surveillance needs to be expanded to cover for the Barth syndrome, a severe metabolic phenotype also caused by TAZ mutation, in addition to DCM.

We reported a

    family with two male siblings affected with infantile dilated cardiomyopathy (DCM)
    FAMILY

.

    Extensive evaluation failed to identify the underlying cause for the DCM
    NEG_FINDINGS

.

    Next generation sequencing (NGS) with targeted enrichment
    PARACLINICAL

 identified a

    hemizygous variant c.718G>C (p.Gly240Arg) in the TAZ gene
    GENETICS

. This variant has been reported in three other families with

    X linked infantile DCM
    GENETICS

 and is therefore likely pathogenic.

    NGS
    GENETICS

 allows efficient screening of a large number of uncommon genes in

    complex disorders
    DIAGNOSIS

 like

    DCM
    DIAGNOSIS

, in which there is substantial genetic and phenotypic heterogeneity. The identification of

    TAZ mutation
    GENETICS

 has major impact on their medical care as the surveillance needs to be expanded to cover for the

    Barth syndrome
    DIAGNOSIS

, a

    severe metabolic phenotype
    DIAGNOSIS

 also caused by

    TAZ mutation
    GENETICS

, in addition to

    DCM
    DIAGNOSIS

.

complex disorders
DCM
Barth syndrome
severe metabolic phenotype
DCM


Peripartum cardiomyopathy in a previously asymptomatic carrier of Duchenne muscular dystrophy.

A 40 year-old woman presented to hospital with 12h of progressive shortness of breath. She was 11 days postpartum, having delivered a full-term male infant. She was discharged on antibiotics for presumed pneumonia, but represented two days later with NYHA class IV symptoms and in acute decompensated heart failure confirmed on clinical examination and chest X-ray. Echocardiography showed a left ventricular ejection fraction (LVEF) of 20%. She was treated for peripartum cardiomyopathy (PPCM) with angiotensin converting enzyme inhibitors (ACEi), beta-blockers and diuretics with normalisation of her cardiac function within six months. Four years later, her son was diagnosed with Duchenne muscular dystrophy (DMD) and she tested positive as a carrier of the mutant gene. It is unclear whether the DMD carrier state alone is associated with increased susceptibility to PPCM or if this is merely the first expression of cardiomyopathy in a previously asymptomatic carrier.

A

    40 year-old
    AGE

    woman
    GENDER

 presented to hospital with 12h of

    progressive shortness of breath
    SYMPTOMS

.

    She
    GENDER

 was

    11 days postpartum
    MEDICATION

,

    having delivered a full-term male infant
    MEDICATION

.

    She
    GENDER

 was

    discharged on antibiotics
    MEDICATION

 for presumed

    pneumonia
    DIAGNOSIS

, but represented two days later with

    NYHA class IV symptoms
    SYMPTOMS

 and in

    acute decompensated heart failure
    SYMPTOMS

 confirmed on

    clinical examination
    PARACLINICAL

 and

    chest X-ray
    PARACLINICAL

.

    Echocardiography
    PARACLINICAL

 showed a

    left ventricular ejection fraction (LVEF) of 20%
    SYMPTOMS

.

    She
    GENDER

 was treated for

    peripartum cardiomyopathy (PPCM)
    DIAGNOSIS

 with

    angiotensin converting enzyme inhibitors (ACEi), beta-blockers and diuretics
    MEDICATION

 with

    normalisation of her cardiac function within six months
    NEG_FINDINGS

. Four years later,

    her son was diagnosed with Duchenne muscular dystrophy (DMD)
    FAMILY

 and

    she
    GENDER

    tested positive as a carrier of the mutant gene
    FAMILY

. It is unclear whether the

    DMD
    DIAGNOSIS

 carrier state alone is associated with increased susceptibility to

    PPCM
    DIAGNOSIS

 or if this is merely the first expression of

    cardiomyopathy
    DIAGNOSIS

 in a previously asymptomatic carrier.

pneumonia
peripartum cardiomyopathy (PPCM)
DMD
PPCM
cardiomyopathy


Camptocormia as a late presentation in a manifesting carrier of duchenne muscular dystrophy.

Camptocormia, or bent spine syndrome, is an abnormal posture consisting of forward flexion of the spine that disappears when a patient is supine. It is associated with a wide variety of myopathic disorders that affect paraspinal muscles, including inflammatory and inherited myopathies.

We describe a woman who presented with camptocormia in her eighth decade.

Skeletal muscle biopsy showed mild nonspecific changes, but her family history was significant for a son who died of Duchenne muscular dystrophy (DMD). Genetic analysis of DMD confirmed that she was a heterozygous carrier of a mutation.

In the absence of any alternate explanation, we interpret her symptoms to be a manifestation of her DMD carrier state. To our knowledge, this represents the first reported example of camptocormia as the presenting symptom in a carrier and suggests that a manifesting carrier state should be considered in the differential diagnosis for women with unexplained camptocormia.

    Camptocormia
    DIAGNOSIS

, or

    bent spine syndrome
    SYMPTOMS

, is an

    abnormal posture consisting of forward flexion of the spine
    SYMPTOMS

 that

    disappears
    SYMPTOMS

 when a patient is supine. It is associated with a wide variety of

    myopathic disorders
    DIAGNOSIS

 that

    affect paraspinal muscles
    SYMPTOMS

, including

    inflammatory and inherited myopathies
    DIAGNOSIS

.

We describe a

    woman
    GENDER

 who presented with

    camptocormia
    SYMPTOMS

    in her eighth decade
    AGE

.

    Skeletal muscle biopsy
    PARACLINICAL

 showed

    mild nonspecific changes
    SYMPTOMS

, but

    her
    GENDER

    family history was significant for a son who died of Duchenne muscular dystrophy (DMD)
    FAMILY

.

    Genetic analysis of DMD
    PARACLINICAL

 confirmed that

    she
    GENDER

 was a

    heterozygous carrier of a mutation
    GENETICS

.

