Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy.

Few cases of dystrophinopathy show an asymptomatic phenotype with mutations in the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene. Our patient showed increased serum creatine kinase levels at 12 years of age. A muscle biopsy at 15 years of age led to a diagnosis of Becker muscular dystrophy. The patient showed a slight decrease in cardiac function at the age of 21 years and was administered a β-blocker, but there was no muscle involvement even at the age of 27 years. A deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene was detected, and dystrophin protein expression was ∼15% that of control level. We propose that in-frame deletion of exons 3-9 may produce a functional protein, and that multiexon skipping therapy targeting these exons may be feasible for severe dystrophic patients with a mutation in the 5' hot spot of the DMD gene.

Few cases of

    dystrophinopathy
    DIAGNOSIS

 show an

    asymptomatic
    SYMPTOMS

 phenotype with

    mutations in the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene
    GENETICS

. Our patient showed

    increased serum creatine kinase levels
    BIOCHEMICAL

 at

    12 years of age
    AGE

. A

    muscle biopsy
    PARACLINICAL

 at

    15 years of age
    AGE

 led to a diagnosis of

    Becker muscular dystrophy
    DIAGNOSIS

. The patient showed a

    slight decrease in cardiac function
    SYMPTOMS

 at the

    age of 21 years
    AGE

 and was administered a

    β-blocker
    MEDICATION

, but there was

    no muscle involvement
    NEG_FINDINGS

 even at the

    age of 27 years
    AGE

. A

    deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene
    GENETICS

 was detected, and

    dystrophin protein expression was ∼15% that of control level
    BIOCHEMICAL

. We propose that

    in-frame deletion of exons 3-9
    GENETICS

 may produce a functional protein, and that

    multiexon skipping therapy targeting these exons
    MEDICATION

 may be feasible for

    severe dystrophic
    DIAGNOSIS

 patients with a

    mutation in the 5' hot spot of the DMD gene
    GENETICS

.

dystrophinopathy
Becker muscular dystrophy
severe dystrophic

asymptomatic
slight decrease in cardiac function


Hybrid minigene splicing assay verified the pathogenicity of a novel splice site variant in the dystrophin gene of a Chinese patient with typical Duchenne muscular dystrophy phenotype.

Duchenne muscular dystrophy (DMD) is typically caused by disrupting the reading frame of the dystrophin gene: approximately 70%-80% of mutational events are represented by deletions or duplications of one or more exons in the dystrophin gene, and the remaining cases by subtle mutations, including point mutations, small indels, small inversions, and complex small rearrangements. The dystrophin gene is the largest known gene with one of the highest known rates of new mutations.

Deletions and duplications were detected in the DMD gene of the proband by using multiple ligation-dependent probe amplification (MLPA). Targeted next-generation sequencing (NGS) was used in the subtle mutation detection, followed by Sanger sequencing confirmation. The effect of the mutation on the splicing of the DMD gene was assessed by bioinformatics prediction and hybrid minigene splicing assay (HMSA).

Neither duplication nor deletion was found in the DMD gene of the proband. While a novel splice site mutation c.6762+1G>C was identified in the proband by NGS and Sanger sequencing, and his mother was heterozygous at the same site. Bioinformatics predicted that the 5' donor splice site of intron 46 disappeared because of the mutation, which would lead to aberrant splicing and introduce premature stop codon. The HMSA results were in agreement with the prediction.

The novel splice site mutation caused DMD in the proband by aberrant splicing. We suggested that combined applications of MLPA, NGS, HMSA and bioinformatics are comprehensive and effective methods for diagnosis and aberrant splicing study of DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is typically caused by

    disrupting the reading frame of the dystrophin gene
    GENETICS

: approximately 70%-80% of mutational events are represented by

    deletions or duplications of one or more exons in the dystrophin gene
    GENETICS

, and the remaining cases by

    subtle mutations
    GENETICS

, including

    point mutations, small indels, small inversions
    GENETICS

, and

    complex small rearrangements
    GENETICS

. The

    dystrophin gene
    GENETICS

 is the largest known gene with one of the highest known rates of new mutations.

    Deletions and duplications
    GENETICS

 were

    detected in the DMD gene
    GENETICS

 of the proband by using

    multiple ligation-dependent probe amplification (MLPA)
    PARACLINICAL

.

    Targeted next-generation sequencing (NGS)
    PARACLINICAL

 was used in the

    subtle mutation detection
    PARACLINICAL

, followed by

    Sanger sequencing confirmation
    PARACLINICAL

. The effect of the

    mutation on the splicing of the DMD gene
    GENETICS

 was assessed by

    bioinformatics prediction
    PARACLINICAL

 and

    hybrid minigene splicing assay (HMSA)
    PARACLINICAL

.

    Neither duplication nor deletion was found in the DMD gene of the proband
    NEG_FINDINGS

. While a

    novel splice site mutation c.6762+1G>C
    GENETICS

 was identified in the

    proband
    GENDER

 by

    NGS and Sanger sequencing
    PARACLINICAL

, and

    his
    GENDER

    mother was heterozygous at the same site
    FAMILY

. Bioinformatics predicted that

    the 5' donor splice site of intron 46 disappeared because of the mutation
    GENETICS

, which would lead to

    aberrant splicing and introduce premature stop codon
    GENETICS

. The

    HMSA
    PARACLINICAL

 results were in agreement with the prediction.

The

    novel splice site mutation
    GENETICS

 caused

    DMD
    DIAGNOSIS

 in the proband by

    aberrant splicing
    GENETICS

. We suggested that combined applications of

    MLPA, NGS, HMSA
    PARACLINICAL

 and bioinformatics are comprehensive and effective methods for diagnosis and

    aberrant splicing study
    PARACLINICAL

 of

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Somatic mosaicism due to a reversion variant causing hemi-atrophy: a novel variant of dystrophinopathy.

We describe a case of hemi-atrophy in a young adult male, with a positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD). The patient showed progressive weakness localized to the left side, an abnormal electromyography, and creatine kinase levels >3000 IU/l. Muscle biopsy showed both dystrophin-positive and -negative myofibers. An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3-7 was inherited, but the muscle biopsy showed dystrophin mRNA with and without the duplication. Dystrophin quantification using mass spectrometry showed 25% normal dystrophin protein levels in the muscle biopsy from the stronger right side. Sex chromosome aneuploidy was ruled out. We conclude that the patient inherited the duplication variant, but early in development an inner cell mass underwent a somatic recombination event removing the duplication and restoring dystrophin expression. To our knowledge, this is the first report of a reversion leading to somatic mosaicism in DMD.

We describe a case of

    hemi-atrophy
    SYMPTOMS

 in a

    young adult
    AGE

    male
    GENDER

, with a

    positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD)
    FAMILY

. The patient showed

    progressive weakness localized to the left side
    SYMPTOMS

, an

    abnormal electromyography
    SYMPTOMS

, and creatine kinase levels >3000 IU/l.

    Muscle biopsy
    PARACLINICAL

 showed

    both dystrophin-positive and -negative myofibers
    MICROSCOPIC

.

    An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3-7 was inherited
    GENETICS

, but the

    muscle biopsy
    PARACLINICAL

 showed

    dystrophin mRNA with and without the duplication
    GENETICS

.

    Dystrophin quantification using mass spectrometry
    PARACLINICAL

 showed

    25% normal dystrophin protein levels in the muscle biopsy from the stronger right side
    BIOCHEMICAL

.

    Sex chromosome aneuploidy was ruled out
    NEG_FINDINGS

. We conclude that the patient

    inherited the duplication variant
    GENETICS

, but early in development an inner cell mass underwent a

    somatic recombination event removing the duplication and restoring dystrophin expression
    GENETICS

. To our knowledge, this is the first report of a

    reversion leading to somatic mosaicism
    GENETICS

 in

    DMD
    DIAGNOSIS

.


Fat Emboli Syndrome in a Child with Duchenne Muscular Dystrophy After Minor Trauma.

Fat embolism syndrome is the result of systemic manifestations of fat emboli in the microcirculation. Duchenne muscular dystrophy is a condition that increases the risk of fracture resulting in fat emboli.

We describe a patient with Duchenne muscular dystrophy who exhibited cardiopulmonary, neurologic, and ophthalmologic sequelae consistent with fat emboli syndrome after minor trauma. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Fat embolism syndrome is a rare but important consideration with significant morbidity and risk of mortality in patients with Duchenne muscular dystrophy after even minor trauma. Early recognition and aggressive resuscitation are crucial to positive clinical outcomes.

    Fat embolism syndrome
    DIAGNOSIS

 is the result of

    systemic manifestations of fat emboli in the microcirculation
    SYMPTOMS

.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is a condition that increases the risk of

    fracture
    SYMPTOMS

 resulting in

    fat emboli
    SYMPTOMS

.

We describe a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 who exhibited

    cardiopulmonary, neurologic, and ophthalmologic sequelae
    SYMPTOMS

 consistent with

    fat emboli syndrome
    SYMPTOMS

 after

    minor trauma
    SYMPTOMS

. WHY SHOULD AN

    EMERGENCY PHYSICIAN
    PARACLINICAL

 BE AWARE OF THIS?:

    Fat embolism syndrome
    DIAGNOSIS

 is a rare but important consideration with significant morbidity and risk of mortality in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 after even

    minor trauma
    SYMPTOMS

. Early recognition and

    aggressive resuscitation
    MEDICATION

 are crucial to positive clinical outcomes.

Fat embolism syndrome
Duchenne muscular dystrophy
Duchenne muscular dystrophy
Fat embolism syndrome
Duchenne muscular dystrophy


Concordant utrophin upregulation in phenotypically discordant DMD/BMD brothers.

Utrophin expression was investigated in two phenotypically discordant Duchenne muscular dystrophy half-brothers. The youngest was wheelchair-bound at age 9, while his mildly affected older brother was able to walk without difficulties at age 15. DNA analysis revealed an out-of-frame exon 2 duplication in the DMD gene, associated with muscle dystrophin protein deficiency. Utrophin localization and quantity was analyzed and compared in both sibs to verify whether this could explain the milder phenotype of the older brother. Immunofluorescence analysis showed a clear sarcolemmal labeling for utrophin in both of them, which was present in regenerating as well as in mature fibers. On western blot analysis, utrophin amount was increased 3.4 and 3.3 fold respectively, as compared to normal controls, while it was increased 1.7 to 4.0 fold in a group of DMD patients within the typical range of clinical progression. These data are in accordance with our previous observations suggesting no correlation between phenotype severity and utrophin up-regulation or sarcolemmal localization in dystrophinopathies. Finding the protective mechanisms in patients with milder course is of utmost interest to direct therapeutic targets.

