Interpretation of acid α-glucosidase activity in creatine kinase elevation: A case of Becker muscular dystrophy.

Diagnosis of Pompe disease is sometimes challenging because it exhibits clinical similarities to muscular dystrophy.

We describe a case of Becker muscular dystrophy (BMD) with a remarkable reduction in activity of the acid α-glucosidase (GAA) enzyme, caused by a combination of pathogenic mutation and polymorphism variants resulting in pseudodeficiency in GAA. The three-year-old boy demonstrated asymptomatic creatine kinase elevation. Neither exon deletion nor duplication was detected on multiplex ligation-dependent probe amplification (MLPA) of DMD. GAA enzyme activity in both dried blood spots and lymphocytes was low, at 11.7% and 7.7% of normal, respectively. However, genetic analysis of GAA detected only heterozygosity for a nonsense mutation (c.118C > T, p.Arg40∗). Muscle pathology showed no glycogen deposits and no high acid phosphatase activity. Hematoxylin-eosin staining detected scattered regenerating fibers; the fibers were faint and patchy on immunochemistry staining of dystrophin. The amount of dystrophin protein was reduced to 11.8% of normal, on Western blotting analysis. Direct sequencing analysis of DMD revealed hemizygosity for a nonsense mutation (c.72G > A, p.Trp24∗). The boy was diagnosed with BMD, despite remarkable reduction in GAA activity; further, he demonstrated heterozygosity for [p.Gly576Ser; p.Glu689Lys] polymorphism variants that indicated pseudodeficiency on another allele in GAA.

Pseudodeficiency alleles are detected in approximately 4% of the Asian population; these demonstrate low activity of acid α-glucosidase (GAA), similar to levels found in Pompe disease. Clinicians should be careful in their interpretations of pseudodeficiency alleles that complicate diagnosis in cases of elevated creatine kinase.

Diagnosis of

    Pompe disease
    DIAGNOSIS

 is sometimes challenging because it exhibits

    clinical similarities to muscular dystrophy
    SYMPTOMS

.

We describe a case of

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 with a

    remarkable reduction in activity of the acid α-glucosidase (GAA) enzyme
    BIOCHEMICAL

, caused by a combination of

    pathogenic mutation and polymorphism variants
    GENETICS

 resulting in

    pseudodeficiency in GAA
    GENETICS

. The

    three-year-old
    AGE

    boy
    GENDER

 demonstrated

    asymptomatic creatine kinase elevation
    BIOCHEMICAL

.

    Neither exon deletion nor duplication was detected
    NEG_FINDINGS

 on

    multiplex ligation-dependent probe amplification (MLPA) of DMD
    PARACLINICAL

.

    GAA enzyme activity in both dried blood spots and lymphocytes was low, at 11.7% and 7.7% of normal, respectively
    BIOCHEMICAL

. However,

    genetic analysis of GAA
    PARACLINICAL

 detected only

    heterozygosity for a nonsense mutation (c.118C > T, p.Arg40∗)
    GENETICS

.

    Muscle pathology
    PARACLINICAL

 showed

    no glycogen deposits
    NEG_FINDINGS

 and

    no high acid phosphatase activity
    NEG_FINDINGS

.

    Hematoxylin-eosin staining
    PARACLINICAL

 detected

    scattered regenerating fibers
    MICROSCOPIC

; the

    fibers were faint and patchy on immunochemistry staining of dystrophin
    SYMPTOMS

. The

    amount of dystrophin protein was reduced to 11.8% of normal
    BIOCHEMICAL

, on

    Western blotting analysis
    PARACLINICAL

.

    Direct sequencing analysis of DMD
    PARACLINICAL

 revealed

    hemizygosity for a nonsense mutation (c.72G > A, p.Trp24∗)
    GENETICS

. The

    boy
    GENDER

 was diagnosed with

    BMD
    DIAGNOSIS

,

    despite remarkable reduction in GAA activity
    NEG_FINDINGS

; further,

    he
    GENDER

 demonstrated

    heterozygosity for [p.Gly576Ser; p.Glu689Lys] polymorphism variants that indicated pseudodeficiency on another allele in GAA
    GENETICS

.

    Pseudodeficiency alleles
    GENETICS

 are detected in approximately 4% of the

    Asian
    ETHNICITY

 population; these demonstrate

    low activity of acid α-glucosidase (GAA), similar to levels found in Pompe disease
    BIOCHEMICAL

. Clinicians should be careful in their interpretations of

    pseudodeficiency alleles
    GENETICS

 that complicate diagnosis in cases of

    elevated creatine kinase
    BIOCHEMICAL

.

Pompe disease
Becker muscular dystrophy (BMD)
BMD


Combination of extracorporeal membrane oxygenation and inline hemofiltration for the acute hyperkalemic cardiac arrest in a patient with Duchenne muscular dystrophy following orthopedic surgery -a case report.

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy that anesthesiologists can encounter in the operation room, and patients with DMD are susceptible to complications such as rhabdomyolysis, hyperkalemic cardiac arrest, and hyperthermia during the perioperative period. Acute onset of hyperkalemic cardiac arrest is a crisis because of the difficulty in achieving satisfactory resuscitation owing to the sustained hyperkalemia accompanied by rhabdomyolysis.

We here report a case of a 13-year-old boy who had multiple leg fractures and other trauma after a car accident and who had suffered from acute hyperkalemic cardiac arrest. He was refractory to cardiopulmonary resuscitation and showed sustained hyperkalemia. With extracorporeal membrane oxygenation and in-line hemofiltration, he recovered from repeated cardiac arrest and hyperkalemia.

Combining ECMO and in-line hemofiltration might be a safe and effective technique for refractory hyperkalemic cardiac arrest and rhabdomyolysis in patients with DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common

    childhood muscular dystrophy
    DIAGNOSIS

 that

    anesthesiologists
    PARACLINICAL

 can encounter in the operation room, and patients with

    DMD
    DIAGNOSIS

 are susceptible to complications such as

    rhabdomyolysis
    DIAGNOSIS

,

    hyperkalemic cardiac arrest
    SYMPTOMS

, and

    hyperthermia
    SYMPTOMS

 during the perioperative period.

    Acute onset of hyperkalemic cardiac arrest
    SYMPTOMS

 is a crisis because of the difficulty in

    achieving satisfactory resuscitation
    NEG_FINDINGS

 owing to the

    sustained hyperkalemia
    BIOCHEMICAL

 accompanied by

    rhabdomyolysis
    BIOCHEMICAL

.