In the

    absence of any alternate explanation
    NEG_FINDINGS

, we interpret

    her
    GENDER

 symptoms to be a manifestation of her

    DMD
    DIAGNOSIS

 carrier state. To our knowledge, this represents the first reported example of

    camptocormia
    SYMPTOMS

 as the presenting symptom in a

    carrier
    DIAGNOSIS

 and suggests that a

    manifesting carrier state
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 for

    women
    GENDER

 with

    unexplained camptocormia
    SYMPTOMS

.

Camptocormia
myopathic disorders
inflammatory and inherited myopathies
DMD
carrier
manifesting carrier state


Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance.

We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with "cryptogenic" hypertransaminasemia.

We report a case with the association of

    well self-compensated hereditary fructose intolerance
    SYMPTOMS

 and

    still poorly symptomatic Duchenne type muscular dystrophy
    NEG_FINDINGS

. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with "

    cryptogenic" hypertransaminasemia
    BIOCHEMICAL

.


Comparison of X-chromosome inactivation in Duchenne muscle/myocardium-manifesting carriers, non-manifesting carriers and related daughters.

Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5-7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X-chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non-manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation-based assay. The results showed that DMD-manifesting carriers had a preferential inactivation of the X-chromosome carrying the normal allele, while non-manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother-daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non-random patterns of X inactivation.

    Female
    GENDER

 carriers of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 are usually

    asymptomatic
    NEG_FINDINGS

. However, 2.5-7.8% of them may present

    muscle symptoms
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

, attributed to a

    reduced production of dystrophin
    BIOCHEMICAL

, probably because of

    skewed patterns of X-chromosome inactivation (XCI)
    GENETICS

. To evaluate the role of

    XCI
    GENETICS

 in

    symptomatic (at muscle or heart level
    SYMPTOMS

) and

    asymptomatic
    NEG_FINDINGS

    DMD
    DIAGNOSIS

 carriers, 44 subjects were selected from our database (12 manifesting, 21

    non-manifesting
    NEG_FINDINGS

, 11 healthy

    females
    GENDER

), and

    XCI pattern determined in the lymphocytes by the androgen receptor methylation-based assay
    GENETICS

. The results showed that

    DMD-manifesting
    DIAGNOSIS

 carriers had a

    preferential inactivation of the X-chromosome carrying the normal allele
    GENETICS

, while

    non-manifesting carriers
    NEG_FINDINGS

 and healthy

    females
    GENDER

 showed a

    random XCI pattern
    GENETICS

. Moreover, when comparing

    muscle with heart manifesting carriers
    SYMPTOMS

, the former group showed a higher degree

    of skewing
    SYMPTOMS

.

    No concordance in XCI was found between mothers and daughters
    FAMILY

, when

    symptomatic/asymptomatic mother-daughter pairs
    FAMILY

 were analyzed. The results confirm that

    DMD
    DIAGNOSIS

 clinical manifestations in carriers are associated with

    non-random patterns of X inactivation
    GENETICS

.

Duchenne muscular dystrophy (DMD)
DMD
DMD-manifesting
DMD

asymptomatic
asymptomatic
non-manifesting
non-manifesting carriers

muscle symptoms
cardiomyopathy
symptomatic (at muscle or heart level
muscle with heart manifesting carriers
of skewing


Automatic single-trial classification of prefrontal hemodynamic activity in an individual with Duchenne muscular dystrophy.

Brain-computer interfaces (BCIs) allow users to control external devices via brain activity alone, circumventing the somatic nervous system and the need for overt movement. Essential to BCI development is the ability to accurately detect and classify patterns of activation associated with different mental tasks. Here, we investigate the ability to automatically distinguish a mental arithmetic (MA) task from a natural baseline state in an individual with Duchenne muscular dystrophy (DMD) using signals acquired via multichannel near-infrared spectroscopy (NIRS). Using dual-wavelength NIRS, we interrogated nine sites around the frontopolar locations while the individual performed MA to answer multiple-choice questions within a system-paced paradigm. An encouraging overall classification accuracy of 71.1% was obtained, which is comparable to the average accuracy we previously reported for healthy individuals performing the same task. This result demonstrates the potential of NIRS-BCI based on task-induced prefrontal activity for use by individuals with DMD.

    Brain-computer interfaces (BCIs
    MEDICATION

) allow users to

    control external devices
    MEDICATION

 via

    brain activity alone
    MEDICATION

,

    circumventing the somatic nervous system and the need for overt movement
    NEG_FINDINGS

. Essential to BCI development is the ability to accurately detect and classify patterns of activation associated with different mental tasks. Here, we investigate the ability to automatically distinguish a

    mental arithmetic (MA) task
    PARACLINICAL

 from a natural baseline state in an individual with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 using signals acquired via

    multichannel near-infrared spectroscopy (NIRS)
    PARACLINICAL

. Using

    dual-wavelength NIRS
    PARACLINICAL

, we

    interrogated nine sites around the frontopolar locations
    PARACLINICAL

 while the individual performed MA to answer multiple-choice questions within a system-paced paradigm. An encouraging overall classification accuracy of 71.1% was obtained, which is comparable to the average accuracy we previously reported for healthy individuals performing the same task. This result demonstrates the potential of

    NIRS-BCI
    PARACLINICAL

 based on

    task-induced prefrontal activity
    PARACLINICAL

 for use by individuals with

    DMD
    DIAGNOSIS

.

Brain-computer interfaces (BCIs
control external devices
brain activity alone


MRI/MRS evaluation of a female carrier of Duchenne muscular dystrophy.

The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFC(DMD)) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFC(DMD) (47 years, 51 kg) on four occasions within 21 months and in a control subject. Heterogeneity and asymmetry among muscles in the MFC(DMD) was observed in lipid fraction and mean transverse relaxation time (T(2)) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21 months a small decrease in CSA(max) and increase in lipid fraction and T(2) was observed in the MFC(DMD) in some muscles. In summary, this MFC(DMD) revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement.