    Utrophin expression
    BIOCHEMICAL

 was investigated in two

    phenotypically discordant Duchenne muscular dystrophy
    FAMILY

    half-brothers
    FAMILY

. The

    youngest
    GENDER

 was

    wheelchair-bound
    MEDICATION

 at

    age 9
    AGE

, while

    his
    GENDER

    mildly affected older brother
    FAMILY

 was

    able to walk without difficulties
    NEG_FINDINGS

 at

    age 15
    AGE

.

    DNA analysis
    PARACLINICAL

 revealed an

    out-of-frame exon 2 duplication in the DMD gene
    GENETICS

, associated with

    muscle dystrophin protein deficiency
    BIOCHEMICAL

. Utrophin localization and quantity was analyzed and compared in both sibs to verify whether this could explain the milder phenotype of the

    older brother
    FAMILY

.

    Immunofluorescence analysis
    PARACLINICAL

 showed a

    clear sarcolemmal labeling for utrophin in
    MICROSCOPIC

 both of them

    , which was present in regenerating as well as in mature fibers
    MICROSCOPIC

. On

    western blot analysis
    PARACLINICAL

,

    utrophin amount was increased 3.4 and 3.3 fold respectively
    BIOCHEMICAL

, as compared to normal controls, while it was

    increased 1.7 to 4.0 fold
    BIOCHEMICAL

 in a group of

    DMD
    DIAGNOSIS

 patients within the typical range of clinical progression. These data are in accordance with our previous observations suggesting

    no correlation between
    NEG_FINDINGS

 phenotype severity and

    utrophin up-regulation or sarcolemmal localization
    NEG_FINDINGS

 in

    dystrophinopathies
    DIAGNOSIS

. Finding the protective mechanisms in patients with milder course is of utmost interest to direct therapeutic targets.


Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems.

The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene.

The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene.

This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

We describe the clinical features of a

    boy
    GENDER

 with

    bilateral Duane retraction syndrome (DRS)
    SYMPTOMS

,

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, and other medical problems.

The

    child
    AGE

 was followed-up for

    five years
    AGE

; his chart was reviewed, including the results of a

    muscle biopsy
    PARACLINICAL

 and

    genetic testing
    PARACLINICAL

.

    Multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

 was used to

    interrogate deletions/duplications in the dystrophin gene
    PARACLINICAL

.

The proband had

    bilateral DRS
    SYMPTOMS

 with

    otherwise normal ocular motility
    NEG_FINDINGS

;

    he
    GENDER

 also had

    developmental delay
    SYMPTOMS

,

    mild mental retardation
    SYMPTOMS

, and

    seizures
    SYMPTOMS

. Clinical diagnosis of

    DMD
    DIAGNOSIS

 included

    progressive proximal weakness
    SYMPTOMS

,

    highly elevated creatine kinase levels
    BIOCHEMICAL

, and a

    muscle biopsy
    PARACLINICAL

 showing

    significant dystrophic changes including contracted, degenerative, and regenerative fibers
    MICROSCOPIC

, and

    negative dystrophin immunostaining
    NEG_FINDINGS

.

    MLPA
    PARACLINICAL

 documented

    duplication of exons 3 and 4 of the dystrophin gene
    GENETICS

.

This

    boy
    GENDER

 is the third patient to be reported with

    DRS
    DIAGNOSIS

 and

    DMD
    DIAGNOSIS

, the second with

    bilateral DRS
    SYMPTOMS

 and the only one with other

    neurologic features
    SYMPTOMS

.

    Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS)
    MICROSCOPIC

 in

    DMD
    DIAGNOSIS

, leaving open the question of whether this co-occurrence is the result of the

    genetic muscle abnormality
    GENETICS

,

    CNS effects
    SYMPTOMS

 caused by

    dystrophin mutations
    GENETICS

, or chance.

Duchenne muscular dystrophy (DMD)
DMD
DRS
DMD
DMD

otherwise normal ocular motility
negative dystrophin immunostaining


A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.

Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy.

The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD.

Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.

    Severe intellectual disability
    SYMPTOMS

 has been reported in a subgroup of patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 but is not typically associated with

    Becker muscular dystrophy
    DIAGNOSIS

.

The authors report a

    13-year-old
    AGE

    boy
    GENDER

, with

    severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile)
    SYMPTOMS

,

    attention-deficit hyperactivity disorder
    DIAGNOSIS

, and

    mild muscle weakness
    SYMPTOMS

.

    He
    GENDER

 had

    elevated serum creatine kinase
    BIOCHEMICAL

 and

    dystrophic changes
    SYMPTOMS

 on

    muscle biopsy
    PARACLINICAL

.

    Dystrophin immunohistochemistry
    PARACLINICAL

 revealed

    decreased staining with the C-terminal and mid-rod antibodies
    BIOCHEMICAL

 and

    essentially absent staining of the N-terminal immunostain
    BIOCHEMICAL

.

    Sequencing of muscle mRNA
    PARACLINICAL

 revealed

    aberrant splicing due to a c.10797+5G > A mutation in DMD
    GENETICS

.

    Dystrophinopathy
    DIAGNOSIS

 may be associated with

    predominantly cognitive impairment
    SYMPTOMS

 and

    neurobehavioral disorder
    DIAGNOSIS

, and should be considered in the

    differential diagnosis
    PARACLINICAL

 of

    unexplained cognitive or psychiatric disturbance
    SYMPTOMS

 in

    males
    GENDER

.


The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype.

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.

    Substitutions, deletions and duplications in the dystrophin gene
    GENETICS

 lead to either the

    severe Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 or

    mild Becker muscular dystrophy
    DIAGNOSIS

 depending on whether

    out-of-frame or in-frame transcripts
    GENETICS

 are produced. We identified a

    DMD
    DIAGNOSIS

 case (

    GSΔ44)
    DIAGNOSIS

 where the correlation between genotype and phenotype is not respected, even if carrying a

    typical Duchenne mutation (exon 44 deletion)
    GENETICS

 a

    Becker-like phenotype
    SYMPTOMS

 was observed. Here we report that in this patient,

    partial restoration of an in-frame transcript
    GENETICS

 occurs by

    natural skipping of exon 45
    GENETICS

 and that this is due to the

    lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA
    GENETICS

. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those

    DMD
    DIAGNOSIS

 therapeutic treatments, which requires

    exon 45 skipping
    MEDICATION

.


Next-generation sequencing discloses a nonsense mutation in the dystrophin gene from long preserved dried umbilical cord and low-level somatic mosaicism in the proband mother.

Duchene muscular dystrophy (DMD) is a progressive muscle wasting disease, caused by mutations in the dystrophin (DMD) on the X chromosome. One-third of patients are estimated to have de novo mutations. To provide in-depth genetic counseling, the comprehensive identification of mutations is mandatory. However, many DMD patients did not undergo genetic diagnosis because detailed genetic diagnosis was not available or their mutational types were difficult to identify. Here we report the genetic testing of a sporadic DMD boy, who died >20 years previously. Dried umbilical cord preserved for 38 years was the only available source of genomic DNA. Although the genomic DNA was severely degraded, multiplex ligation-dependent probe amplification analysis was performed but no gross mutations found. Sanger sequencing was attempted but not conclusive. Next-generation sequencing (NGS) was performed by controlling the tagmentation during library preparation. A nonsense mutation in DMD (p.Arg2095*) was clearly identified in the proband. Consequently, the identical mutation was detected as an 11% mosaic mutation from his healthy mother. Finally, the proband's sister was diagnosed as a non-carrier of the mutation. Thus using NGS we have identified a pathogenic DMD mutation from degraded DNA and low-level somatic mosaicism, which would have been overlooked using Sanger sequencing.

    Duchene muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    progressive muscle wasting disease
    DIAGNOSIS

, caused by

    mutations in the dystrophin (DMD) on the X chromosome
    GENETICS

. One-third of patients are estimated to have

    de novo mutations
    GENETICS

. To provide in-depth genetic counseling, the comprehensive identification of mutations is mandatory. However, many

    DMD
    DIAGNOSIS

 patients did not undergo

    genetic diagnosis
    PARACLINICAL

 because

    detailed genetic diagnosis was not
    NEG_FINDINGS

 available or their mutational types were difficult to identify. Here we report the

    genetic testing
    PARACLINICAL

 of a

    sporadic DMD
    DIAGNOSIS

    boy
    GENDER

, who

    died
    SYMPTOMS

 >20 years previously.

    Dried umbilical cord preserved for 38 years
    PARACLINICAL

 was the only available source of genomic DNA. Although the

    genomic DNA was severely degraded
    MICROSCOPIC

,

    multiplex ligation-dependent probe amplification analysis
    PARACLINICAL

 was performed but

    no gross mutations found
    NEG_FINDINGS

.

    Sanger sequencing was attempted but not conclusive
    NEG_FINDINGS

.

    Next-generation sequencing (NGS)
    PARACLINICAL

 was performed by

    controlling the tagmentation during library preparation
    PARACLINICAL

. A

    nonsense mutation in DMD (p.Arg2095*)
    GENETICS

 was clearly identified in the proband. Consequently,

    the identical mutation was detected as an 11% mosaic mutation from his healthy mother
    FAMILY

. Finally,

    the proband's sister was diagnosed as a non-carrier of the mutation
    FAMILY

. Thus using

    NGS
    PARACLINICAL

 we have identified a

    pathogenic DMD mutation
    GENETICS

 from degraded DNA and

    low-level somatic mosaicism
    GENETICS

, which

    would have been overlooked using Sanger sequencing
    NEG_FINDINGS

.

Duchene muscular dystrophy (DMD)
progressive muscle wasting disease
DMD
sporadic DMD


Peripheral nerve blocks as the sole anesthetic technique in a patient with severe Duchenne muscular dystrophy.

General anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are associated with high risks of complications, including rhabdomyolysis, malignant hyperthermia, hemodynamic instability, and postoperative mechanical ventilation. Here, we describe peripheral nerve blocks as a safe approach to anesthesia in a patient with severe Duchenne muscular dystrophy who was scheduled to undergo surgery. A 22-year-old male patient was scheduled to undergo reduction and internal fixation of a left distal femur fracture. He had been diagnosed with Duchenne muscular dystrophy at 5 years of age, and had no locomotive capability except for that of the finger flexors and toe extensors. He had developed symptoms associated with dyspnea 5 years before and required intermittent ventilation. We blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus under ultrasound on the left leg. The patient underwent a successful operation using peripheral nerve blocks with no complications. In conclusion general anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are unsafe approaches to anesthesia because of hemodynamic instability and respiratory depression. Peripheral nerve blocks are the best way to reduce the risks of critical complications, and are a safe and feasible approach to anesthesia in patients with severe Duchenne muscular dystrophy.