We here report a case of a

    13-year-old
    AGE

    boy
    GENDER

 who had

    multiple leg fractures and other trauma
    SYMPTOMS

 after a

    car accident
    SYMPTOMS

 and who had suffered from

    acute hyperkalemic cardiac arrest
    SYMPTOMS

.

    He
    GENDER

 was

    refractory to cardiopulmonary resuscitation
    NEG_FINDINGS

 and showed

    sustained hyperkalemia
    BIOCHEMICAL

. With

    extracorporeal membrane oxygenation and in-line hemofiltration
    MEDICATION

,

    he
    GENDER

 recovered from

    repeated cardiac arrest
    SYMPTOMS

 and

    hyperkalemia
    BIOCHEMICAL

.

    Combining ECMO and in-line hemofiltration
    MEDICATION

 might be a safe and effective technique for

    refractory hyperkalemic cardiac arrest
    SYMPTOMS

 and

    rhabdomyolysis
    DIAGNOSIS

 in patients with

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
childhood muscular dystrophy
DMD
rhabdomyolysis
rhabdomyolysis
DMD

sustained hyperkalemia
rhabdomyolysis
sustained hyperkalemia
hyperkalemia


Anaesthetic Management in a Duchennne Muscle Dystrophy Patient for Treatment of Recurrent Pneumothorax.

Duchenne muscular dystrophy (DMD) is an x linked recessive disorder. Long term prognosis is ominous, with development of respiratory distress and cardiomyopathy in advanced stage of the disease and expected death in the teens-to-mid 20s due to respiratory or cardiac failure. Peri-operative management of this patients is challenging due to difficult airway anatomy (macroglossia, limited neck and mandibular mobility). Additionally, they are at risk of developing malignant hyperthermia, rhabdomyolysis and hyperkalemic cardiac arrest when exposed to halogenated inhalational anaesthetics and depolarizing muscle relaxants.

We describe a case of DMD proposed to a thoracotomy for treatment of recurrent pneumothorax and its anaesthetic approach.

A 22-year-old male patient with DMD presented at emergency department due dyspnoea starting at 3 days associated with right scapular pain, enhanced by breathing. The patient already presents with mild cardiomyopathy (ejection fraction of 55%, mild mitral and tricuspid regurgitation), severe restrictive respiratory defect, requiring continuous BiPAP. The patient was markedly denourished (BMI of 12 kg/m2) and presented with nearly absent breathing sounds on the right side. Chest radiography showed large pneumothorax on the right side with no signs of tension. Drainage was performed. Despite initial success, recurrence of pneumothorax occurred on the several attempts of clamping. A bronchopleural fistula was suspected and operative treatment was considered. Considering the comorbidities, he was graded ASA IV with a difficult airway due to macroglossia, limited neck and mandibular mobility. Oro-tracheal intubation was performed with slight sedation (propofol, without neuromuscular blocks). Difficult airway anatomy (direct laryngoscopy - Cormack 4) successfully approached with a bougie and Mccoy blade. Fibreoptic intubation approach was immediately available in the operating room, if required. Total intravenous anaesthesia was decided (remifentanil and propofol, administered by continuous infusion, without neuromuscular blockers). Volume controlled protective ventilation as used (tidal volume 6-8ml/kg, respiratory frequency of 14-16/ min; FiO2: 0,5). No bronchopleural fistula was detected and pleurodesis was performed with biologic glue. Patient remained intubated and was transferred to the ICU for monitoring, having been discharged on the 2nd day to the ward. Despite this, pneumothorax recurrence occurred, and surgery was performed again, using the same anaesthetic approach, this time with successful closure of the bronchopleural fistula.

Total intravenous anaesthesia, without neuromuscular blockers, is a safe and effective option for DMD patients. Anaesthesiologists must consider the possibility of cardio-pulmonary disabilities, difficult airway management, as well as the high risk of malignant hyperthermia in these patients.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    x linked recessive disorder
    GENETICS

. Long term prognosis is ominous, with development of

    respiratory distress
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

 in advanced stage of the disease and expected

    death
    SYMPTOMS

    in the teens-to-mid 20s
    AGE

 due to

    respiratory or cardiac failure
    SYMPTOMS

. Peri-operative management of this patients is challenging due to

    difficult airway anatomy
    SYMPTOMS

 (

    macroglossia
    SYMPTOMS

,

    limited neck and mandibular mobility)
    SYMPTOMS

. Additionally, they are at risk of developing

    malignant hyperthermia
    SYMPTOMS

,

    rhabdomyolysis
    SYMPTOMS

 and

    hyperkalemic cardiac arrest
    SYMPTOMS

 when exposed to

    halogenated inhalational anaesthetics
    MEDICATION

 and

    depolarizing muscle relaxants
    MEDICATION

.

We describe a case of

    DMD
    DIAGNOSIS

 proposed

    to a thoracotomy
    MEDICATION

 for treatment of

    recurrent pneumothorax
    DIAGNOSIS

 and its anaesthetic approach.

A

    22-year-old
    AGE

    male
    GENDER

 patient with

    DMD
    DIAGNOSIS

 presented at emergency department due

    dyspnoea starting at 3 days
    SYMPTOMS

 associated with

    right scapular pain
    SYMPTOMS

,

    enhanced by breathing
    SYMPTOMS

. The patient already presents with

    mild cardiomyopathy (ejection fraction of 55%
    SYMPTOMS

,

    mild mitral and tricuspid regurgitation)
    SYMPTOMS

,

    severe restrictive respiratory defect
    SYMPTOMS

, requiring

    continuous BiPAP
    MEDICATION

. The patient was

    markedly denourished
    SYMPTOMS

 (

    BMI of 12 kg/m2)
    SYMPTOMS

 and presented with

    nearly absent breathing sounds on the right side
    SYMPTOMS

.

    Chest radiography
    PARACLINICAL

 showed

    large pneumothorax on the right side
    SYMPTOMS

    with no signs of tension
    NEG_FINDINGS

.

    Drainage
    MEDICATION

 was performed.

    Despite initial success
    NEG_FINDINGS

,

    recurrence of pneumothorax
    SYMPTOMS

 occurred

    on the several attempts of clamping
    NEG_FINDINGS

. A

    bronchopleural fistula
    SYMPTOMS

 was suspected and

    operative treatment
    MEDICATION

 was considered. Considering the comorbidities,

    he
    GENDER

 was graded ASA IV with a

    difficult airway
    SYMPTOMS

 due to

    macroglossia
    SYMPTOMS

,

    limited neck and mandibular mobility
    SYMPTOMS

.

    Oro-tracheal intubation
    MEDICATION

 was performed with

    slight sedation (propofol, without neuromuscular blocks
    MEDICATION

).