The purpose of this study was to evaluate

    skeletal muscle composition of lower extremity muscles
    SYMPTOMS

 in a manifesting

    female
    GENDER

 carrier of

    Duchenne muscular dystrophy (MFC(DMD))
    DIAGNOSIS

 using

    magnetic resonance imaging (MRI) and spectroscopy (MRS)
    PARACLINICAL

.

    MRI/MRS was performed on the lower extremities and heart
    PARACLINICAL

 of a

    MFC(DMD)
    DIAGNOSIS

 (

    47 years
    AGE

, 51 kg) on four occasions within 21 months and in a control subject.

    Heterogeneity and asymmetry among muscles in the MFC(DMD)
    SYMPTOMS

 was observed

    in lipid fraction and mean transverse relaxation time (T(2)) of lower extremity muscles
    SYMPTOMS

 with

    some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles)
    SYMPTOMS

. There was an association of

    abnormal MRI findings and strength and motor function
    SYMPTOMS

. Over the 21 months a

    small decrease in CSA(max)
    SYMPTOMS

 and

    increase in lipid fraction and T(2)
    BIOCHEMICAL

 was observed

    in the MFC(DMD) in some muscles
    SYMPTOMS

. In summary, this

    MFC(DMD)
    DIAGNOSIS

 revealed significant

    imaging evidence of pathologic heterogeneity among muscles
    SYMPTOMS

. Furthermore, this study shows the feasibility of combining various

    quantitative MRI and MRS
    PARACLINICAL

 approaches to

    monitor skeletal muscle involvement
    PARACLINICAL

.

Duchenne muscular dystrophy (MFC(DMD))
MFC(DMD)
MFC(DMD)


[Complete atrioventricular block in Duchenne muscular dystrophy].

We report a case of complete atrioventricular (AV) block in a 40-year-old patient with Duchenne muscular dystrophy (DMD). While he was bed-ridden and required mechanical ventilation, his cardiac involvement was mild. He had the deletion of exon 45-52 in the dystrophin gene. He underwent transient complete AV block and came to require pacemaker implantation due to recurrence of complete AV block ten days after the first attack. Electrophysiological study revealed mild prolonged AH and HV interval. Although DMD patients with AV block have been rarely reported so far, attention should be paid to AV block for patients who prolonged their lives.

We report a case of

    complete atrioventricular (AV) block
    SYMPTOMS

 in a

    40-year-old
    AGE

 patient with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. While

    he
    GENDER

 was

    bed-ridden
    MEDICATION

 and

    required mechanical ventilation
    MEDICATION

, his

    cardiac involvement was mild
    SYMPTOMS

.

    He
    GENDER

 had the

    deletion of exon 45-52 in the dystrophin gene
    GENETICS

.

    He
    GENDER

 underwent

    transient complete AV block
    SYMPTOMS

 and came to require

    pacemaker implantation
    MEDICATION

 due to

    recurrence of complete AV block
    SYMPTOMS

 ten days after the first attack.

    Electrophysiological study
    PARACLINICAL

 revealed

    mild prolonged AH and HV interval
    SYMPTOMS

. Although

    DMD
    DIAGNOSIS

 patients with

    AV block
    DIAGNOSIS

 have been rarely reported so far, attention should be paid to

    AV block
    DIAGNOSIS

 for patients who prolonged their lives.

complete atrioventricular (AV) block
cardiac involvement was mild
transient complete AV block
recurrence of complete AV block
mild prolonged AH and HV interval

Duchenne muscular dystrophy (DMD)
DMD
AV block
AV block

bed-ridden
required mechanical ventilation
pacemaker implantation


Coexistence of two distinct intragenic dystrophin deletions in two maternal cousins with Duchenne Muscular Dystrophy.

The identification of two independent mutations is rarely described between affected members of the same family with Duchenne Muscular Dystrophy. This study reports the presence of two distinct intragenic dystrophin deletions in a Turkish family. Exon 54 deletion was identified originally in the proband, whereas his maternal cousin had deletions of exons 43-50 in the dystrophin gene. As indicated, only the mother of the proband was identified as exon 54 deletion carrier however, the proband's cousin was detected as a sporadic case. These molecular genetic data reveal an interesting and novel mixture, in the same family, of both mutations of the same gene.

The

    identification of two independent mutations
    FAMILY

 is rarely described between

    affected members of the same family with Duchenne Muscular Dystrophy
    FAMILY

. This study reports the presence of

    two distinct intragenic dystrophin deletions
    GENETICS

 in a

    Turkish
    ETHNICITY

 family.

    Exon 54 deletion was identified originally in the proband
    GENETICS

, whereas

    his maternal cousin had deletions of exons 43-50 in the dystrophin gene
    FAMILY

. As indicated,

    only the mother of the proband was identified as exon 54 deletion carrier
    FAMILY

 however,

    the proband's cousin was detected as a sporadic case
    FAMILY

. These

    molecular genetic
    PARACLINICAL

 data reveal an interesting and novel mixture, in the same family, of

    both mutations of the same gene
    GENETICS

.


Classic manifestations of Duchenne dystrophy in a young female patient: a case report.

Duchenne and Becker muscular dystrophies (DMD/DMB) are neuromuscular diseases linked to chromosome X and affect mainly male individuals. Duchenne muscular dystrophy is the most severe form of the disease, leading to a decreased patient survival compared with individuals with Becker type and female carriers of the mutated gene. In this paper we present the case of a female adolescent whose clinical picture and disease course closely resembled male individuals.

    Duchenne and Becker muscular dystrophies (DMD/DMB)
    DIAGNOSIS

 are

    neuromuscular diseases
    DIAGNOSIS

    linked to chromosome X
    GENETICS

 and affect mainly

    male
    GENDER

 individuals.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is the most severe form of the disease, leading to a decreased patient survival compared with individuals with

    Becker type
    DIAGNOSIS

 and

    female
    GENDER

    carriers of the mutated gene
    GENETICS

. In this paper we present the case of a

    female
    GENDER

    adolescent
    AGE

 whose clinical picture and disease course closely resembled

    male
    GENDER

 individuals.

linked to chromosome X
carriers of the mutated gene


Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site.