    General anesthesia
    MEDICATION

 and

    central neuraxial blockades
    MEDICATION

 in patients with

    severe Duchenne muscular dystrophy
    DIAGNOSIS

 are associated with high risks of complications, including

    rhabdomyolysis
    SYMPTOMS

,

    malignant hyperthermia
    SYMPTOMS

,

    hemodynamic instability
    SYMPTOMS

, and

    postoperative mechanical ventilation
    MEDICATION

. Here, we describe

    peripheral nerve blocks
    MEDICATION

 as a safe approach to

    anesthesia
    MEDICATION

 in a patient with

    severe Duchenne muscular dystrophy
    DIAGNOSIS

 who was scheduled to undergo

    surgery
    MEDICATION

. A

    22-year-old
    AGE

    male
    GENDER

 patient was scheduled to undergo

    reduction and internal fixation of a left distal femur fracture
    MEDICATION

.

    He
    GENDER

 had been diagnosed with

    Duchenne muscular dystrophy
    DIAGNOSIS

    at 5 years of age
    AGE

, and had

    no locomotive capability except for that of the finger flexors and toe extensors
    NEG_FINDINGS

.

    He
    GENDER

 had developed

    symptoms associated with dyspnea
    SYMPTOMS

 5 years before and required

    intermittent ventilation
    MEDICATION

. We

    blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus
    MEDICATION

 under

    ultrasound on the left leg
    PARACLINICAL

. The patient underwent a

    successful operation
    MEDICATION

 using

    peripheral nerve blocks
    MEDICATION

 with

    no complications
    NEG_FINDINGS

. In conclusion

    general anesthesia
    MEDICATION

 and

    central neuraxial blockades
    MEDICATION

 in patients with

    severe Duchenne muscular dystrophy
    DIAGNOSIS

 are unsafe approaches to

    anesthesia
    MEDICATION

 because of

    hemodynamic instability
    SYMPTOMS

 and

    respiratory depression
    SYMPTOMS

.

    Peripheral nerve blocks
    MEDICATION

 are the best way to reduce the risks of critical complications, and are a safe and feasible approach to

    anesthesia
    MEDICATION

 in patients with

    severe Duchenne muscular dystrophy
    DIAGNOSIS

.

severe Duchenne muscular dystrophy
severe Duchenne muscular dystrophy
Duchenne muscular dystrophy
severe Duchenne muscular dystrophy
severe Duchenne muscular dystrophy

rhabdomyolysis
malignant hyperthermia
hemodynamic instability
symptoms associated with dyspnea
hemodynamic instability
respiratory depression


Laparoscopic suture repair of idiopathic gastric perforation in Duchenne muscular dystrophy.

We report herein an adolescent case of Duchenne muscular dystrophy (DMD) with idiopathic gastric perforation, in which emergency surgical repair was performed laparoscopically. A 14-year-old nonambulatory boy with DMD was brought to our emergency department with sudden onset of severe abdominal pain and distention. Plain radiograph and computed tomography confirmed the presence of free intraperitoneal air and intrapelvic effusion. The patient elected to undergo laparoscopic inspection with 4 trocars, revealing a focal perforation, 3-4 cm in diameter, on the upper gastric body near the diaphragm. The stomach was also found to have a thin wall without evidence of peptic ulcer disease or other abnormalities. An interrupted suture was placed using 4-0 PDS. The abdomen was extensively irrigated, and multiple J-Vac drains were left in situ. Total operation time was 90 min, and no intraoperative complications were encountered. Enteral feeding through a nasogastric tube was started on postoperative day 7. The postoperative course has been uneventful as of the 12-month follow-up. Pediatric surgeons should be aware of the increased risk of gastric perforation associated with DMD, and that laparoscopic repair can be safely performed even in emergency settings.

We report herein an

    adolescent
    AGE

 case of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 with

    idiopathic gastric perforation
    SYMPTOMS

, in which

    emergency surgical repair
    MEDICATION

 was performed

    laparoscopically
    MEDICATION

. A

    14-year-old
    AGE

    nonambulatory
    NEG_FINDINGS

    boy
    GENDER

 with

    DMD
    DIAGNOSIS

 was brought to our emergency department with

    sudden onset
    SYMPTOMS

 of

    severe abdominal pain
    SYMPTOMS

 and

    distention
    SYMPTOMS

.

    Plain radiograph and computed tomography
    PARACLINICAL

 confirmed the presence of

    free intraperitoneal air and intrapelvic effusion
    SYMPTOMS

. The patient elected to undergo

    laparoscopic inspection with 4 trocars
    MEDICATION

, revealing a

    focal perforation, 3-4 cm in diameter, on the upper gastric body near the diaphragm
    SYMPTOMS

. The

    stomach was also found to have a thin wall
    SYMPTOMS

    without evidence of peptic ulcer disease or other abnormalities
    NEG_FINDINGS

.

    An interrupted suture was placed using 4-0 PDS
    MEDICATION

. The

    abdomen was extensively irrigated
    MEDICATION

, and

    multiple J-Vac drains were left in situ
    MEDICATION

.

    Total operation time was 90 min
    MEDICATION

, and

    no intraoperative complications
    NEG_FINDINGS

 were encountered.

    Enteral feeding through a nasogastric tube
    MEDICATION

 was started on postoperative day 7. The postoperative course has been uneventful as of the 12-month follow-up. Pediatric surgeons should be aware of the increased risk of

    gastric perforation
    SYMPTOMS

 associated with

    DMD
    DIAGNOSIS

, and that

    laparoscopic repair
    MEDICATION

 can be safely performed even in emergency settings.


Restless leg syndrome exacerbated by amytriptiline in a patient with Duchenne Muscular Dystrophy.

We report an unusual case of a Duchenne Muscular Dystrophy(DMD) patient who initiated a restless leg syndrome after the use of amytriptiline. The prescription and use of this medication for patients with persistent neuropathic pain is relatively common, especially for patients with DMD. Normally, this medication is well tolerated, however, we now report the occurrence of an induction or intensification of a restless leg syndrome case in a young patient with DMD, treated with amytriptiline for his chronic pain.

We report an unusual case of a

    Duchenne Muscular Dystrophy(DMD)
    DIAGNOSIS

 patient who initiated a

    restless leg syndrome
    SYMPTOMS

 after the use of

    amytriptiline
    MEDICATION

. The prescription and use of this

    medication
    MEDICATION

 for patients with

    persistent neuropathic pain
    DIAGNOSIS

 is relatively common, especially for patients with

    DMD
    DIAGNOSIS

. Normally, this medication is well tolerated, however, we now report the occurrence of an

    induction or intensification of a restless leg syndrome
    SYMPTOMS

 case in a

    young
    AGE

 patient with

    DMD
    DIAGNOSIS

, treated with

    amytriptiline
    MEDICATION

 for his

    chronic pain
    DIAGNOSIS

.

Duchenne Muscular Dystrophy(DMD)
persistent neuropathic pain
DMD
DMD
chronic pain


Novel Use of Tolvaptan in a Pediatric Patient With Congestive Heart Failure Due to Duchenne Muscular Dystrophy and Congenital Adrenal Hyperplasia.

Successful management of hyponatremia in heart failure patients requires a multifaceted approach in order to preserve end-organ function. We describe the novel use of a selective vasopressin receptor antagonist, tolvaptan, for management of hyponatremia in a 17-year-old Caucasian male with severe Duchenne muscular dystrophy, congestive heart failure (CHF), and congenital adrenal hyperplasia. The medical history was significant for recurrent admissions for hyponatremia secondary to adrenal crises, which was also exacerbated by his CHF. After initiation of tolvaptan and its extended administration, he had no further hyponatremia-related admissions and no adverse reactions. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed.

Successful management of

    hyponatremia
    DIAGNOSIS

 in

    heart failure
    DIAGNOSIS

 patients requires a

    multifaceted approach
    MEDICATION

 in order to preserve

    end-organ function
    SYMPTOMS

. We describe the

    novel use of a selective vasopressin receptor antagonist, tolvaptan
    MEDICATION

, for management of

    hyponatremia
    DIAGNOSIS

 in a

    17-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

 with

    severe Duchenne muscular dystrophy
    DIAGNOSIS

,

    congestive heart failure (CHF)
    DIAGNOSIS

, and

    congenital adrenal hyperplasia
    DIAGNOSIS

. The medical history was significant for

    recurrent admissions for hyponatremia secondary to adrenal crises
    SYMPTOMS

, which was also exacerbated by his

    CHF
    DIAGNOSIS

. After

    initiation of tolvaptan and its extended administration
    MEDICATION

,

    he
    GENDER

 had

    no further hyponatremia-related admissions
    NEG_FINDINGS

 and

    no adverse reactions
    NEG_FINDINGS

. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed.

hyponatremia
heart failure
hyponatremia
severe Duchenne muscular dystrophy
congestive heart failure (CHF)
congenital adrenal hyperplasia
CHF


Obesity and Premature Loss of Mobility in Two Adolescents with Becker Muscular Dystrophy After HeartMate II Implantation.

Weight gain is common after implantation of continuous-flow ventricular assist devices. Obesity can have a significant negative impact on mobility. For adolescents with Becker muscular dystrophy (BMD), for whom the ability to ambulate often persists into the mid-3rd decade, preservation of functional ability is critical. We report two cases of Thoratec HeartMate II left ventricular assist device (LVAD) implantation in adolescents with BMD for whom postoperative weight gain contributed significantly to an accelerated loss of ambulation and, in one case, driveline fracture in the context of repeated falls. As LVADs become an increasingly common therapy for endstage heart failure in adolescents with BMD, care must be focused not only on maintenance of device functionality, but also on management of aggressive weight, and preservation of ambulation, and skeletal muscle strength.

    Weight gain
    SYMPTOMS

 is common after

    implantation of continuous-flow ventricular assist devices
    MEDICATION

.

    Obesity
    SYMPTOMS

 can have a significant

    negative impact on mobility
    SYMPTOMS

. For

    adolescents
    AGE

 with

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

, for whom the ability to

    ambulate
    NEG_FINDINGS

 often persists into the

    mid-3rd decade
    AGE

,

    preservation of functional ability
    SYMPTOMS

 is critical. We report two cases of

    Thoratec HeartMate II left ventricular assist device (LVAD) implantation
    MEDICATION

 in

    adolescents
    AGE

 with

    BMD
    DIAGNOSIS

 for whom

    postoperative weight gain
    SYMPTOMS

 contributed significantly to an

    accelerated loss of ambulation
    SYMPTOMS

 and, in one case,

    driveline fracture
    SYMPTOMS

 in the context of

    repeated falls
    SYMPTOMS

. As

    LVADs
    MEDICATION

 become an increasingly common therapy for

    endstage heart failure
    DIAGNOSIS

 in

    adolescents
    AGE

 with

    BMD
    DIAGNOSIS

, care must be focused not only on

    maintenance of device functionality
    MEDICATION

, but also on management of

    aggressive weight
    MEDICATION

, and

    preservation of ambulation
    SYMPTOMS

, and

    skeletal muscle strength
    SYMPTOMS

.