    Difficult airway
    SYMPTOMS

 anatomy (

    direct laryngoscopy - Cormack 4
    MEDICATION

) successfully approached with

    a bougie and Mccoy blade
    MEDICATION

.

    Fibreoptic intubation approach
    MEDICATION

 was immediately available in the operating room, if required.

    Total intravenous anaesthesia was decided (remifentanil and propofol, administered by continuous infusion, without neuromuscular blockers
    MEDICATION

    )
    MEDICATION

.

    Volume controlled protective ventilation as used (tidal volume 6-8ml/kg, respiratory frequency of 14-16/ min; FiO2: 0,5)
    MEDICATION

.

    No bronchopleural fistula was detected
    NEG_FINDINGS

 and

    pleurodesis was performed with biologic glue
    MEDICATION

. Patient

    remained intubated
    MEDICATION

 and was

    transferred to the ICU for monitoring
    MEDICATION

, having been discharged on the 2nd day

    to the ward
    MEDICATION

. Despite this,

    pneumothorax recurrence
    SYMPTOMS

 occurred, and

    surgery
    MEDICATION

 was performed again,

    using the same anaesthetic approach
    MEDICATION

, this time with

    successful closure of the bronchopleural fistula
    MEDICATION

.

    Total intravenous anaesthesia
    MEDICATION

,

    without neuromuscular blockers
    NEG_FINDINGS

, is a safe and effective option for

    DMD
    DIAGNOSIS

 patients.

    Anaesthesiologists
    PARACLINICAL

 must consider the possibility of

    cardio-pulmonary disabilities
    SYMPTOMS

,

    difficult airway management
    MEDICATION

, as well as the high risk of

    malignant hyperthermia
    DIAGNOSIS

 in these patients.

Duchenne muscular dystrophy (DMD)
DMD
recurrent pneumothorax
DMD
DMD
malignant hyperthermia

with no signs of tension
Despite initial success
on the several attempts of clamping
No bronchopleural fistula was detected
without neuromuscular blockers


Generation of Duchenne muscular dystrophy patient-specific induced pluripotent stem cell line lacking exons 45-50 of the dystrophin gene (IITi001-A).

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease caused by mutations in the dystrophin gene. We generated induced pluripotent stem cells (iPSCs) from a 13-year-old male patient carrying a deletion mutation of exons 45-50; iPSCs were subsequently differentiated into cardiomyocytes. iPSCs exhibit expression of the pluripotent markers (SOX2, NANOG, OCT4), differentiation capacity into the three germ layers, normal karyotype, genetic identity to the skin biopsy dermal fibroblasts and the patient-specific dystrophin mutation.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    progressive muscle degenerative disease
    DIAGNOSIS

 caused by

    mutations in the dystrophin gene
    GENETICS

. We generated

    induced pluripotent stem cells (iPSCs)
    MICROSCOPIC

 from a

    13-year-old
    AGE

    male
    GENDER

 patient carrying a

    deletion mutation of exons 45-50
    GENETICS

;

    iPSCs
    MICROSCOPIC

 were subsequently

    differentiated into cardiomyocytes
    MICROSCOPIC

.

    iPSCs
    MICROSCOPIC

 exhibit

    expression of the pluripotent markers (SOX2, NANOG, OCT4)
    GENETICS

,

    differentiation capacity into the three germ layers
    MICROSCOPIC

,

    normal karyotype
    NEG_FINDINGS

,

    genetic identity to the skin biopsy dermal fibroblasts
    SYMPTOMS

 and the

    patient-specific dystrophin mutation
    GENETICS

.

Duchenne muscular dystrophy (DMD)
progressive muscle degenerative disease


Efficacy of Denosumab for Glucocorticoid-Induced Osteoporosis in an Adolescent Patient with Duchenne Muscular Dystrophy: A Case Report.

We report the case of a 13-year-old boy with Duchenne muscular dystrophy (DMD) who sustained bilateral femoral neck fractures associated with glucocorticoid-induced osteoporosis. Denosumab therapy for 18 months markedly improved the lumbar bone mineral density and the bone turnover markers. No fractures or complications were recorded during the treatment period.

To the best of our knowledge, this is the first description of denosumab treatment for glucocorticoid-induced osteoporosis in a patient with DMD. The drug merits additional testing as an effective therapy for osteoporosis in patients with DMD.

We report the case of a

    13-year-old
    AGE

    boy
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 who sustained

    bilateral femoral neck fractures
    SYMPTOMS

 associated with

    glucocorticoid-induced osteoporosis
    SYMPTOMS

.

    Denosumab therapy for 18 months
    MEDICATION

 markedly

    improved the lumbar bone mineral density and the bone turnover markers
    SYMPTOMS

.

    No fractures or complications
    NEG_FINDINGS

 were recorded during the treatment period.

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

    denosumab treatment
    MEDICATION

 for

    glucocorticoid-induced osteoporosis
    DIAGNOSIS

 in a patient with

    DMD
    DIAGNOSIS

. The drug merits additional testing as an effective therapy for

    osteoporosis
    DIAGNOSIS

 in patients with

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
glucocorticoid-induced osteoporosis
DMD
osteoporosis
DMD

Denosumab therapy for 18 months
denosumab treatment


Pectoralis blocks for insertion of an implantable cardioverter defibrillator in two patients with Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) often have systemic manifestations with comorbid involvement of the cardiac and respiratory systems that increase the risk of anesthetic and perioperative morbidity. These patients frequently develop progressive myocardial involvement with cardiomyopathy, depressed cardiac function, and arrhythmias. The latter may necessitate the placement of an automatic implantable cardioverter defibrillator (AICD) insertion. As a means of avoiding the need for general anesthesia and its inherent potential of morbidity, regional anesthesia may be used in specific cases. We present two cases of successful AICD insertion in patients with DMD using unilateral pectoralis and intercostal nerve blocks supplemented with intravenous sedation. Relevant anatomy for this regional anesthetic technique is reviewed and benefits of this anesthetic technique compared to general anesthesia are discussed.

Patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 often have

    systemic manifestations
    SYMPTOMS

 with

    comorbid involvement of the cardiac and respiratory systems
    SYMPTOMS

 that increase the risk of anesthetic and

    perioperative morbidity
    SYMPTOMS

. These patients frequently develop

    progressive myocardial involvement
    SYMPTOMS

 with

    cardiomyopathy
    SYMPTOMS

,

    depressed cardiac function
    SYMPTOMS

, and

    arrhythmias
    SYMPTOMS

. The latter may necessitate the

    placement of
    MEDICATION

 an

    automatic implantable cardioverter defibrillator (AICD) insertion
    MEDICATION

. As a means of avoiding the need for

    general anesthesia
    MEDICATION

 and its inherent potential of morbidity,

    regional anesthesia
    MEDICATION

 may be used in specific cases. We present two cases of successful

    AICD insertion
    MEDICATION

 in patients with

    DMD
    DIAGNOSIS

 using

    unilateral pectoralis and intercostal nerve blocks supplemented with intravenous sedation
    MEDICATION

. Relevant anatomy for this

    regional anesthetic technique
    MEDICATION

 is reviewed and benefits of this

    anesthetic technique
    MEDICATION

 compared to

    general anesthesia
    MEDICATION

 are discussed.


Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome.

A previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation.

This is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.

    Juvenile dermatomyositis (JDM)
    DIAGNOSIS

 is an

    auto-immune muscle disease
    DIAGNOSIS

 which presents with

    skin manifestations
    SYMPTOMS

 and

    muscle weakness
    SYMPTOMS

. At least 10% of the patients with

    JDM
    DIAGNOSIS

 present with

    acquired lipodystrophy
    SYMPTOMS

.

    Laminopathies
    DIAGNOSIS

 are caused by

    mutations in the lamin genes
    GENETICS

 and cover a wide spectrum of diseases including

    muscular dystrophies
    DIAGNOSIS

 and

    lipodystrophy
    DIAGNOSIS

. The

    p.T10I LMNA variant
    GENETICS

 is associated with a phenotype of

    generalized lipodystrophy
    SYMPTOMS

 that has also been called

    atypical progeroid syndrome
    DIAGNOSIS

.

A previously healthy

    female
    GENDER

 presented with

    bilateral proximal lower extremity muscle weakness
    SYMPTOMS

 at

    age 4
    AGE

.

    She
    GENDER

 was diagnosed with

    JDM
    DIAGNOSIS

 based on

    her
    GENDER

 clinical presentation,

    laboratory tests
    PARACLINICAL

 and

    magnetic resonance imaging (MRI)
    PARACLINICAL

.

    She
    GENDER

 had

    subcutaneous fat loss which started in her extremities and progressed to her whole body
    SYMPTOMS

. At

    age 7
    AGE

,

    she
    GENDER

 had

    diabetes
    SYMPTOMS

,

    hypertriglyceridemia
    BIOCHEMICAL

,

    low leptin levels
    BIOCHEMICAL

 and

    low body fat
    SYMPTOMS

 on

    dual energy X-ray absorptiometry (DEXA) scan
    PARACLINICAL

, and was diagnosed with

    acquired generalized lipodystrophy (AGL)
    DIAGNOSIS

.

    Whole exome sequencing (WES)
    PARACLINICAL

 revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C.

    Muscle biopsy
    PARACLINICAL

 confirmed

    JDM
    DIAGNOSIS

 rather than

    muscular dystrophy
    DIAGNOSIS

, showing

    perifascicular atrophy
    SYMPTOMS

 and

    perivascular mononuclear cell infiltration
    MICROSCOPIC

.

    Immunofluroscence of skin fibroblasts
    PARACLINICAL

 confirmed

    nuclear atypia and fragmentation
    MICROSCOPIC

.

This is a unique case with

    p.T10I LMNA variant
    GENETICS

 displaying

    concurrent JDM and AGL
    DIAGNOSIS

. This co-occurrence raises the intriguing possibility that

    LMNA
    GENETICS

, and possibly

    p.T10I
    GENETICS

, may have a pathogenic role in not only the occurrence of

    generalized lipodystrophy
    SYMPTOMS

, but also

    juvenile dermatomyositis
    DIAGNOSIS

. Careful phenotypic characterization of additional patients with

    laminopathies
    DIAGNOSIS

 as well as individuals with

    JDM
    DIAGNOSIS

 is warranted.

mutations in the lamin genes
p.T10I LMNA variant
p.T10I LMNA variant
LMNA
p.T10I


Unusual Presentations of Dystrophinopathies in Childhood.

X-linked recessive mutations in the dystrophin gene are one of the most common causes of inherited neuromuscular disorders in humans. Duchenne muscular dystrophy, the most common phenotype, and Becker muscular dystrophy are often recognizable by certain clinical features; however, less frequent presentations require a higher degree of suspicion. In this article, we describe a series of 6 children (4 boys, 2 girls) referred to a tertiary pediatric neuromuscular clinic for isolated elevated creatine kinase levels (range: 720-7000 IU/L) identified on initial assessment for otherwise unexplained transaminase elevations (n = 2), a social communication disorder (n = 3), and exertional myalgia and/or rhabdomyolysis (n = 1). There was no preceding family history of neuromuscular disease. One boy had an additional history of severe cerebral palsy and cyclical vomiting, and 1 girl had a history of maternal hepatitis C. There was no significant weakness at presentation, and the majority remained stable over a prolonged period of follow-up (age range at last follow-up: 9-16 years). All 6 children were found to carry dystrophin gene mutations resulting in milder phenotypes. This series highlights that dystrophinopathies may not uncommonly present with features distinct from the classic Duchenne muscular dystrophy and Becker muscular dystrophy phenotypes in both boys and girls. Pediatricians should be aware of such atypical presentations to initiate a timely and adequate diagnostic process. Establishing the correct genetic diagnosis of a dystrophinopathy is important to allow appropriate genetic counseling, to implement relevant surveillance and management strategies, and to avoid unnecessary investigations in search of an incorrect alternative diagnosis.

    X-linked recessive mutations in the dystrophin gene
    GENETICS

 are one of the most common causes of

    inherited neuromuscular disorders
    DIAGNOSIS

 in humans.

    Duchenne muscular dystrophy
    DIAGNOSIS

, the most common phenotype, and

    Becker muscular dystrophy
    DIAGNOSIS

 are often recognizable by certain clinical features; however, less frequent presentations require a higher degree of suspicion. In this article, we describe a series of 6

    children
    AGE

 (4

    boys
    GENDER

, 2

    girls
    GENDER

) referred to a tertiary pediatric neuromuscular clinic for

    isolated elevated creatine kinase levels (range: 720-7000 IU/L)
    BIOCHEMICAL

 identified on initial assessment for

    otherwise unexplained transaminase elevations
    NEG_FINDINGS

 (n = 2), a

    social communication disorder
    SYMPTOMS

 (n = 3), and

    exertional myalgia
    SYMPTOMS

 and/or

    rhabdomyolysis
    SYMPTOMS

 (n = 1). There was

    no preceding family history of neuromuscular disease
    NEG_FINDINGS

. One

    boy
    GENDER

 had an additional history of

    severe cerebral palsy
    SYMPTOMS

 and

    cyclical vomiting
    SYMPTOMS

, and 1

    girl
    GENDER

 had a history of maternal hepatitis C. There was

    no significant weakness
    NEG_FINDINGS

 at presentation, and the majority

    remained stable over a prolonged period of follow-up
    SYMPTOMS

 (

    age range at last follow-up: 9-16 years)
    AGE

. All 6

    children
    AGE

 were found to carry

    dystrophin gene mutations
    GENETICS

 resulting in

    milder phenotypes
    SYMPTOMS

. This series highlights that

    dystrophinopathies
    DIAGNOSIS

 may not uncommonly present with

    features distinct from the classic Duchenne muscular dystrophy
    SYMPTOMS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 phenotypes in both

    boys
    GENDER

 and

    girls
    GENDER

.