    Becker muscular dystrophy
    DIAGNOSIS

 features

    progressive proximal weakness
    SYMPTOMS

,

    wasting
    SYMPTOMS

 and often

    focal hypertrophy
    SYMPTOMS

. We present a patient with

    pain and cramps
    SYMPTOMS

 from

    adolescence
    AGE

.

    Widespread muscle hypertrophy
    SYMPTOMS

,

    preserved muscle strength
    SYMPTOMS

 and

    a 10-20-fold raised CPK
    BIOCHEMICAL

 were noted.

    Muscle biopsy
    PARACLINICAL

 was

    dystrophic
    PARACLINICAL

, and

    Western blot
    PARACLINICAL

 showed a

    95% reduction of dystrophin levels
    BIOCHEMICAL

.

    Genetic analyses
    PARACLINICAL

 revealed a

    non-sense mutation in exon 2 of the dystrophin gene
    GENETICS

. This mutation is

    predicted to result in a Duchenne
    NEG_FINDINGS

 phenotype, but resulted in a

    mild Becker muscular dystrophy
    DIAGNOSIS

 with

    widespread muscle hypertrophy
    SYMPTOMS

. We suggest that this unusual phenotype is caused by

    translation re-initiation downstream from the mutation site
    GENETICS

.

Becker muscular dystrophy
mild Becker muscular dystrophy

progressive proximal weakness
wasting
focal hypertrophy
pain and cramps
Widespread muscle hypertrophy
preserved muscle strength
widespread muscle hypertrophy

a 10-20-fold raised CPK
95% reduction of dystrophin levels


Fat Embolism Syndrome following minor trauma in Duchenne muscular dystrophy.

We describe five patients with Duchenne muscular dystrophy who presented with acute neurologic and respiratory symptoms following minor trauma. Four of the five deteriorated rapidly and died within 36 h after falling. X-rays for fractures were negative. Four of the five patients were taking corticosteroids daily. All five patients fulfilled the clinical criteria for Fat Embolism Syndrome. Autopsy findings were consistent with fat embolism in two cases. Fat Embolism Syndrome needs to be considered in patients with Duchenne muscular dystrophy following minor trauma even without fractures. Early recognition of Fat Embolism Syndrome and aggressive resuscitation are important to improve survival. This report serves as an important reminder that seatbelts need to be used at all times.

We describe five patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 who presented with

    acute neurologic and respiratory symptoms
    SYMPTOMS

 following

    minor trauma
    SYMPTOMS

. Four of the five

    deteriorated rapidly
    SYMPTOMS

 and

    died
    SYMPTOMS

 within 36 h after falling.

    X-rays for fractures were negative
    NEG_FINDINGS

. Four of the five patients were

    taking corticosteroids daily
    MEDICATION

. All five patients fulfilled the clinical criteria for

    Fat Embolism Syndrome
    DIAGNOSIS

.

    Autopsy findings
    PARACLINICAL

 were consistent with

    fat embolism
    MICROSCOPIC

 in two cases.

    Fat Embolism Syndrome
    DIAGNOSIS

 needs to be considered in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 following

    minor trauma
    SYMPTOMS

 even

    without fractures
    NEG_FINDINGS

. Early recognition of

    Fat Embolism Syndrome
    DIAGNOSIS

 and

    aggressive resuscitation
    MEDICATION

 are important to improve survival. This report serves as an important reminder that

    seatbelts
    MEDICATION

 need to be used at all times.

Duchenne muscular dystrophy
Fat Embolism Syndrome
Fat Embolism Syndrome
Duchenne muscular dystrophy
Fat Embolism Syndrome

X-rays for fractures were negative
without fractures

taking corticosteroids daily
aggressive resuscitation
seatbelts


Angioedema in progressive muscular dystrophy: a case report.

Systemic allergic reactions, which include angioedema, are very common in clinical practice. There is great diversity in the etiological factors known to trigger angioedema, and in the pathogenetic mechanisms defining this condition. Beside the broad spectrum of immuno-allergic reactions involved in the angioedemic pathogenesis, this condition is known to also develop on the background of other disorders. These disorders may be of different etiology and have different pathogenesis (either non-immune or immune) but have one common feature referred to as "serological overlap". From research and clinical perspective, it is interesting to explore the combination of some rare neurological diseases, such as myopathies and in particular muscular dystrophies with systemic allergic reactions such as angioedema, urticaria and others. It is known that progressive muscular dystrophies (PMD) are hereditary diseases with different types of inheritance--X-chromosome recessive, X-chromosome dominant, autosomal dominant and others. In some forms, such as Duchenne muscular dystrophy (DMD), an increased expression of perforin in muscle is found which is evidence for involvement of the cellular immune response in the pathogenesis of myopathy. It is in this sense that it is interesting to explore and discuss a clinical case diagnosed as a facioscapulohumeral form of PMD, which also manifests angioedema with urticaria.

We present a 41-year-old male hospitalized in the Division of Occupational Diseases and Allergology at St. George University Hospital in Plovdiv who suffered two incidents of massive angioedema on the face, back and chest, accompanied by an itchy urticarial rash. In 1985, after hospitalization to the Clinic of Neurology, he was diagnosed with PMD of facioscapulohumeral type. The medical history could not reveal any of the most common etiologic factors such as drugs, food, insects and other allergens that may be associated with the systemic allergic reactions. The abnormalities we found (although they are only of specific indices of humoral immunity) give some reasons to assume the hypothesis of possible causation between the primary neurological disorder as a trigger for this kind of allergy.

The reported case demonstrates that in addition to the cellular immunity abnormalities we identified, the abnormalities in some components of humoral immunity should also be taken into consideration. Good knowledge of the allergic factors and the mechanisms of allergic reactions is of paramount importance for an efficacious approach to the problems faced by patients with such rare pathology.