Weight gain
Obesity
negative impact on mobility
preservation of functional ability
postoperative weight gain
accelerated loss of ambulation
driveline fracture
repeated falls
preservation of ambulation
skeletal muscle strength

Becker muscular dystrophy (BMD)
BMD
endstage heart failure
BMD


Duchenne muscular dystrophy (DMD) is an recessive X-linked mediated, musculoskeletal disorder that affects only males. It is the most common and severe form of muscular dystrophy where there is failure to manufacture dystrophin. Clinically, it is characterized by progressive muscle wasting eventually leading to premature death. This case report describes the genetic, oral and systemic findings in two cases of DMD in male siblings. How to cite this article: Suneja B, Suneja ES, Adlakha VK, Chandna P. A Rare Case Report of Neurodegenerative Disease: Duchenne Muscular Dystrophy in Two Male Siblings. Int J Clin Pediatr Dent 2015;8(2):163-165.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    recessive X-linked mediated
    GENETICS

,

    musculoskeletal disorder
    DIAGNOSIS

 that affects only

    males
    GENDER

. It is the most common and severe form of

    muscular dystrophy
    DIAGNOSIS

 where there is

    failure to manufacture dystrophin
    NEG_FINDINGS

. Clinically, it is characterized by

    progressive muscle wasting
    SYMPTOMS

 eventually leading to

    premature death
    SYMPTOMS

. This case report describes the genetic, oral and systemic findings in two cases of

    DMD
    DIAGNOSIS

 in

    male
    GENDER

 siblings. How to cite this article: Suneja B, Suneja ES, Adlakha VK, Chandna P. A Rare Case Report of

    Neurodegenerative Disease
    DIAGNOSIS

:

    Duchenne Muscular Dystrophy
    DIAGNOSIS

    in Two Male
    FAMILY

 Siblings. Int J Clin Pediatr Dent 2015;8(2):163-165.

Duchenne muscular dystrophy (DMD)
musculoskeletal disorder
muscular dystrophy
DMD
Neurodegenerative Disease
Duchenne Muscular Dystrophy

progressive muscle wasting
premature death


Ethical Challenges in Early-Phase Pediatric Research for Life-Limiting Illness.

Research with children is necessary to assure more effective treatments and potential cures of childhood illnesses. Ethical conduct of research requires minimizing the inherent risks of research, especially when it involves vulnerable populations such as children. Duchenne muscular dystrophy (DMD) is a progressive and fatal disease with no Food and Drug Administration-approved treatment. Clinical trials investigating so-called gene therapies are viewed by many in the DMD community with great promise. The goal of research is to secure generalizable knowledge and not directly benefit patients, yet many parents of boys with DMD hope, and even expect, that their sons will derive medical benefit by participating in early-phase "gene therapy" trials, raising concern for the therapeutic misconception. Physician-investigators must assist patient-subjects to distinguish realistic from unrealistic hope while maintaining reasonable expectations. In this article, I examine the therapeutic misconception and related concepts as framed within the context of "gene therapy" for DMD.

Research with

    children
    AGE

 is necessary to assure more effective treatments and potential cures of

    childhood
    AGE

    illnesses
    DIAGNOSIS

. Ethical conduct of research requires minimizing the inherent risks of research, especially when it involves vulnerable populations such as

    children
    AGE

.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    progressive and fatal disease
    DIAGNOSIS

 with no Food and Drug Administration-approved treatment. Clinical trials investigating so-called

    gene therapies
    MEDICATION

 are viewed by many in the

    DMD
    DIAGNOSIS

 community with great promise. The goal of research is to secure generalizable knowledge and not directly benefit patients, yet many parents of

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 hope, and even expect, that their

    sons
    GENDER

 will derive medical benefit by participating in

    early-phase "gene therapy" trials
    MEDICATION

, raising concern for the therapeutic misconception. Physician-investigators must assist patient-subjects to distinguish realistic from unrealistic hope while maintaining reasonable expectations. In this article, I examine the therapeutic misconception and related concepts as framed within the context of "

    gene therapy"
    MEDICATION

 for

    DMD
    DIAGNOSIS

.

illnesses
Duchenne muscular dystrophy (DMD)
progressive and fatal disease
DMD
DMD
DMD

gene therapies
early-phase "gene therapy" trials
gene therapy"


Cardiac resynchronization therapy in a young patient with Duchenne muscular dystrophy.

A 32-year-old man with Duchenne muscular dystrophy (DMD) was admitted to the hospital because of worsening dyspnea and general fatigue. He had received medication therapy for cardiomyopathy with heart failure and home mechanical ventilation for respiratory failure. An electrocardiogram on admission showed intermittent third-degree atrioventricular block. Echocardiography showed global mild left ventricular systolic dysfunction with dyssynchrony (ejection fraction: 45%). He underwent implantation of a cardiac resynchronization therapy-defibrillator. His B-type natriuretic peptide level was improved after cardiac resynchronization therapy-defibrillator implantation, and he remains asymptomatic. The incidence of cardiomyopathy increases with age. By adulthood, 100% of patients have cardiac involvement.

A

    32-year-old
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 was admitted to the hospital because of

    worsening dyspnea
    SYMPTOMS

 and

    general fatigue
    SYMPTOMS

.

    He
    GENDER

 had received

    medication therapy
    MEDICATION

 for

    cardiomyopathy with heart failure
    DIAGNOSIS

 and

    home mechanical ventilation
    MEDICATION

 for

    respiratory failure
    SYMPTOMS

. An

    electrocardiogram
    PARACLINICAL

 on admission showed

    intermittent third-degree atrioventricular block
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 showed

    global mild left ventricular systolic dysfunction with dyssynchrony (ejection fraction: 45%)
    SYMPTOMS

.

    He
    GENDER

 underwent

    implantation of a cardiac resynchronization therapy-defibrillator
    MEDICATION

. His

    B-type natriuretic peptide level was improved
    BIOCHEMICAL

 after

    cardiac resynchronization therapy-defibrillator implantation
    MEDICATION

, and

    he
    GENDER

 remains

    asymptomatic
    NEG_FINDINGS

. The incidence of

    cardiomyopathy
    DIAGNOSIS

 increases with age. By

    adulthood
    AGE

, 100% of patients have

    cardiac involvement
    SYMPTOMS

.

Duchenne muscular dystrophy (DMD)
cardiomyopathy with heart failure
cardiomyopathy


Markedly High B-type Natriuretic Peptide Level in a Patient with Duchenne Muscular Dystrophy and Left Ventricular Non-Compaction.

A boy with Duchenne muscular dystrophy was admitted to our hospital due to a transient loss of consciousness. Transthoracic echocardiography revealed left ventricular (LV) dilatation and diffuse hypokinesis of the LV wall. The LV wall was thin, and both non-compaction of the LV wall and marked thinning of the posterior LV wall resulting from a lesion were observed. The plasma B-type natriuretic peptide (BNP) level ultimately increased to 7,795 pg/mL, and the patient died of cardiac arrest following ventricular tachycardia. Severe heart failure, a critical condition, and thinning of the LV wall may have contributed to the markedly high plasma BNP level in this case.

A

    boy
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 was admitted to our hospital due to a

    transient loss of consciousness
    SYMPTOMS

.

    Transthoracic echocardiography
    PARACLINICAL

 revealed

    left ventricular (LV) dilatation
    SYMPTOMS

 and

    diffuse hypokinesis of the LV wall
    SYMPTOMS

.

    The LV wall was thin
    SYMPTOMS

, and both

    non-compaction of the LV wall
    SYMPTOMS

 and

    marked thinning of the posterior LV wall resulting from a lesion
    SYMPTOMS

 were observed. The

    plasma B-type natriuretic peptide (BNP) level ultimately increased to 7,795 pg/mL
    BIOCHEMICAL

, and the patient

    died
    SYMPTOMS

 of

    cardiac arrest
    SYMPTOMS

 following

    ventricular tachycardia
    SYMPTOMS

.

    Severe heart failure
    SYMPTOMS

, a

    critical condition
    SYMPTOMS

, and

    thinning of the LV wall
    SYMPTOMS

 may have contributed to the

    markedly high plasma BNP level
    BIOCHEMICAL

 in this case.


Treatable renal failure found in non-ambulatory Duchenne muscular dystrophy patients.

Duchenne muscular dystrophy (DMD) is a progressive muscular disorder in which respiratory and heart failures are the main causes of death. Intensive intervention in respiratory and cardiac function has dramatically improved the prognosis; however, dysfunction in other multiple organs may emerge in the later stages of the disease. We report the case of four non-ambulatory DMD patients who presented with renal failure. Common findings included decreased fluid intake, use of diuretics, and presence of chronic heart failure. The levels of serum cystatin C (CysC), a marker of kidney function unaffected by reduced muscle mass, were elevated in all four patients. In two patients, renal failure improved by increasing fluid intake, and discontinuing or reducing the dose of diuretics. The findings suggest that non-ambulatory DMD patients are at a risk of reduced kidney perfusion, which potentially leads to prerenal failure. Therefore, in DMD patients, dehydration signs and CysC levels should be monitored.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    progressive muscular disorder
    DIAGNOSIS

 in which

    respiratory and heart failures
    SYMPTOMS

 are the main causes of

    death
    SYMPTOMS

.

    Intensive intervention in respiratory and cardiac function
    MEDICATION

 has dramatically improved the prognosis; however,

    dysfunction in other multiple organs
    SYMPTOMS

 may emerge in the later stages of the disease. We report the case of four

    non-ambulatory
    MEDICATION

    DMD
    DIAGNOSIS

 patients who presented with

    renal failure
    SYMPTOMS

. Common findings included

    decreased fluid intake
    MEDICATION

,

    use of diuretics
    MEDICATION

, and presence of

    chronic heart failure
    SYMPTOMS

. The

    levels of serum cystatin C (CysC)
    BIOCHEMICAL

, a

    marker of kidney function unaffected by reduced muscle mass
    BIOCHEMICAL

    , were elevated
    BIOCHEMICAL

 in all four patients. In two patients,

    renal failure
    SYMPTOMS

 improved by

    increasing fluid intake
    MEDICATION

, and

    discontinuing or reducing the dose of diuretics
    MEDICATION

. The findings suggest that

    non-ambulatory
    MEDICATION

    DMD
    DIAGNOSIS

 patients are at a risk of

    reduced kidney perfusion
    SYMPTOMS

, which potentially leads to

    prerenal failure
    SYMPTOMS

. Therefore, in

    DMD
    DIAGNOSIS

 patients,

    dehydration signs
    SYMPTOMS

 and

    CysC levels
    BIOCHEMICAL

 should be monitored.