    Pediatricians
    PARACLINICAL

 should be aware of such atypical presentations to initiate a timely and adequate diagnostic process. Establishing the correct genetic diagnosis of a

    dystrophinopathy
    DIAGNOSIS

 is important to allow appropriate

    genetic counseling
    MEDICATION

, to implement relevant surveillance and management strategies, and to avoid unnecessary investigations in search of an

    incorrect alternative diagnosis
    NEG_FINDINGS

.

inherited neuromuscular disorders
Duchenne muscular dystrophy
Becker muscular dystrophy
dystrophinopathies
Becker muscular dystrophy
dystrophinopathy


Dystrophin Exon 29 Nonsense Mutations Cause a Variably Mild Phenotype.

Nonsense mutations in the dystrophin gene usually result in a severe Duchenne muscular dystrophy phenotype.

We describe a 7-year-old boy with a rare pathogenic mutation in exon 29 c.3940C>T p.(Arg1314Ter) resulting in exon skipping, in turn rescuing the phenotype from a severe Duchenne type to a milder Becker muscular dystrophy type. No adults have been described with this mutation to date.

Exon skipping of exon 29 results in a higher level of functional dystrophin. Some cases of muscular dystrophy may still require muscle biopsy to determine optimal management and pharmaceutical treatment options.

    Nonsense mutations in the dystrophin gene
    GENETICS

 usually result in a

    severe Duchenne muscular dystrophy
    DIAGNOSIS

 phenotype.

We describe a

    7-year-old
    AGE

    boy
    GENDER

 with a

    rare pathogenic mutation in exon 29 c.3940C>T p.(Arg1314Ter) resulting in exon skipping
    GENETICS

, in turn rescuing the phenotype from a

    severe Duchenne type to a milder Becker muscular dystrophy type
    DIAGNOSIS

. No adults have been described with this mutation to date.

    Exon skipping of exon 29
    GENETICS

 results in a

    higher level of functional dystrophin
    BIOCHEMICAL

. Some cases of

    muscular dystrophy
    DIAGNOSIS

 may still require

    muscle biopsy
    PARACLINICAL

 to determine optimal management and pharmaceutical treatment options.


Bilateral Cerebral Infarctions and Intracardiac Thrombus in a Young Duchenne Muscular Dystrophy Patient.

A 31-year-old man with Duchenne muscular dystrophy was admitted to our center, having infarctions in bilateral cerebral hemispheres and an occluded right middle cerebral artery. His right middle cerebral artery was spontaneous recanalization on the next day, and thrombus in the left ventricle vanished on the eighth day after giving warfarin.

A

    31-year-old
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 was admitted to our center, having

    infarctions in bilateral cerebral hemispheres
    SYMPTOMS

 and an

    occluded right middle cerebral artery
    SYMPTOMS

. His

    right middle cerebral artery was spontaneous recanalization
    SYMPTOMS

 on the next day, and

    thrombus in the left ventricle vanished
    SYMPTOMS

 on the eighth day after giving

    warfarin
    MEDICATION

.


Clinical and molecular consequences of exon 78 deletion in DMD gene.

We present a 13-year-old patient with persistent increase of serum Creatine Kinase (CK) and myalgia after exertion. Skeletal muscle biopsy showed marked reduction of dystrophin expression leading to genetic analysis of DMD gene by MLPA, which detected a single deletion of exon 78. To the best of our knowledge, DMD exon 78 deletion has never been described in literature and, according to prediction, it should lead to loss of reading frame in the dystrophin gene. To further assess the actual effect of exon 78 deletion, we analysed cDNA from muscle mRNA. This analysis confirmed the absence of 32 bp of exon 78. Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids. Albeit loss of reading frame usually leads to protein degradation and severe phenotype, in this case, we demonstrated that deletion of DMD exon 78 can be associated with a functional protein able to bind DGC complex and a very mild phenotype. This study adds a novel deletion in DMD gene in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease.

We present a

    13-year-old
    AGE

 patient with

    persistent increase of serum Creatine Kinase (CK)
    BIOCHEMICAL

 and

    myalgia
    SYMPTOMS

 after

    exertion
    SYMPTOMS

.

    Skeletal muscle biopsy
    PARACLINICAL

 showed

    marked reduction of dystrophin expression
    BIOCHEMICAL

 leading to

    genetic analysis of DMD gene
    PARACLINICAL

 by

    MLPA
    PARACLINICAL

, which detected a

    single deletion of exon 78
    GENETICS

. To the best of our knowledge,

    DMD exon 78 deletion
    GENETICS

 has never been described in literature and, according to prediction, it should lead to

    loss of reading frame in the dystrophin gene
    GENETICS

. To further assess the actual effect of

    exon 78 deletion
    GENETICS

, we

    analysed cDNA from muscle mRNA
    PARACLINICAL

. This analysis confirmed the

    absence of 32 bp of exon 78
    GENETICS

.

    Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids
    GENETICS

. Albeit

    loss of reading frame
    GENETICS

 usually leads to

    protein degradation
    BIOCHEMICAL

 and

    severe phenotype
    SYMPTOMS

, in this case, we demonstrated that

    deletion of DMD exon 78
    GENETICS

 can be associated with a functional protein able to

    bind DGC complex
    BIOCHEMICAL

 and a

    very mild phenotype
    SYMPTOMS

. This study adds a

    novel deletion in DMD gene
    GENETICS

 in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease.

myalgia
exertion
severe phenotype
very mild phenotype


Mechanical thrombectomy in a young stroke patient with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive skeletal muscle myopathy which is caused by mutations in the dystrophin gene. Lack of dystrophin also results to cardiomyopathy, which raises significantly the stroke risk in DMD-patients. However, data about therapeutic opportunities in the acute setting are scarce in literature. So far, only two cases receiving IV thrombolysis are described, one of them with fatal outcome.