    Systemic allergic reactions
    SYMPTOMS

, which include

    angioedema
    SYMPTOMS

, are very common in clinical practice. There is great diversity in the etiological factors known to trigger

    angioedema
    DIAGNOSIS

, and in the pathogenetic mechanisms defining this condition. Beside the broad spectrum of

    immuno-allergic reactions
    SYMPTOMS

 involved in the

    angioedemic pathogenesis
    SYMPTOMS

, this condition is known to also develop on the background of other disorders. These disorders may be of different etiology and have different pathogenesis (either

    non-immune
    DIAGNOSIS

 or immune) but have one common feature referred to as "

    serological overlap"
    SYMPTOMS

. From research and clinical perspective, it is interesting to explore the combination of some

    rare neurological diseases
    DIAGNOSIS

, such as

    myopathies
    DIAGNOSIS

 and in particular

    muscular dystrophies
    DIAGNOSIS

 with

    systemic allergic reactions
    SYMPTOMS

 such as

    angioedema
    SYMPTOMS

,

    urticaria
    SYMPTOMS

 and others. It is known that

    progressive muscular dystrophies (PMD)
    DIAGNOSIS

 are

    hereditary diseases
    GENETICS

 with

    different types of inheritance--X-chromosome recessive, X-chromosome dominant, autosomal dominant
    GENETICS

 and others. In some forms, such as

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, an

    increased expression of perforin in muscle
    MICROSCOPIC

 is found which is evidence for involvement of the

    cellular immune response
    BIOCHEMICAL

 in the pathogenesis of

    myopathy
    DIAGNOSIS

. It is in this sense that it is interesting to explore and discuss a clinical case diagnosed as a

    facioscapulohumeral form of PMD
    DIAGNOSIS

, which also manifests

    angioedema with urticaria
    SYMPTOMS

.

We present a

    41-year-old
    AGE

    male
    GENDER

 hospitalized in the Division of

    Occupational Diseases and Allergology
    PARACLINICAL

 at St. George University Hospital in

    Plovdiv
    ETHNICITY

 who suffered two incidents of

    massive angioedema on the face, back and chest
    SYMPTOMS

, accompanied by an

    itchy urticarial rash
    SYMPTOMS

. In 1985, after hospitalization to the Clinic of

    Neurology
    PARACLINICAL

,

    he
    GENDER

 was diagnosed with

    PMD of facioscapulohumeral type
    DIAGNOSIS

. The

    medical history could not reveal any of the most common etiologic factors such as drugs, food, insects and other allergens that may be associated with the systemic allergic reactions
    NEG_FINDINGS

. The abnormalities we found (although they are only of

    specific indices of humoral immunity
    BIOCHEMICAL

) give some reasons to assume the hypothesis of possible causation between the

    primary neurological disorder
    DIAGNOSIS

 as a trigger for this kind

    of allergy
    DIAGNOSIS

.

The reported case demonstrates that in addition to the

    cellular immunity abnormalities
    BIOCHEMICAL

 we identified, the

    abnormalities in some components of humoral immunity
    BIOCHEMICAL

 should also be taken into consideration. Good knowledge of the allergic factors and the mechanisms of

    allergic reactions
    SYMPTOMS

 is of paramount importance for an efficacious approach to the problems faced by patients with such rare pathology.

angioedema
non-immune
rare neurological diseases
myopathies
muscular dystrophies
progressive muscular dystrophies (PMD)
Duchenne muscular dystrophy (DMD)
myopathy
facioscapulohumeral form of PMD
PMD of facioscapulohumeral type
primary neurological disorder
of allergy


[Spinal muscular atrophy mimicking myotonic dystrophy: a case report and clinical, pathological and genetic analysis].

To investigate a patient featuring a complex neuromuscular disease phenotype.

A comprehensive analysis integrating clinical investigation, electrophysiological testing, pathological analysis and mutation screening was carried out.

The patient has presented clinical and pathological manifestations mimicking Duchenne muscular dystrophy. However, genetic analysis has identified no deletion in 21 exons of Dystrophin gene, no pathologic expansion of CTG repeats in DMPK gene or CCTG repeats in ZFN9 gene. Instead, a homozygous deletion of exons 7 and 8 in SMN gene was discovered.

A rare case of spinal muscular atrophy (SMA) was verified by genetic diagnosis. SMA is a group of neuromuscular disorders with great phenotypic heterogeneity and sometimes cannot be diagnosed by clinical manifestations, electrophysiological and pathological changes alone. Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.

To investigate a patient featuring a

    complex neuromuscular disease
    DIAGNOSIS

 phenotype.

A comprehensive analysis integrating

    clinical investigation
    PARACLINICAL

,

    electrophysiological testing
    PARACLINICAL

,

    pathological analysis
    PARACLINICAL

 and

    mutation screening
    PARACLINICAL

 was carried out.

The patient has presented

    clinical and pathological manifestations mimicking Duchenne muscular dystrophy
    SYMPTOMS

. However,

    genetic analysis
    PARACLINICAL

 has identified

    no deletion in 21 exons of Dystrophin gene
    NEG_FINDINGS

,

    no pathologic expansion of CTG repeats in DMPK gene
    NEG_FINDINGS

    or CCTG repeats in ZFN9 gene
    NEG_FINDINGS

. Instead, a

    homozygous deletion of exons 7 and 8 in SMN gene
    GENETICS

 was discovered.

A rare case of

    spinal muscular atrophy (SMA)
    DIAGNOSIS

 was verified by

    genetic diagnosis
    PARACLINICAL

.

    SMA
    DIAGNOSIS

 is a group of

    neuromuscular disorders
    DIAGNOSIS

 with great phenotypic heterogeneity and sometimes cannot be diagnosed by clinical manifestations, electrophysiological and pathological changes alone.

    Genetic diagnosis
    PARACLINICAL

 has become indispensable for accurate diagnosis for patients suspected to have the disease.

complex neuromuscular disease
spinal muscular atrophy (SMA)
SMA
neuromuscular disorders


[Abdominal free air without signs of perforated abdominal viscus during non-invasive ventilation].