Duchenne muscular dystrophy (DMD)
progressive muscular disorder
DMD
DMD
DMD

respiratory and heart failures
death
dysfunction in other multiple organs
renal failure
chronic heart failure
renal failure
reduced kidney perfusion
prerenal failure
dehydration signs


Novel Rod Domain Duplication in Dystrophin Resulting in X-Linked Dilated Cardiomyopathy.

X-linked dilated cardiomyopathy is a rare, cardio-specific form of dystrophinopathy allelic to Duchenne and Becker muscular dystrophy that results in heart failure without skeletal muscle weakness.

We describe a previously healthy 16-year-old boy who presented with palpitations progressing to heart failure who was ultimately found to have a novel duplication of exons 13-16 in the dystrophin gene resulting in diagnosis of X-linked dilated cardiomyopathy.

The patient was diagnosed with X-linked dilated cardiomyopathy through clinical diagnosis and genetic testing.

X-linked dilated cardiomyopathy shares genotypic overlap with Duchenne and Becker muscular dystrophy, with its distinctive feature being a lack of progressive muscular weakness.

    X-linked dilated cardiomyopathy
    GENETICS

 is a rare,

    cardio-specific form of dystrophinopathy
    DIAGNOSIS

    allelic to Duchenne and Becker muscular dystrophy
    DIAGNOSIS

 that results in

    heart failure
    SYMPTOMS

    without skeletal muscle weakness
    NEG_FINDINGS

.

We describe a previously healthy

    16-year-old
    AGE

    boy
    GENDER

 who presented with

    palpitations
    SYMPTOMS

 progressing to

    heart failure
    SYMPTOMS

 who was ultimately found to have a

    novel duplication of exons 13-16 in the dystrophin gene
    GENETICS

 resulting in diagnosis of

    X-linked dilated cardiomyopathy
    DIAGNOSIS

.

The patient was diagnosed with

    X-linked dilated cardiomyopathy
    DIAGNOSIS

 through

    clinical diagnosis
    PARACLINICAL

 and

    genetic testing
    PARACLINICAL

.

    X-linked
    GENETICS

    dilated cardiomyopathy
    DIAGNOSIS

 shares

    genotypic overlap with Duchenne and Becker muscular dystrophy
    SYMPTOMS

, with its distinctive feature being a

    lack of progressive muscular weakness
    NEG_FINDINGS

.

without skeletal muscle weakness
lack of progressive muscular weakness


A splicing mutation in the DMD gene detected by next-generation sequencing and confirmed by mRNA and protein analysis.

Dystrophinopathies, either the severe Duchenne Muscular Dystrophy (DMD) or the milder Becker Muscular Dystrophy (BMD), are X-linked recessive disorders caused by mutations in the DMD gene. DMD is one of the longest human genes. Large deletions or duplications account for 60-80% of the mutations. Remaining anomalies consist in point mutations or small rearrangements. Routinely, the molecular diagnosis is done by a Multiplex Ligation-dependent Probe Amplification (MLPA) or array Comparative Genome Hybridization (aCGH), followed, if negative, by Sanger sequencing of all exons.

In this study, massive parallel sequencing (MPS) or next generation sequencing (NGS) was used to make a rapid and costless molecular diagnosis in a young boy suspected of DMD.

A small deletion: NM_004006.2:c.2803+5_2803+8del was identified. The diagnosis was performed in one single manipulation and within a week. The consequence of this intronic mutation is a skipping of exon 21 confirmed by mRNA and protein analysis.

NGS appears to be an efficient new strategy in DMD molecular diagnosis. It highlights the major evolution of the diagnostic strategy towards high throughput technologies, where bioinformatics analysis becomes the real challenge for variations detection. This is the first study reporting in vivo impact of this intronic mutation.

    Dystrophinopathies
    DIAGNOSIS

, either the

    severe Duchenne Muscular Dystrophy (DMD)
    DIAGNOSIS

 or the

    milder Becker Muscular Dystrophy (BMD)
    DIAGNOSIS

, are

    X-linked recessive disorders
    GENETICS

 caused by

    mutations in the DMD gene
    GENETICS

.

    DMD
    DIAGNOSIS

 is one of the longest human genes.

    Large deletions or duplications
    GENETICS

 account for 60-80% of the mutations. Remaining anomalies consist in

    point mutations
    GENETICS

 or

    small rearrangements
    GENETICS

. Routinely, the

    molecular diagnosis
    PARACLINICAL

 is done by a

    Multiplex Ligation-dependent Probe Amplification (MLPA)
    PARACLINICAL

 or

    array Comparative Genome Hybridization (aCGH)
    PARACLINICAL

, followed, if negative, by

    Sanger sequencing of all exons
    PARACLINICAL

.

In this study,

    massive parallel sequencing (MPS) or next generation sequencing (NGS)
    PARACLINICAL

 was used to make a rapid and costless

    molecular diagnosis
    PARACLINICAL

 in a

    young
    AGE

    boy
    GENDER

 suspected of

    DMD
    DIAGNOSIS

.

A

    small deletion: NM_004006.2:c.2803+5_2803+8del was identified
    GENETICS

. The diagnosis was performed in one single manipulation and within a week. The consequence of this

    intronic mutation
    GENETICS

 is a

    skipping of exon 21
    GENETICS

 confirmed by

    mRNA and protein analysis
    PARACLINICAL

.

    NGS
    GENETICS

 appears to be an efficient new strategy in

    DMD
    DIAGNOSIS

    molecular diagnosis
    PARACLINICAL

. It highlights the major evolution of the diagnostic strategy towards high throughput technologies, where

    bioinformatics analysis
    PARACLINICAL

 becomes the real challenge for variations detection. This is the first study reporting in vivo impact of this

    intronic mutation
    GENETICS

.


Contributions of Japanese patients to development of antisense therapy for DMD.

Duchenne muscular dystrophy (DMD) is a fatal progressive muscle wasting disease considered untreatable since its first description in 1868. In 1987, the dystrophin gene responsible for DMD was cloned. This paved the way for the development of therapies. Antisense oligonucleotide (AO)-mediated exon skipping therapy is now reaching the stage of marketing authorization. On the 20th anniversary of the proposal of AO-mediated exon skipping therapy for DMD, this review explores the contributions of Japanese patients.

In 1990, a Japanese DMD patient was reported as having a small deletion within dystrophin exon 19 and complicating exon 19 skipping in the absence of any mutation at the consensus splice sites. This led to identification of a splicing enhancer sequence within exon 19. Remarkably, AOs against this sequence were shown to induce exon skipping. This encouraged us to propose AO-mediated exon skipping therapy for DMD in 1995. The therapy's effectiveness was verified in a Japanese patient with a nonsense dystrophin mutation manifesting as Becker muscular dystrophy. The patient showed skipping of the nonsense mutation-encoding exon. Finally, a DMD patient carrying a deletion of exon 20 volunteered to undergo intravenous AO infusion, enabling us to obtain proof of concept. The findings from these three patients greatly facilitated studies on exon skipping therapy. As a result, more than 300 reports on AO-mediated exon skipping therapy for DMD have been published, including at least two a month during the last few years.

We greatly appreciate the important contributions of Japanese patients to development of the exon skipping therapy for DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    fatal progressive muscle wasting disease
    DIAGNOSIS

 considered

    untreatable
    NEG_FINDINGS

 since its first description in 1868. In 1987, the

    dystrophin gene responsible for DMD
    GENETICS

 was cloned. This paved the way for the development of therapies.

    Antisense oligonucleotide (AO)-mediated exon skipping therapy
    MEDICATION

 is now reaching the stage of marketing authorization. On the 20th anniversary of the proposal of

    AO-mediated exon skipping therapy
    MEDICATION

 for

    DMD
    DIAGNOSIS

, this review explores the contributions of

    Japanese
    ETHNICITY

 patients.

In 1990, a

    Japanese
    ETHNICITY

    DMD
    DIAGNOSIS

 patient was reported as having a

    small deletion within dystrophin exon 19
    GENETICS

 and

    complicating exon 19 skipping
    NEG_FINDINGS

 in the

    absence of any mutation at the consensus splice sites
    NEG_FINDINGS

. This led to identification of a splicing enhancer sequence within exon 19. Remarkably,

    AOs against
    MEDICATION

 this sequence were shown to

    induce exon skipping
    BIOCHEMICAL

. This encouraged us to propose

    AO-mediated exon skipping therapy
    MEDICATION

 for

    DMD
    DIAGNOSIS

 in 1995. The therapy's effectiveness was verified in a

    Japanese
    ETHNICITY

 patient with a

    nonsense dystrophin mutation
    GENETICS

 manifesting as

    Becker muscular dystrophy
    DIAGNOSIS

. The patient showed

    skipping of the nonsense mutation-encoding exon
    GENETICS

. Finally, a

    DMD
    DIAGNOSIS

 patient carrying a

    deletion of exon 20
    GENETICS

 volunteered to undergo

    intravenous AO infusion
    MEDICATION

, enabling us to obtain proof of concept. The findings from these three patients greatly facilitated studies on

    exon skipping therapy
    MEDICATION

. As a result, more than 300 reports on

    AO-mediated exon skipping therapy
    MEDICATION

 for

    DMD
    DIAGNOSIS

 have been published, including at least two a month during the last few years.

We greatly appreciate the important contributions of

    Japanese
    ETHNICITY

 patients to development of the

    exon skipping therapy
    MEDICATION

 for

    DMD
    DIAGNOSIS

.


Neuromuscular Scoliosis: Current Concepts.

Scoliosis is a common deformity in neuromuscular disorders. This spinal deformity usually presents at an early age, rapidly progresses during growth, and continues to progress even after skeletal maturity. Neuromuscular scoliosis classically involves the entire thoracolumbar spine, often extending to the pelvis and causing pelvic obliquity. Physical examination can be challenging, but it is important to assess the flexibility of the spinal curve and associated joint contractures. Upright anteroposterior and lateral radiographs are the preferred imaging. When formulating a treatment plan, it is important to take into account not only the degree of curvature, but also each patient's needs and quality of life, the potentially high perioperative complication rates, and the natural history of the underlying neuromuscular disorder. Different neuromuscular conditions behave differently and should therefore be treated differently. With the exception of steroids for Duchenne muscular dystrophy, bracing remains the only reliable nonoperative intervention available. Preoperative optimization of medical comorbidities is crucial given the relatively high complication rate. Posterior segmental instrumentation has revolutionized the surgical management of neuromuscular scoliosis and is the most commonly used technique today. Despite reported improvement in postoperative quality of life, there are several limitations with currently used outcome measures that prevent a well-informed discussion on the outcomes after surgery.