Case report of a case of successful mechanical thrombectomy (MTE) in an acute ischemic stroke (AIS) patient with DMD and associated dilatative cardiomyopathy.

A 20-year old DMD-patient was transferred at 08:56 h to our department due to wake up stroke with severe right-sided hemiparesis and aphasia (NIHSS=20). Last-seen-normal was at 03:00 h. Cerebral CT-scan revealed only slight early ischemic changes (ASPECT-Score=8). CT-angiography detected occlusion of left middle cerebral artery (LMCA). MTE started rapidly at 9:23 h and using direct thrombus aspiration (Penumbra System®) complete recanalization was achieved 20 min later (TICI-grade 3). Considering the specific risks of general anesthesia in DMD, the procedure was performed with propofol, remifentanil and rocuronium. The patient recovered quickly from the acute symptoms, due to preexisting hypotonic tetraparesis his NIHSS-score at discharge was 12 points.

To the best of our knowledge, this is the first report on MTE in a patient with DMD related cardioembolic stroke. In contrast to the few reports with IV thrombolysis, MTE seems to represent an optimal treatment option. Specific characteristics of DMD-patients like anesthetic regimen should be taken into account.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    skeletal muscle myopathy
    DIAGNOSIS

 which is caused by

    mutations in the dystrophin gene
    GENETICS

.

    Lack of dystrophin
    BIOCHEMICAL

 also results to

    cardiomyopathy
    SYMPTOMS

, which raises significantly the

    stroke
    SYMPTOMS

 risk in

    DMD
    DIAGNOSIS

-patients. However, data about therapeutic opportunities in the acute setting are scarce in literature. So far, only two cases receiving

    IV thrombolysis
    MEDICATION

 are described, one of them with

    fatal outcome
    SYMPTOMS

.

Case report of a case of

    successful mechanical thrombectomy (MTE)
    MEDICATION

 in an

    acute ischemic stroke (AIS)
    SYMPTOMS

 patient with

    DMD
    DIAGNOSIS

 and associated

    dilatative cardiomyopathy
    DIAGNOSIS

.

A

    20-year old
    AGE

 DMD-patient was transferred at 08:56 h to our department due to

    wake up stroke
    SYMPTOMS

 with

    severe right-sided hemiparesis
    SYMPTOMS

 and

    aphasia
    SYMPTOMS

 (

    NIHSS=20)
    SYMPTOMS

. Last-seen-normal was at 03:00 h.

    Cerebral CT-scan
    PARACLINICAL

 revealed

    only slight early ischemic changes (ASPECT-Score=8)
    SYMPTOMS

.

    CT-angiography
    PARACLINICAL

 detected

    occlusion of left middle cerebral artery (LMCA)
    SYMPTOMS

.

    MTE
    MEDICATION

 started rapidly at 9:23 h and using

    direct thrombus aspiration (Penumbra System®)
    MEDICATION

    complete recanalization was achieved
    SYMPTOMS

 20 min later

    (TICI-grade 3)
    SYMPTOMS

. Considering the specific risks of

    general anesthesia
    MEDICATION

 in

    DMD
    DIAGNOSIS

, the procedure was performed with

    propofol, remifentanil and rocuronium
    MEDICATION

. The patient

    recovered quickly from the acute symptoms
    SYMPTOMS

, due to

    preexisting hypotonic tetraparesis
    SYMPTOMS

 his

    NIHSS-score at discharge was 12 points
    SYMPTOMS

.

To the best of our knowledge, this is the first report on

    MTE
    MEDICATION

 in a patient with

    DMD
    DIAGNOSIS

 related

    cardioembolic stroke
    SYMPTOMS

. In contrast to the few reports with

    IV thrombolysis
    MEDICATION

,

    MTE
    MEDICATION

 seems to represent an optimal treatment option. Specific characteristics of

    DMD
    DIAGNOSIS

-patients like anesthetic regimen should be taken into account.

Duchenne muscular dystrophy (DMD)
skeletal muscle myopathy
DMD
DMD
dilatative cardiomyopathy
DMD
DMD
DMD

X-linked recessive
mutations in the dystrophin gene


Duchenne muscular dystrophy: Case report and review.

Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

    Muscular dystrophies
    DIAGNOSIS

 are a clinically and heterogeneous group of disorders that all share clinical characteristics of

    progressive muscular weakness
    SYMPTOMS

.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common

    X-linked
    GENETICS

    disorder muscular dystrophy
    DIAGNOSIS

 in

    children
    AGE

, presenting in

    early childhood
    AGE

 and characterized by

    proximal muscle weakness
    SYMPTOMS

 and

    calf hypertrophy
    SYMPTOMS

 in affected

    boys
    GENDER

. There is usually

    delay in motor development
    SYMPTOMS

 and eventually

    wheelchair confinement
    MEDICATION

 followed by

    premature death
    SYMPTOMS

 from

    cardiac or respiratory complications
    SYMPTOMS

. Treatment modalities such as

    corticosteroid therapy
    MEDICATION

 and

    use of intermittent positive pressure ventilation
    MEDICATION

 have provided

    improvements in function, ambulation
    SYMPTOMS

,

    quality of life
    SYMPTOMS

, and

    life expectancy
    SYMPTOMS

, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of

    DMD
    DIAGNOSIS

 in a

    12-year-old
    AGE

    male
    GENDER

 with

    remarkable clinical and oral manifestations
    SYMPTOMS

.

Muscular dystrophies
Duchenne muscular dystrophy (DMD)
disorder muscular dystrophy
DMD


Prenatal diagnosis for a Chinese family with a de novo DMD gene mutation: A case report.

Patients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis.

First, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified.

MLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient.

The pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic.

Patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 usually have

    severe and fatal symptoms
    SYMPTOMS

. At present, there is no effective treatment for

    DMD
    DIAGNOSIS

, thus it is very important to avoid the birth of children with

    DMD
    DIAGNOSIS

 by effective prenatal diagnosis. We identified a

    de novo DMD gene mutation
    GENETICS

 in a

    Chinese
    ETHNICITY

 family, and make a

    prenatal diagnosis
    PARACLINICAL

.

First,

    multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

 was applied to

    analyze DMD gene exon deletion/duplication
    PARACLINICAL

    in all family members
    FAMILY

.

    The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing
    PARACLINICAL

 in the patient; and then according to

    DMD gene exon mutation
    GENETICS

 in the patient,

    DMD gene sequencing
    PARACLINICAL

 was performed in the

    family members
    PARACLINICAL

. On the basis of results above, the

    pathogenic mutation in DMD gene
    GENETICS

 was identified.