A 19-year-old patient suffering from Duchenne muscular dystrophy was admitted to our hospital with an acute bronchopulmonary infection. Four months ago noninvasive ventilation was started because of hypercapnic respiratory failure. Mechanical ventilation had been used so far only at night. At the time of admission spontaneous breathing was not possible due to exhaustion of the respiratory muscles. The patient suffered from fever, limited cough strength and dyspnoea at rest. The abdomen was distended because of intestinal gas without clinical signs of acute abdomen.

Blood gas analysis showed respiratory acidosis even under mechanical ventilation. Laboratory tests showed an elevation of the inflammation indicating parameters. X-rays of the chest showed elevated diaphragms. Within the next days pneumonia could be seen in the left lower lobe. The patient had to be under mechanical ventilation almost 24 hours per day. Hypercapnia and respiratory acidosis normalized and the patient was able to breathe spontaneously for longer periods. The following days cutaneous emphysema developed and X-rays revealed free abdominal air on day 9 of the hospital stay.

The radiological findings have been confirmed during follow up X-rays without any clinical correlate. Inflammatory markers were decreasing. After the pneumonia had healed almost completely, the times on mechanical ventilation could be reduced. Subphrenic air resolved completely without any intervention.

Free subphrenic air without any clinical signs of acute abdomen does not necessarily force a surgical exploration. Under frequent follow up investigations a wait-and-see strategy could be justified. An explanation for the subphrenic air could be an interstitial emphysema due to increased intrathoracic pressure caused by the prolonged noninvasive ventilation, releasing the air through the diaphragmatic gaps into the abdomen.

A

    19-year-old
    AGE

 patient suffering from

    Duchenne muscular dystrophy
    DIAGNOSIS

 was admitted to our hospital with an

    acute bronchopulmonary infection
    DIAGNOSIS

. Four months ago

    noninvasive ventilation
    MEDICATION

 was started because of

    hypercapnic respiratory failure
    SYMPTOMS

.

    Mechanical ventilation
    MEDICATION

 had been used so far only at night. At the time of admission

    spontaneous breathing was not possible
    NEG_FINDINGS

 due to

    exhaustion of the respiratory muscles
    NEG_FINDINGS

. The patient suffered from

    fever
    SYMPTOMS

,

    limited cough strength
    SYMPTOMS

 and

    dyspnoea at rest
    SYMPTOMS

. The

    abdomen was distended because of intestinal gas
    SYMPTOMS

    without clinical signs of acute abdomen
    NEG_FINDINGS

.

    Blood gas analysis
    PARACLINICAL

 showed

    respiratory acidosis
    BIOCHEMICAL

    even under mechanical ventilation
    NEG_FINDINGS

.

    Laboratory tests
    PARACLINICAL

 showed an

    elevation of the inflammation indicating parameters
    BIOCHEMICAL

.

    X-rays of the chest
    PARACLINICAL

 showed

    elevated diaphragms
    SYMPTOMS

. Within the next days

    pneumonia could be seen in the left lower lobe
    SYMPTOMS

. The patient had to be

    under mechanical ventilation almost 24 hours per day
    MEDICATION

.

    Hypercapnia
    BIOCHEMICAL

 and

    respiratory acidosis normalized
    BIOCHEMICAL

 and the patient was

    able to breathe spontaneously for longer periods
    SYMPTOMS

. The following days

    cutaneous emphysema
    SYMPTOMS

 developed and

    X-rays
    PARACLINICAL

 revealed

    free abdominal air
    SYMPTOMS

 on day 9 of the

    hospital stay
    MEDICATION

.

The radiological findings have been confirmed during

    follow up X-rays
    PARACLINICAL

    without any clinical correlate
    NEG_FINDINGS

.

    Inflammatory markers were decreasing
    BIOCHEMICAL

. After the

    pneumonia had healed almost completely
    SYMPTOMS

, the

    times on mechanical ventilation could be reduced
    MEDICATION

.

    Subphrenic air resolved completely
    SYMPTOMS

    without any intervention
    NEG_FINDINGS

.

    Free subphrenic air
    SYMPTOMS

    without any clinical signs of acute abdomen
    NEG_FINDINGS

 does

    not necessarily force a surgical exploration
    NEG_FINDINGS

. Under frequent follow up investigations a

    wait-and-see strategy
    MEDICATION

 could be justified. An explanation for the

    subphrenic air
    SYMPTOMS

 could be an

    interstitial emphysema
    MICROSCOPIC

 due to

    increased intrathoracic pressure
    SYMPTOMS

 caused by the

    prolonged noninvasive ventilation
    MEDICATION

,

    releasing the air through the diaphragmatic gaps into the abdomen
    MICROSCOPIC

.

Duchenne muscular dystrophy
acute bronchopulmonary infection


Consider muscle disease in children with elevated transaminase.

The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markers of hepatocellular injury but are highly concentrated in muscle cells. Consequently, muscular dystrophies such as Duchenne muscular dystrophy, lead to hypertransaminasemia. Elevation in ALT and AST is most striking during the early stages of disease, before onset of or when only subtle signs of muscle disease are present. Thus, the incidental finding of elevated ALT/AST may be the presenting sign of muscle disease in many children and provides an opportunity for early diagnosis. Many physicians, however, pursue extensive workup for liver disease in children who present with the incidental finding of elevated ALT/AST. This results in delayed diagnosis and initiation of treatment and increased expense and may lead to unnecessary invasive procedures. We report 12 patients with muscle disease who presented with a variety of symptoms and were found to have an incidental finding of elevated ALT/AST. We propose a rapid screening process for evaluating children with the incidental finding of elevated ALT/AST to shorten the time to diagnosis of muscle disease.

The

    transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
    BIOCHEMICAL

 are markers of

    hepatocellular injury
    BIOCHEMICAL

 but are

    highly concentrated in muscle cells
    MICROSCOPIC

. Consequently,

    muscular dystrophies
    DIAGNOSIS

 such as

    Duchenne muscular dystrophy
    DIAGNOSIS

, lead to

    hypertransaminasemia
    BIOCHEMICAL

.