    Scoliosis
    DIAGNOSIS

 is a common deformity in

    neuromuscular disorders
    DIAGNOSIS

. This

    spinal deformity
    SYMPTOMS

 usually presents at an

    early age
    AGE

, rapidly progresses during growth, and continues to progress even

    after skeletal maturity
    AGE

.

    Neuromuscular scoliosis
    DIAGNOSIS

 classically

    involves the entire thoracolumbar spine
    SYMPTOMS

, often

    extending to the pelvis
    SYMPTOMS

 and causing

    pelvic obliquity
    SYMPTOMS

.

    Physical examination
    PARACLINICAL

 can be challenging, but it is important to assess the flexibility of the

    spinal curve
    SYMPTOMS

 and associated

    joint contractures
    SYMPTOMS

.

    Upright anteroposterior and lateral radiographs
    PARACLINICAL

 are the preferred imaging. When formulating a treatment plan, it is important to take into account not only the degree of curvature, but also each patient's needs and quality of life, the potentially high perioperative complication rates, and the natural history of the underlying

    neuromuscular disorder
    DIAGNOSIS

. Different

    neuromuscular conditions
    DIAGNOSIS

 behave differently and should therefore be treated differently. With the exception of

    steroids
    MEDICATION

 for

    Duchenne muscular dystrophy
    DIAGNOSIS

,

    bracing
    MEDICATION

 remains the only reliable

    nonoperative intervention
    MEDICATION

 available.

    Preoperative optimization of medical comorbidities
    MEDICATION

 is crucial given the relatively high complication rate.

    Posterior segmental instrumentation
    MEDICATION

 has revolutionized the

    surgical management
    MEDICATION

 of

    neuromuscular scoliosis
    DIAGNOSIS

 and is the most commonly used technique today. Despite reported

    improvement in postoperative quality of life
    SYMPTOMS

, there are several limitations with currently used outcome measures that prevent a well-informed discussion on the outcomes after surgery.

Scoliosis
neuromuscular disorders
Neuromuscular scoliosis
neuromuscular disorder
neuromuscular conditions
Duchenne muscular dystrophy
neuromuscular scoliosis


[Duchenne muscular dystrophy: Case of atypical presentation and early diagnosis].

Duchenne muscular dystrophy is the most common form of muscular dystrophy, with an incidence of 1/3300 male live births and a prevalence rate in the total population of 3/100000 individuals. It is often hereditary (X-linked recessive) but sporadic cases are also frequent. The average age at diagnosis is 4.83 years but an early diagnosis is possible.

An 18-month male infant in ambulatory study for failure to thrive and malnutrition was admitted in our hospital for respiratory problems. Hypertransaminasemia without other data of hepatic involvement in addition to hypotonia detected in the examination oriented diagnosis towards myopathy, confirmed by elevated creatine kinase and electromyogram. The genetic study for Duchenne muscular dystrophy was negative. Mutations were not detected. Muscle biopsy showed complete absence of dystrophin. A more sensitive genetic study showed a previously undescribed mutation.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is the most common form of

    muscular dystrophy
    DIAGNOSIS

, with an incidence of 1/3300

    male
    AGE

 live births and a prevalence rate in the total population of 3/100000 individuals. It is often

    hereditary (X-linked recessive)
    GENETICS

 but sporadic cases are also frequent. The

    average age at diagnosis is 4.83 years
    AGE

 but an early diagnosis is possible.

An

    18-month
    AGE

    male
    GENDER

    infant
    AGE

 in

    ambulatory study
    MEDICATION

 for

    failure to thrive
    SYMPTOMS

 and

    malnutrition
    SYMPTOMS

 was admitted in our hospital for

    respiratory problems
    SYMPTOMS

.

    Hypertransaminasemia
    BIOCHEMICAL

    without other data of hepatic involvement
    NEG_FINDINGS

 in addition to

    hypotonia
    SYMPTOMS

 detected in the examination oriented diagnosis towards

    myopathy
    DIAGNOSIS

, confirmed by

    elevated creatine kinase
    BIOCHEMICAL

 and

    electromyogram
    PARACLINICAL

.

    The genetic study for Duchenne muscular dystrophy was negative
    NEG_FINDINGS

.

    Mutations were not detected
    NEG_FINDINGS

.

    Muscle biopsy
    PARACLINICAL

 showed

    complete absence of dystrophin
    SYMPTOMS

. A more sensitive

    genetic study
    PARACLINICAL

 showed a

    previously undescribed mutation
    GENETICS

.

Duchenne muscular dystrophy
muscular dystrophy
myopathy

hereditary (X-linked recessive)
previously undescribed mutation

failure to thrive
malnutrition
respiratory problems
hypotonia
complete absence of dystrophin

Hypertransaminasemia
elevated creatine kinase


Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature.

Xp21 continuous gene deletion syndrome is characterized by complex glycerol kinase deficiency (GK), adrenal hypoplasia congenital (NROB1), intellectual disability and/or Duchenne muscular dystrophy (DMD). The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100 male patients have been reported so far, while only a few cases of symptomatic female carriers have been described. We report here detailed clinical features and X chromosome inactivation analysis in two unrelated female patients with overlapping Xp21 deletions presenting with intellectual disability and inconstant muscular symptoms.

    Xp21 continuous gene deletion syndrome
    GENETICS

 is characterized by

    complex glycerol kinase deficiency (GK)
    BIOCHEMICAL

,

    adrenal hypoplasia congenital (NROB1)
    DIAGNOSIS

,

    intellectual disability
    SYMPTOMS

 and/or

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. The clinical features depend on the size of the deletion, as well as on the number and the nature of the encompassed genes. More than 100

    male
    GENDER

 patients have been reported so far, while only a few cases of symptomatic

    female
    GENDER

 carriers have been described. We report here detailed clinical features and

    X chromosome inactivation analysis
    PARACLINICAL

 in two unrelated

    female
    GENDER

 patients with

    overlapping Xp21 deletions
    GENETICS

 presenting with

    intellectual disability
    SYMPTOMS

 and

    inconstant muscular symptoms
    SYMPTOMS

.

Xp21 continuous gene deletion syndrome
overlapping Xp21 deletions

adrenal hypoplasia congenital (NROB1)
Duchenne muscular dystrophy (DMD)

intellectual disability
intellectual disability
inconstant muscular symptoms


Hypoglycemia detected during cardiac arrest of a non-diabetic patient with heart failure.

Hypoglycemia in non-diabetic patients with heart failure is a rare finding. It is thought to be caused by hepatic dysfunction secondary to chronic passive congestion, and reduced gluconeogenesis. In this report we present a 23-year-old man with a history of Duchenne muscular dystrophy hospitalized for decompensated heart failure and implantable cardioverter defibrillator shock. Laboratory examination on admission showed slightly elevated levels of hepatic enzymes. Despite the therapy for heart failure the patient's clinical status deteriorated, and sinus bradycardia and then cardiac arrest occured. After successful 5-minute cardiopulmonary resuscitation, an arterial blood sample revealed metabolic acidosis with a level of pH 7.04, bicarbonate 9.3, and glucose of 22 mg/dl. Acute treatment of metabolic acidosis with hypoglycemia was successfully performed. Based on this case, possible causes of unexplained hypoglycemia in non-diabetic patients with heart failure were described in a short literature review.

    Hypoglycemia
    BIOCHEMICAL

 in

    non-diabetic
    NEG_FINDINGS

 patients with

    heart failure
    DIAGNOSIS

 is a rare finding. It is thought to be caused by

    hepatic dysfunction
    SYMPTOMS

 secondary to

    chronic passive congestion
    SYMPTOMS

, and

    reduced gluconeogenesis
    BIOCHEMICAL

. In this report we present a

    23-year-old
    AGE

    man
    GENDER

 with a history of

    Duchenne muscular dystrophy
    DIAGNOSIS

 hospitalized for

    decompensated heart failure
    DIAGNOSIS

 and

    implantable cardioverter defibrillator shock
    MEDICATION

.

    Laboratory examination
    PARACLINICAL

 on admission showed

    slightly elevated levels of hepatic enzymes
    BIOCHEMICAL

.

    Despite the therapy for heart failure
    NEG_FINDINGS

 the patient's

    clinical status deteriorated
    SYMPTOMS

, and

    sinus bradycardia
    SYMPTOMS

 and then

    cardiac arrest
    SYMPTOMS

 occured. After

    successful 5-minute cardiopulmonary resuscitation
    MEDICATION

, an

    arterial blood sample
    PARACLINICAL

 revealed

    metabolic acidosis with a level of pH 7.04, bicarbonate 9.3
    BIOCHEMICAL

, and

    glucose of 22 mg/dl
    BIOCHEMICAL

.

    Acute treatment of metabolic acidosis with hypoglycemia
    MEDICATION

 was successfully performed. Based on this case, possible causes of

    unexplained hypoglycemia
    BIOCHEMICAL

 in

    non-diabetic
    NEG_FINDINGS

 patients with

    heart failure
    DIAGNOSIS

 were described in a short literature review.

non-diabetic
Despite the therapy for heart failure
non-diabetic

heart failure
Duchenne muscular dystrophy
decompensated heart failure
heart failure

hepatic dysfunction
chronic passive congestion
clinical status deteriorated
sinus bradycardia
cardiac arrest


[Mitral valve replacement for a manifesting carrier of duchenne muscular dystrophy].

Duchenne muscular dystrophy (DMD) is an X-linked disease, but female carriers infrequently have some symptoms, who are called manifesting carriers. Here we report a case of a manifesting carrier of DMD with skeletal muscle weakness and cardiac abnormalities such as deterioration of cardiac function and left ventricular dilatation, who successfully underwent cardiac surgery. A 79-year-old female with acute heart failure for severe mitral regurgitation was admitted to our hospital. Surgical replacement of the mitral valve was performed under general anesthesia with intravenous anesthetics and non-depolarizing muscle relaxant. Cardiac surgery on a manifesting carrier of DMD is rare and requires a careful preoperative assessment of the heart function and anesthetic management.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked disease
    GENETICS

, but

    female
    GENDER

 carriers infrequently have some symptoms, who are called manifesting carriers. Here we report a case of a manifesting carrier of

    DMD
    DIAGNOSIS

 with

    skeletal muscle weakness
    SYMPTOMS

 and

    cardiac abnormalities
    SYMPTOMS

 such as

    deterioration of cardiac function
    SYMPTOMS

 and

    left ventricular dilatation
    SYMPTOMS

, who successfully underwent

    cardiac surgery
    MEDICATION

. A

    79-year-old
    AGE

    female
    GENDER

 with

    acute heart failure
    SYMPTOMS

 for

    severe mitral regurgitation
    SYMPTOMS

 was admitted to our hospital.