    MLPA
    PARACLINICAL

 showed

    no DMD gene exon deletion/duplication in all family members
    NEG_FINDINGS

.

    Sanger sequencing
    PARACLINICAL

 revealed

    c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene
    GENETICS

 of the patient.

    Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister
    GENETICS

. The

    analyses of amniotic fluid samples
    PARACLINICAL

 indicated

    negative Y chromosome sex-determining gene
    NEG_FINDINGS

,

    no DMD gene exon deletion/duplication
    NEG_FINDINGS

,

    no mutations at c.2767 locus
    NEG_FINDINGS

, and

    the inherited maternal X chromosome different from that of the patient
    FAMILY

.

    The pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26]
    GENETICS

, identified in this

    family is a de novo mutation
    GENETICS

. On the basis of specific conditions, it is necessary to select suitable methods to make

    prenatal diagnosis
    PARACLINICAL

 more effective, accurate, and economic.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Late-onset Becker-type muscular dystrophy in a Border terrier dog.

A 9-year-old Border terrier was presented to a referral hospital after a 1-year history of progressive stiffness and exercise intolerance. Neurological examination was consistent with a neuromuscular disorder. Serum creatine kinase activity was mildly elevated. A myopathy was suspected based on MRI findings and electrophysiological examination. Muscle histopathology was consistent with a severe non-inflammatory myopathy of a dystrophic type. Immunofluorescence and western blotting confirmed a dystrophinopathy with an 80-kDa truncated dystrophin fragment similar to Becker muscular dystrophy in people. To our knowledge, this is the first description of a late-onset Becker-type muscular dystrophy in a dog, and the first description of a dystrophinopathy in a Border terrier. Muscular dystrophy in dogs should not be ruled out based on late onset clinical signs and only mildly elevated creatine kinase.

A

    9-year-old
    AGE

    Border terrier
    ETHNICITY

 was presented to a referral hospital after a 1-year history of

    progressive stiffness
    SYMPTOMS

 and

    exercise intolerance
    SYMPTOMS

.

    Neurological examination
    PARACLINICAL

 was consistent with a

    neuromuscular disorder
    DIAGNOSIS

.

    Serum creatine kinase activity was mildly elevated
    BIOCHEMICAL

. A

    myopathy
    DIAGNOSIS

 was suspected based on

    MRI findings
    PARACLINICAL

 and

    electrophysiological examination
    PARACLINICAL

.

    Muscle histopathology
    PARACLINICAL

 was consistent with a

    severe non-inflammatory myopathy of a dystrophic type
    DIAGNOSIS

.

    Immunofluorescence and western blotting
    PARACLINICAL

 confirmed a

    dystrophinopathy
    DIAGNOSIS

 with an

    80-kDa truncated dystrophin fragment
    BIOCHEMICAL

 similar to

    Becker muscular dystrophy
    DIAGNOSIS

 in people. To our knowledge, this is the first description of a

    late-onset Becker-type muscular dystrophy
    DIAGNOSIS

 in a

    dog
    GENDER

, and the first description of a

    dystrophinopathy
    DIAGNOSIS

 in a

    Border terrier
    ETHNICITY

.

    Muscular dystrophy
    DIAGNOSIS

 in

    dogs
    GENDER

 should

    not be ruled out
    NEG_FINDINGS

 based on

    late onset clinical signs
    SYMPTOMS

 and only

    mildly elevated creatine kinase
    BIOCHEMICAL

.

progressive stiffness
exercise intolerance
late onset clinical signs


A novel point mutation affecting Asn76 of dystrophin protein leads to dystrophinopathy.

Mutations in the DMD gene lead to Duchenne and Becker muscular dystrophy (DMD/BMD). Missense mutations are rare cause of DMD/BMD. A six-month-old male patient presented with mild generalized muscle weakness, hypotonia, and delayed motor development. Dystrophinopathy was suspected because of highly elevated serum creatine kinase level (1497 U/L) and tiered DMD gene analysis was performed. Multiplex ligation-dependent probe amplification (MLPA) assay showed deletion of exon 4, which could not be confirmed by another method. Sequencing of exon 4 revealed a novel de novo point mutation (c.227A>T, p.Asn76Ile) in the N-terminal actin-binding domain (N-ABD) of dystrophin protein. The false positive MLPA result was explained by the fact that the affected nucleotide lies directly at the 3' ligation site of the MLPA probe. Sequencing of the whole coding region of DMD gene proved c.227A>T to be the sole variant being potentially pathogenic. According to in silico analyses the mutation was predicted to be highly destabilizing on N-ABD structure possibly leading to protein malfunction. Muscle biopsy was performed and dystrophin immunohistochemistry results were suggestive of BMD. Our results highlight the importance of confirmatory testing of single-exon deletions detected by MLPA and we describe a novel, destabilizing missense mutation in the DMD gene.

    Mutations in the DMD gene
    GENETICS

 lead to

    Duchenne and Becker muscular dystrophy (DMD/BMD)
    DIAGNOSIS

.

    Missense mutations
    GENETICS

 are rare cause of

    DMD/BMD
    DIAGNOSIS

. A

    six-month-old
    AGE

    male
    GENDER

 patient presented with

    mild generalized muscle weakness
    SYMPTOMS

,

    hypotonia
    SYMPTOMS

, and

    delayed motor development
    SYMPTOMS

.

    Dystrophinopathy
    DIAGNOSIS

 was suspected because of

    highly elevated serum creatine kinase level (1497 U/L)
    BIOCHEMICAL

 and

    tiered DMD gene analysis
    PARACLINICAL

 was performed.

    Multiplex ligation-dependent probe amplification (MLPA) assay
    PARACLINICAL

 showed

    deletion of exon 4
    GENETICS

, which could not be confirmed by another method.

    Sequencing of exon 4
    PARACLINICAL

 revealed a

    novel de novo point mutation (c.227A>T, p.Asn76Ile) in the N-terminal actin-binding domain (N-ABD) of dystrophin protein
    GENETICS

. The

    false positive MLPA
    NEG_FINDINGS

 result was explained by the fact that

    the affected nucleotide lies directly at the 3' ligation site of the MLPA probe
    GENETICS

.

    Sequencing of the whole coding region of DMD gene
    PARACLINICAL

 proved

    c.227A>T to be the sole variant being potentially pathogenic
    GENETICS

. According to

    in silico analyses
    PARACLINICAL

 the

    mutation was predicted to be highly destabilizing on N-ABD structure
    GENETICS

 possibly leading to

    protein malfunction
    GENETICS

.