    Elevation in ALT and AST
    BIOCHEMICAL

 is most striking during the early stages of disease, before onset of or when only

    subtle signs of muscle disease
    SYMPTOMS

 are present. Thus, the incidental finding of

    elevated ALT/AST
    BIOCHEMICAL

 may be the presenting sign of

    muscle disease
    DIAGNOSIS

 in many

    children
    AGE

 and provides an opportunity for early diagnosis. Many physicians, however, pursue

    extensive workup
    PARACLINICAL

 for

    liver disease
    DIAGNOSIS

 in

    children
    AGE

 who present with the incidental finding of

    elevated ALT/AST
    BIOCHEMICAL

. This results in delayed diagnosis and

    initiation of treatment
    MEDICATION

 and increased expense and may lead to

    unnecessary invasive procedures
    NEG_FINDINGS

. We report 12 patients with

    muscle disease
    DIAGNOSIS

 who presented with a variety of symptoms and were found to have an incidental finding of

    elevated ALT/AST
    BIOCHEMICAL

. We propose a rapid screening process for evaluating

    children
    AGE

 with the incidental finding of

    elevated ALT/AST
    BIOCHEMICAL

 to shorten the time to diagnosis of

    muscle disease
    DIAGNOSIS

.

muscular dystrophies
Duchenne muscular dystrophy
muscle disease
liver disease
muscle disease
muscle disease


Beneficial effect of ivabradine in dilated cardiomyopathy from Becker muscular dystrophy.

The I(f) blocker ivabradine reduces heart rate and improves systolic function without causing arterial hypotension. Ivabradine has not been reported to improve cardiac involvement in Becker muscular dystrophy (BMD).

In a 22-year-old Vietnamese male with BMD, cardiac involvement became apparent at age 19 years with reduced systolic function, which was treated with ramipril. At the age of 20 years, he developed sinus tachycardia, leg edema, coughing, and arterial hypotension. Dilated cardiomyopathy was diagnosed and ramipril was successfully replaced by candesartan, ivabradine, and furosemide. An attempt to discontinue ivabradine and increase candesartan was followed by recurrence of sinus tachycardia and reduction of blood pressure. Under ivabradine, candesartan, and spironolactone, which replaced furosemide, he achieved heart rates between 60 and 80 beats/min and systolic blood pressure values between 85 and 105 mmHg without heart failure.

Ivabradine normalizes sinus tachycardia and resolves heart failure in patients with dilated cardiomyopathy from BMD. In addition to normalization of the heart rate and remodeling of the left ventricle, ivabradine seems to also have a positive inotropic effect in dilated cardiomyopathy of BMD patients.

The

    I(f) blocker ivabradine
    MEDICATION

    reduces heart rate
    SYMPTOMS

 and

    improves systolic function
    SYMPTOMS

    without causing arterial hypotension
    NEG_FINDINGS

.

    Ivabradine
    NEG_FINDINGS

 has not been reported to

    improve cardiac involvement
    NEG_FINDINGS

 in

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

.

In a

    22-year-old
    AGE

    Vietnamese
    ETHNICITY

    male
    GENDER

 with

    BMD
    DIAGNOSIS

,

    cardiac involvement
    SYMPTOMS

 became apparent at

    age 19 years
    AGE

 with

    reduced systolic function
    SYMPTOMS

, which was treated with

    ramipril
    MEDICATION

. At the

    age of 20 years
    AGE

,

    he
    GENDER

 developed

    sinus tachycardia
    SYMPTOMS

,

    leg edema
    SYMPTOMS

,

    coughing
    SYMPTOMS

, and

    arterial hypotension
    SYMPTOMS

.

    Dilated cardiomyopathy
    DIAGNOSIS

 was diagnosed and

    ramipril was successfully replaced by candesartan, ivabradine, and furosemide
    MEDICATION

. An

    attempt to discontinue ivabradine and increase candesartan
    MEDICATION

 was followed by

    recurrence of sinus tachycardia
    SYMPTOMS

 and

    reduction of blood pressure
    SYMPTOMS

.

    Under ivabradine, candesartan, and spironolactone, which replaced furosemide
    MEDICATION

, he achieved

    heart rates between 60 and 80 beats/min
    SYMPTOMS

 and

    systolic blood pressure values between 85 and 105 mmHg
    SYMPTOMS

    without heart failure
    NEG_FINDINGS

.

    Ivabradine
    MEDICATION

    normalizes sinus tachycardia
    SYMPTOMS

 and

    resolves heart failure
    SYMPTOMS

 in patients with

    dilated cardiomyopathy
    DIAGNOSIS

 from

    BMD
    DIAGNOSIS

. In addition to

    normalization of the heart rate and remodeling of the left ventricle
    SYMPTOMS

,

    ivabradine
    MEDICATION

 seems to also have a

    positive inotropic effect
    SYMPTOMS

 in

    dilated cardiomyopathy
    DIAGNOSIS

 of

    BMD
    DIAGNOSIS

 patients.

without causing arterial hypotension
Ivabradine
improve cardiac involvement
without heart failure

Becker muscular dystrophy (BMD)
BMD
Dilated cardiomyopathy
dilated cardiomyopathy
BMD
dilated cardiomyopathy
BMD


Anaplastic medulloblastoma in a child with Duchenne muscular dystrophy.

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.

A

    9-year-old
    AGE

    boy
    GENDER

 with known

    Duchenne type muscular dystrophy (DMD)
    DIAGNOSIS

 presented with

    signs of increased intracranial pressure
    SYMPTOMS

.

    Radiological investigations
    PARACLINICAL

 revealed a

    lesion in the midline of the posterior fossa
    SYMPTOMS

.

    Subtotal resection
    MEDICATION

 was performed.

    Pathology findings
    PARACLINICAL

 were consistent with the diagnosis of

    anaplastic medulloblastoma
    DIAGNOSIS

. The

    postoperative lumbar CSF
    PARACLINICAL

 was

    positive for malignant cells
    MICROSCOPIC

. Postoperatively, the patient showed

    severe neurological deterioration
    SYMPTOMS

 and

    lost his capacity to walk
    SYMPTOMS

.