    Surgical replacement of the mitral valve
    MEDICATION

 was performed under

    general anesthesia with intravenous anesthetics and non-depolarizing muscle relaxant
    MEDICATION

.

    Cardiac surgery
    MEDICATION

 on a manifesting carrier of

    DMD
    DIAGNOSIS

 is rare and requires a careful

    preoperative assessment of the heart function
    PARACLINICAL

 and

    anesthetic management
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
DMD
DMD

skeletal muscle weakness
cardiac abnormalities
deterioration of cardiac function
left ventricular dilatation
acute heart failure
severe mitral regurgitation


Back pain in Duchenne muscular dystrophy: steroids are not always the culprit.

We report on a child with Duchenne muscular dystrophy on prolonged corticosteroid treatment who presented with back pain and was subsequently found to have a monostotic fibrous dysplasia lesion of the spine. It is the intent of this case report to emphasize the need to maintain a high index of suspicion for other potential causes of back pain in Duchenne muscular dystrophy besides vertebral compression fractures.

We report on a

    child
    AGE

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 on

    prolonged corticosteroid treatment
    MEDICATION

 who presented with

    back pain
    SYMPTOMS

 and was subsequently found to have a

    monostotic fibrous dysplasia lesion of the spine
    DIAGNOSIS

. It is the intent of this case report to emphasize the need to maintain a high index of suspicion for other potential causes of

    back pain
    SYMPTOMS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

 besides

    vertebral compression fractures
    SYMPTOMS

.

back pain
back pain
vertebral compression fractures


Orthodontic treatment in a patient with unilateral open-bite and Becker muscular dystrophy. A 5-year follow-up.

Becker muscular dystrophy is an X-chromosomal linked anomaly characterized by progressive muscle wear and weakness. This case report shows the orthodontic treatment of a Becker muscular dystrophy patient with unilateral open bite.

To correct patient's malocclusion, general anesthesia and orthognathic surgery were not considered as an option. Conventional orthodontic treatment with intermaxillary elastics and muscular functional therapy were employed instead.

After 36 months, open bite was corrected. The case remains stable after a 5-year post-treatment retention period.

    Becker muscular dystrophy
    DIAGNOSIS

 is an

    X-chromosomal linked anomaly
    GENETICS

 characterized by

    progressive muscle wear
    SYMPTOMS

    and weakness
    SYMPTOMS

. This case report shows the

    orthodontic treatment
    MEDICATION

 of a

    Becker muscular dystrophy
    DIAGNOSIS

 patient with

    unilateral open bite
    SYMPTOMS

.

To correct patient's

    malocclusion
    MEDICATION

,

    general anesthesia
    MEDICATION

 and

    orthognathic surgery
    MEDICATION

    were not considered as an option
    NEG_FINDINGS

.

    Conventional orthodontic treatment with intermaxillary elastics
    MEDICATION

 and

    muscular functional therapy
    MEDICATION

 were employed instead.

After

    36 months
    MEDICATION

,

    open bite was corrected
    SYMPTOMS

. The case remains stable

    after a 5-year post-treatment retention period
    MEDICATION

.

Becker muscular dystrophy
Becker muscular dystrophy

progressive muscle wear
and weakness
unilateral open bite
open bite was corrected


Longitudinal Evaluation of Muscle Composition Using Magnetic Resonance in 4 Boys With Duchenne Muscular Dystrophy: Case Series.

Duchenne muscular dystrophy (DMD), an inherited recessive X chromosome-linked disease, is the most severe childhood form of muscular dystrophy. Boys with DMD experience muscle loss, with infiltration of intramuscular fat into muscles.

This case series describes the progression of DMD in boys using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Magnetic resonance results are then compared with an established functional timed test.

Four boys with DMD and 4 healthy age-matched controls were chosen from a larger cohort. Boys with DMD were assessed at 4 time points over 2 years, with controls assessed at baseline only. Progression of the disease was documented by assessing the plantar flexors using MRI and MRS techniques and by assessing ambulation using the 30-Foot Fast Walk Test.

Transverse relaxation time (T2) values were elevated in all boys with DMD at baseline. The lipid ratio increased rapidly as the disease progressed in 2 boys. Discrete changes in T2 in the other 2 boys with DMD indicated a slower disease progression. Magnetic resonance imaging and MRS allowed monitoring of the disease over all time periods regardless of ambulation status.

The magnetic resonance data were collected with 2 different magnets at 2 different field strengths (1.5 and 3.0 T). Although we corrected for this difference, care must be taken in interpreting data when different image collection systems are used. This was a case series of 4 boys with DMD taken from a larger cohort study.

Magnetic resonance imaging and MRS are objective, noninvasive techniques for measuring muscle pathology and can be used to detect discrete changes in both people who are ambulatory and those who are nonambulatory. These techniques should be considered when monitoring DMD progression and assessing efficacy of therapeutic interventions.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, an

    inherited recessive X chromosome-linked disease
    GENETICS

, is the most severe

    childhood
    AGE

 form of

    muscular dystrophy
    DIAGNOSIS

.

    Boys
    GENDER

 with

    DMD
    DIAGNOSIS

 experience

    muscle loss
    SYMPTOMS

, with

    infiltration of intramuscular fat into muscles
    MICROSCOPIC

.

This case series describes the progression of

    DMD
    DIAGNOSIS

 in

    boys
    GENDER

 using

    magnetic resonance imaging (MRI)
    PARACLINICAL

 and

    magnetic resonance spectroscopy (MRS)
    PARACLINICAL

.

    Magnetic resonance results
    PARACLINICAL

 are then compared with an established

    functional timed test
    PARACLINICAL

.

Four

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 and 4 healthy age-matched controls were chosen from a larger cohort.

    Boys
    GENDER

 with

    DMD
    DIAGNOSIS

 were assessed at 4 time points over 2 years, with controls assessed at baseline only. Progression of the disease was documented by

    assessing the plantar flexors using MRI and MRS techniques
    PARACLINICAL

 and by

    assessing ambulation using the 30-Foot Fast Walk Test
    PARACLINICAL

.

    Transverse relaxation time (T2) values were elevated
    SYMPTOMS

 in all

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 at baseline. The

    lipid ratio increased
    BIOCHEMICAL

 rapidly as the disease progressed in 2

    boys
    GENDER

.

    Discrete changes in T2
    SYMPTOMS

 in the other 2

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 indicated a slower disease progression.

    Magnetic resonance imaging and MRS
    PARACLINICAL

 allowed

    monitoring of the disease over all time periods
    PARACLINICAL

 regardless of

    ambulation status
    NEG_FINDINGS

.

The

    magnetic resonance data
    PARACLINICAL

 were collected with 2 different magnets at 2 different field strengths (1.5 and 3.0 T). Although we corrected for this difference, care must be taken in interpreting data when different image collection systems are used. This was a case series of 4

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 taken from a larger cohort study.

    Magnetic resonance imaging
    PARACLINICAL

 and

    MRS
    PARACLINICAL

 are objective, noninvasive techniques for

    measuring muscle pathology
    PARACLINICAL

 and can be used to detect discrete changes in both people who are ambulatory and those who are

    nonambulatory
    NEG_FINDINGS

. These techniques should be considered when monitoring

    DMD
    DIAGNOSIS

 progression and assessing efficacy of therapeutic interventions.

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


Delayed diagnosis of congenital myasthenia due to associated mitochondrial enzyme defect.

Clinical phenotypes of congenital myasthenic syndromes and primary mitochondrial disorders share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis. Next generation sequencing is transforming molecular diagnosis of inherited neuromuscular disorders by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were initially suspected to have a mitochondrial myopathy, but in whom a clear diagnosis of congenital myasthenic syndromes was made through whole exome sequencing. In patient 1, whole exome sequencing revealed compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ). In patient 2, in whom a deletion of exon 52 in Dystrophin gene was previously detected by multiplex ligation-dependent probe amplification, Sanger sequencing revealed an additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7). These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like congenital myasthenic syndromes, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that whole exome sequencing is an effective diagnostic tool in providing molecular diagnosis in patients with complex phenotypes.

Clinical phenotypes of

    congenital myasthenic syndromes
    DIAGNOSIS

 and

    primary mitochondrial disorders
    DIAGNOSIS

 share significant overlap in their clinical presentations, leading to challenges in making the correct diagnosis.

    Next generation sequencing
    PARACLINICAL

 is transforming molecular diagnosis of

    inherited neuromuscular disorders
    DIAGNOSIS

 by identifying novel disease genes and by identifying previously known genes in undiagnosed patients. This is evident in two patients who were

    initially suspected to have a mitochondrial myopathy
    NEG_FINDINGS

, but in whom a clear diagnosis of

    congenital myasthenic syndromes
    DIAGNOSIS

 was made through

    whole exome sequencing
    PARACLINICAL

. In patient 1,

    whole exome sequencing
    PARACLINICAL

 revealed

    compound heterozygous mutations c.1228C > T (p.Arg410Trp) and c.679C > T (p.Arg227*) in collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase (COLQ)
    GENETICS

. In patient 2, in whom a

    deletion of exon 52 in Dystrophin gene
    GENETICS

 was previously detected by

    multiplex ligation-dependent probe amplification
    PARACLINICAL

,

    Sanger sequencing
    PARACLINICAL

 revealed an

    additional homozygous mutation c.1511_1513delCTT (p.Pro504Argfs*183) in docking protein7 (DOK7)
    GENETICS

. These case reports highlight the need for careful diagnosis of clinically heterogeneous syndromes like

    congenital myasthenic syndromes
    DIAGNOSIS

, which are treatable, and for which delayed diagnosis is likely to have implications for patient health. The report also demonstrates that

    whole exome sequencing
    PARACLINICAL

 is an effective diagnostic tool in providing

    molecular diagnosis
    PARACLINICAL

 in patients with complex phenotypes.

congenital myasthenic syndromes
primary mitochondrial disorders
inherited neuromuscular disorders
congenital myasthenic syndromes
congenital myasthenic syndromes


Regional anaesthesia in a Duchenne muscular dystrophy patient for upper extremity amputation.

Duchenne muscular dystrophy (DMD) is the most common of the neuromuscular disorders. DMD is usually a challenge for the anaesthesiologist, with poor cardiac function, a high risk of developing rhabdomyolysis, and the probable life-threatening complications of general anaesthesia. To avoid possible morbidity associated with general anaesthesia, we applied a supraclavicular blockade. In this report, we present a 17-year-old DMD patient with a massive rhabdomyosarcoma, for whom a left arm amputation was indicated. In the post-operative period, a malignant hyperthermia-like reaction occurred, which resolved in a short time. We suggest a regional blockade as a safer alternative to general anaesthesia for the management of high risk DMD patients during orthopedic procedures.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common of the

    neuromuscular disorders
    DIAGNOSIS

.