    He
    GENDER

 was treated with

    craniospinal radiation followed by nonintensive chemotherapy
    MEDICATION

. At 30 months postsurgery, he was

    still in complete remission
    SYMPTOMS

 but

    had not recovered his walking ability
    NEG_FINDINGS

. This is the second report of a

    malignant brain tumor
    DIAGNOSIS

 in a

    boy
    GENDER

 with

    DMD
    DIAGNOSIS

. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of

    medulloblastoma
    DIAGNOSIS

 in

    children
    AGE

 with

    DMD
    DIAGNOSIS

.

Duchenne type muscular dystrophy (DMD)
anaplastic medulloblastoma
malignant brain tumor
DMD
medulloblastoma
DMD


Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone.

Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.

Recently we reported a

    cytoplasmic sodium overload
    MICROSCOPIC

 to cause a

    severe osmotic oedema
    SYMPTOMS

 in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. Our results suggested that this

    dual overload of sodium ions and water
    MICROSCOPIC

 precedes the dystrophic process and persists until

    fatty muscle degeneration
    SYMPTOMS

 is complete. The present paper addresses the questions as to whether these

    overloads
    SYMPTOMS

 are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various

    diuretic drugs
    MEDICATION

 on a cell model of

    DMD
    DIAGNOSIS

, i.e.

    rat diaphragm strips
    MICROSCOPIC

 previously exposed to amphotericin B. We found that both

    carbonic anhydrase inhibitors
    MEDICATION

 and

    aldosterone antagonists
    MEDICATION

 were able to

    repolarise depolarised muscle fibres
    SYMPTOMS

. Since

    carbonic anhydrase inhibitors
    MEDICATION

 are known to have

    acidifying effects
    SYMPTOMS

 and this might be detrimental to the ventilation of

    DMD
    DIAGNOSIS

 patients, we mainly concentrated on the

    modern spironolactone derivative, eplerenone
    MEDICATION

. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we

    administered this drug
    MEDICATION

 to a

    22-yr-old
    AGE

    female
    GENDER

    DMD
    DIAGNOSIS

 patient who was

    bound to an electric wheelchair
    MEDICATION

 and

    has had no corticosteroid therapy before
    NEG_FINDINGS

.

    Eplerenone
    MEDICATION

    decreased both cytoplasmic sodium and water overload
    MICROSCOPIC

 and

    increased muscle strength and mobility
    SYMPTOMS

. We conclude that

    eplerenone
    MEDICATION

 has beneficial effects on

    DMD muscle
    DIAGNOSIS

. In our opinion the

    cytoplasmic oedema
    MICROSCOPIC

 is cytotoxic and should be treated before

    fatty degeneration
    SYMPTOMS

 takes place.

severe osmotic oedema
fatty muscle degeneration
overloads
repolarise depolarised muscle fibres
acidifying effects
increased muscle strength and mobility
fatty degeneration

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD
DMD muscle


Phenotype-genotype analysis of dystrophinopathy caused by duplication mutation in Dystrophin gene in an African patient.

The dystrophinopathies, duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are common X-linked genetic myopathies resulting from mutations in the dystrophin gene. Duplication is an uncommon mechanism of mutation occurring in about 5% of DMD cases. The global prevalence of DMD is reported as 1/18,000 males. There is little clinical or epidemiological data on African patients.

To present the genotype-phenotype analysis of dystrophinopathy with an exon 8 through 9 duplication mutation in a patient of African/Ghanaian descent and his asymptomatic mother.

Investigations including a biopsy of the vastus lateralis muscle and genetic testing of the patient and his mother.

Genetic testing demonstrated a duplication of exons 8 through 9 of the dystrophin gene in both the patient and his mother. The muscle biopsy of the patient showed partial expression of the dystrophin protein. In the absence of a family history of dystrophinopathy, we hypothesize that this is a sporadic mutation occurring in the grand maternal lineage.

This case extends the world wide epidemiology of this disease to include the African/Ghanaian population and confirms the vulnerability of the dystrophin gene to recurrent spontaneous mutations at the exon 8 and 9 site.

The

    dystrophinopathies
    DIAGNOSIS

,

    duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 are common

    X-linked
    GENETICS

    genetic myopathies
    DIAGNOSIS

 resulting from

    mutations in the dystrophin gene
    GENETICS

.

    Duplication
    GENETICS

 is an uncommon mechanism of mutation occurring in about 5% of

    DMD
    DIAGNOSIS

 cases. The global prevalence of

    DMD
    DIAGNOSIS

 is reported as 1/18,000

    males
    GENDER

. There is little clinical or epidemiological data on

    African
    ETHNICITY

 patients.

To present the

    genotype-phenotype analysis
    PARACLINICAL

 of

    dystrophinopathy
    DIAGNOSIS

 with an

    exon 8 through 9 duplication mutation
    GENETICS

 in a patient of

    African/Ghanaian descent
    ETHNICITY

 and

    his
    GENDER

    asymptomatic mother
    FAMILY

.

    Investigations including a biopsy of the vastus lateralis muscle
    PARACLINICAL

 and

    genetic testing of the patient and his mother
    PARACLINICAL

.

    Genetic testing
    PARACLINICAL

 demonstrated a

    duplication of exons 8 through 9 of the dystrophin gene in both the patient and his mother
    GENETICS

. The

    muscle biopsy
    PARACLINICAL

 of the patient showed

    partial expression of the dystrophin protein
    MICROSCOPIC

. In the

    absence of a family history of dystrophinopathy
    NEG_FINDINGS

, we hypothesize that this is a

    sporadic mutation occurring in the grand maternal lineage
    GENETICS

.

This case extends the world wide epidemiology of this disease to include the

    African/Ghanaian
    ETHNICITY

 population and confirms the

    vulnerability of the dystrophin gene to recurrent spontaneous mutations at the exon 8 and 9 site
    GENETICS

.

dystrophinopathies
duchenne muscular dystrophy (DMD)
Becker muscular dystrophy
genetic myopathies
DMD
DMD
dystrophinopathy

African
African/Ghanaian descent
African/Ghanaian