    DMD
    DIAGNOSIS

 is usually a challenge for the

    anaesthesiologist
    PARACLINICAL

, with

    poor cardiac function
    SYMPTOMS

, a high risk of developing

    rhabdomyolysis
    SYMPTOMS

, and the probable

    life-threatening complications
    SYMPTOMS

 of

    general anaesthesia
    MEDICATION

. To avoid possible

    morbidity associated with general anaesthesia
    SYMPTOMS

, we applied a

    supraclavicular blockade
    MEDICATION

. In this report, we present a

    17-year-old
    AGE

    DMD
    DIAGNOSIS

 patient with a

    massive rhabdomyosarcoma
    DIAGNOSIS

, for whom a

    left arm amputation
    MEDICATION

 was indicated. In the post-operative period, a

    malignant hyperthermia-like reaction
    SYMPTOMS

 occurred, which resolved in a short time. We suggest a

    regional blockade
    MEDICATION

 as a

    safer alternative to general anaesthesia
    MEDICATION

 for the management of high risk

    DMD
    DIAGNOSIS

 patients during

    orthopedic procedures
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
neuromuscular disorders
DMD
DMD
massive rhabdomyosarcoma
DMD


Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

We report a

    family in which two male
    FAMILY

    siblings with Becker muscular dystrophy (BMD)
    FAMILY

 developed

    severe dilated cardiomyopathy (DCM)
    DIAGNOSIS

 and

    progressive heart failure (HF)
    SYMPTOMS

 at

    age 11 years
    AGE

; one

    died
    SYMPTOMS

 at

    age 14 years
    AGE

 while

    awaiting heart transplant
    MEDICATION

 and the other underwent

    left ventricular assist device implantation
    MEDICATION

 at the same age.

    Genetic analysis of one sibling
    PARACLINICAL

 showed a

    novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted
    GENETICS

. Although this predicts an

    amino-acid substitution and premature termination (p.Thr1260Argfs*8)
    GENETICS

,

    muscle biopsy dystrophin immunostaining
    PARACLINICAL

 instead indicates that the

    mutation is more likely to alter splicing
    GENETICS

.

    Despite relatively preserved skeletal muscular performance
    NEG_FINDINGS

,

    both the siblings
    FAMILY

 developed

    progressive HF secondary to early-onset DCM
    SYMPTOMS

. In addition, their

    7-year-old
    AGE

    nephew with delayed gross motor development
    FAMILY

,

    mild proximal muscle weakness
    SYMPTOMS

 and

    markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months
    BIOCHEMICAL

    was recently demonstrated to have the familial DMD mutation
    FAMILY

. Here, we report a novel genotype of

    BMD
    DIAGNOSIS

 with

    early-onset DCM
    SYMPTOMS

 and

    progressive lethal HF
    SYMPTOMS

 during

    early adolescence
    AGE

.


Implantation of a left ventricular assist device as a destination therapy in Duchenne muscular dystrophy patients with end stage cardiac failure: management and lessons learned.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive skeletal muscle weakness, loss of ambulation, and death secondary to cardiac or respiratory failure. End-stage dilated cardiomyopathy (DCM) is a frequent finding in DMD patients, they are rarely candidates for cardiac transplantation. Recently, the use of ventricular assist devices as a destination therapy (DT) as an alternative to cardiac transplantation in DMD patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. We describe the preoperative, intraoperative and postoperative management of Jarvik 2000 implantation in 4 DMD pediatric (age range 12-17 years) patients. We also describe the complications that may occur. The most frequent were bleeding and difficulty in weaning from mechanical ventilation. Our standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2) preoperative and postoperative non-invasive ventilation and cough machine cycles, 3) intraoperative use of near infrared spectroscopy (NIRS) and transesophageal echocardiography, 4) attention on surgical blood loss, use of tranexamic acid and prothrombin complexes, 5) early extubation and 6) avoiding the use of nasogastric feeding tubes and nasal temperature probes. Our case reports describe the use of Jarvik 2000 as a destination therapy in young patients emphasizing the use of ventricular assist devices as a new therapeutic option in DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked recessive disorder
    GENETICS

, characterized by

    progressive skeletal muscle weakness
    SYMPTOMS

,

    loss of ambulation
    SYMPTOMS

, and

    death
    SYMPTOMS

 secondary to

    cardiac or respiratory failure
    SYMPTOMS

.

    End-stage dilated cardiomyopathy (DCM)
    DIAGNOSIS

 is a frequent finding in

    DMD
    DIAGNOSIS

 patients, they are rarely candidates for

    cardiac transplantation
    MEDICATION

. Recently, the use of

    ventricular assist devices as a destination therapy (DT)
    MEDICATION

 as an

    alternative to cardiac transplantation
    MEDICATION

 in

    DMD
    DIAGNOSIS

 patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. We describe the preoperative, intraoperative and postoperative management of

    Jarvik 2000 implantation
    MEDICATION

 in 4

    DMD
    DIAGNOSIS

    pediatric
    AGE

    (age range 12-17 years)
    AGE

 patients. We also describe the complications that may occur. The most frequent were

    bleeding
    SYMPTOMS

 and

    difficulty in weaning from mechanical ventilation
    NEG_FINDINGS

. Our standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2)

    preoperative and postoperative non-invasive ventilation and cough machine cycles
    MEDICATION

, 3)

    intraoperative use of near infrared spectroscopy (NIRS)
    PARACLINICAL

 and

    transesophageal echocardiography
    PARACLINICAL

, 4) attention on

    surgical blood loss
    MEDICATION

,

    use of tranexamic acid and prothrombin complexes
    MEDICATION

, 5)

    early extubation
    MEDICATION

 and 6)

    avoiding the use of nasogastric feeding tubes and nasal temperature probes
    NEG_FINDINGS

. Our case reports describe the use of

    Jarvik 2000 as a destination therapy
    MEDICATION

 in

    young
    AGE

 patients emphasizing the use of

    ventricular assist devices
    MEDICATION

 as a new therapeutic option in

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
End-stage dilated cardiomyopathy (DCM)
DMD
DMD
DMD
DMD

progressive skeletal muscle weakness
loss of ambulation
death
cardiac or respiratory failure
bleeding


Massive reflux and aspiration after radiographically inserted gastrostomy tube placement.

To the authors' knowledge, fatal postgastrostomy aspiration within 2 days of enteral nutrition has not been reported. The authors report consecutive cases of severe postgastrotomy aspiration with one being fatal for a 26-yr-old with Duchenne muscular dystrophy 2 days after initiation of gastrostomy feedings. Previous to these consecutive radiographically inserted gastrostomies, all gastrotomies at the institution were percutaneous endoscopic gastrostomies or open gastrostomies. Radiographically inserted gastrostomy tubes have an increased likelihood of being oriented toward the esophagus as opposed to the duodenum, which may increase the risk for reflux. Elimination of invasive airway tubes should be delayed until after gastrostomy feedings are documented to be well tolerated. Oximetry and repeated measurements of vital capacity can suggest changes in the status of airway clearance.

To the authors' knowledge,

    fatal postgastrostomy aspiration within 2 days of enteral nutrition
    SYMPTOMS

 has not been reported. The authors report consecutive cases of

    severe postgastrotomy aspiration
    SYMPTOMS

 with one being fatal for a

    26-yr-old
    AGE

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 2 days after

    initiation of gastrostomy feedings
    MEDICATION

. Previous to these consecutive

    radiographically inserted gastrostomies
    MEDICATION

, all

    gastrotomies
    MEDICATION

 at the institution were

    percutaneous endoscopic gastrostomies or open gastrostomies
    MEDICATION

. Radiographically inserted

    gastrostomy tubes
    MEDICATION

 have an increased likelihood of being oriented toward the esophagus as opposed to the duodenum, which may increase the risk for

    reflux
    SYMPTOMS

.

    Elimination of invasive airway tubes
    MEDICATION

 should be delayed until after

    gastrostomy feedings
    MEDICATION

 are documented to be well tolerated.

    Oximetry
    PARACLINICAL

 and

    repeated measurements of vital capacity
    PARACLINICAL

 can suggest changes in the status

    of airway clearance
    SYMPTOMS

.


Left ventricular noncompaction cardiomyopathy in Duchenne muscular dystrophy carriers.

Duchenne and Becker muscular dystrophies are X-linked hereditary myopathies secondary to a dystrophinopathy resulting in progressive cardiomyopathy and heart failure. The most commonly associated cardiac involvements in these patients are dilated cardiomyopathy and conduction abnormalities; however, recent studies have shown a high prevalence of left ventricular noncompaction cardiomyopathy in patients with Duchenne muscular dystrophy. Furthermore, there is increasing awareness of cardiomyopathy in female heterozygous dystrophinopathy carriers. We report a case series of two dystrophinopathy carriers with the dilated form of left ventricular noncompaction cardiomyopathy, a newly identified association. <Learning objective: Dystrophinopathy carriers can manifest cardiac disease in the form of cardiomyopathy. We present a novel finding of carriers who manifest their cardiomyopathy in the form of left ventricular noncompaction, dilated phenotype. This has been described previously in patients with Duchenne muscular dystrophy.>.

    Duchenne and Becker muscular dystrophies
    DIAGNOSIS

 are

    X-linked
    GENETICS

    hereditary myopathies
    DIAGNOSIS

 secondary to a

    dystrophinopathy
    DIAGNOSIS

 resulting in

    progressive cardiomyopathy
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

. The most commonly associated

    cardiac involvements
    SYMPTOMS

 in these patients are

    dilated cardiomyopathy
    SYMPTOMS

 and

    conduction abnormalities
    SYMPTOMS

; however, recent studies have shown a high prevalence of

    left ventricular noncompaction cardiomyopathy
    SYMPTOMS

 in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

. Furthermore, there is increasing awareness of

    cardiomyopathy
    DIAGNOSIS

 in

    female
    GENDER

    heterozygous dystrophinopathy
    GENETICS

 carriers. We report a case series of two

    dystrophinopathy
    DIAGNOSIS

 carriers with the

    dilated form of left ventricular noncompaction cardiomyopathy
    SYMPTOMS

, a newly identified association. <Learning objective:

    Dystrophinopathy
    DIAGNOSIS

 carriers can manifest

    cardiac disease
    SYMPTOMS

 in the form of

    cardiomyopathy
    DIAGNOSIS

. We present a novel finding of carriers who manifest their

    cardiomyopathy in the form of left ventricular noncompaction, dilated phenotype
    SYMPTOMS

. This has been described previously in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

.>.