    Muscle biopsy
    PARACLINICAL

 was performed and

    dystrophin immunohistochemistry
    PARACLINICAL

 results were suggestive of

    BMD
    DIAGNOSIS

. Our results highlight the importance of

    confirmatory testing
    PARACLINICAL

 of

    single-exon deletions
    GENETICS

 detected by

    MLPA
    PARACLINICAL

 and we describe a

    novel, destabilizing missense mutation in the DMD gene
    GENETICS

.

mild generalized muscle weakness
hypotonia
delayed motor development


Novel Mutation of the Dystrophin Gene in a Child with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked autosomal recessive genetic disorder caused by mutations in DMD gene. Approximately 70% of the mutations are caused by deletions or duplications of DMD exons, while the remaining were minor mutations.

We present a 5-year-old boy with typical clinical features of DMD. A novel mutation was identified as a c.9358_9359insA of DMD gene by next-generation sequencing. This mutation which was origined from mother, generated a frameshift mutation and resulted in abnormal synthesis of protein polypeptide chains.

We demonstrated a novel mutation of DMD gene and expanded the spectrum of mutations causing DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked autosomal recessive genetic disorder
    GENETICS

 caused by

    mutations in DMD gene
    GENETICS

. Approximately 70% of the mutations are caused by

    deletions or duplications of DMD exons
    GENETICS

, while the remaining were

    minor mutations
    GENETICS

.

We present a

    5-year-old
    AGE

    boy
    GENDER

 with

    typical clinical features
    SYMPTOMS

 of

    DMD
    DIAGNOSIS

. A

    novel mutation was identified as a c.9358_9359insA of DMD gene
    GENETICS

 by

    next-generation sequencing
    PARACLINICAL

. This

    mutation which was origined from mother, generated a frameshift mutation
    GENETICS

 and resulted in

    abnormal synthesis of protein polypeptide chains
    BIOCHEMICAL

.

We demonstrated a

    novel mutation of DMD gene
    GENETICS

 and expanded the

    spectrum of mutations causing DMD
    GENETICS

.


Low-level dystrophin expression attenuating the dystrophinopathy phenotype.

The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and an in-frame transcript. Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy. RNA sequencing analysis from a muscle biopsy revealed only 6.0-9.8% of DMD transcripts were in-frame, excluding exon 42, and immunoblot demonstrated only 3.2% dystrophin protein expression. Another potential genetic modifier noted was homozygosity for the protective IAAM LTBP4 haplotype. This case suggests that very low levels of DMD exon skipping and dystrophin protein expression may result in amelioration of skeletal muscle weakness, a finding relevant to current dystrophin-restoring therapies.

The reading frame rule suggests that

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 results from

    DMD mutations causing an out-of-frame transcript
    GENETICS

, whereas the

    milder Becker muscular dystrophy
    DIAGNOSIS

 results from

    mutations causing an in-frame transcript
    GENETICS

. However,

    predicted nonsense mutations
    GENETICS

 may instead result in

    altered splicing and an in-frame transcript
    GENETICS

. Here we report a

    10-year-old
    AGE

    boy
    GENDER

 with a

    predicted nonsense mutation in exon 42
    GENETICS

 who had a

    6-minute walk time of 157% of that of age matched DMD controls
    SYMPTOMS

, characterized as

    intermediate muscular dystrophy
    DIAGNOSIS

.

    RNA sequencing analysis from a muscle biopsy
    PARACLINICAL

 revealed

    only 6.0-9.8% of DMD transcripts were in-frame, excluding exon 42
    GENETICS

, and

    immunoblot
    PARACLINICAL

 demonstrated

    only 3.2% dystrophin protein expression
    BIOCHEMICAL

. Another potential genetic modifier noted was

    homozygosity for the protective IAAM LTBP4 haplotype
    GENETICS

. This case suggests that

    very low levels of DMD exon skipping and dystrophin protein expression
    BIOCHEMICAL

 may result in

    amelioration of skeletal muscle weakness
    SYMPTOMS

, a finding relevant to current

    dystrophin-restoring therapies
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
milder Becker muscular dystrophy
intermediate muscular dystrophy


Novel noncontiguous duplications identified with a comprehensive mutation analysis in the DMD gene by DMD gene-targeted sequencing.

Genomic rearrangements, such as intragenic deletions and duplications, are the most prevalent types of mutation in the DMD gene, and DMD mutations underlie Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Using multiplex ligation dependent probe amplification (MLPA) and DMD gene-targeted sequencing, we performed a molecular characterization of two cases of complex noncontiguous duplication rearrangements that involved inverted duplications. The breakpoint sequences were analyzed to investigate the mechanisms of the rearrangement. The two cases shared the same duplication events (Dup-nml-Dup/inv), and both involved microhomology and small insertions at the breakpoints. Additionally, in case 1, SNP sequencing results indicated that the de novo duplication mutation arose in the allele that originated from the grandfather. This study has identified a novel type of DMD complex rearrangement and provides insight into the molecular basis of this genomic rearrangement.

    Genomic rearrangements
    GENETICS

, such as

    intragenic deletions and duplications
    GENETICS

, are the most prevalent types of

    mutation in the DMD gene
    GENETICS

, and

    DMD mutations
    GENETICS

 underlie

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

. Using

    multiplex ligation dependent probe amplification (MLPA) and DMD gene-targeted sequencing
    PARACLINICAL

, we performed a

    molecular characterization
    PARACLINICAL

 of two cases of

    complex noncontiguous duplication rearrangements
    GENETICS

 that involved

    inverted duplications
    GENETICS

.

    The breakpoint sequences were analyzed
    PARACLINICAL

 to investigate the mechanisms of the rearrangement. The two cases

    shared the same duplication events (Dup-nml-Dup/inv)
    GENETICS

, and both involved

    microhomology and small insertions at the breakpoints
    GENETICS

. Additionally, in case 1,

    SNP sequencing results
    PARACLINICAL

 indicated that

    the de novo duplication mutation arose in the allele that originated from the grandfather
    FAMILY

. This study has identified a novel type of

    DMD complex rearrangement
    DIAGNOSIS

 and provides insight into the molecular basis of this

    genomic rearrangement
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
DMD complex rearrangement
genomic rearrangement


Next Generation Sequencing approach to molecular diagnosis of Duchenne muscular dystrophy; identification of a novel mutation.

Duchenne Muscular Dystrophy (DMD; MIM 310200) is one of the most common and severe type of hereditary muscular dystrophies. The disease is caused by mutations in the dystrophin gene. The dystrophin gene is associated with X-linked recessive Duchenne and Becker muscular dystrophy. This disease occurs almost exclusively in males. The clinical symptoms of muscle weakness usually begin at childhood. The main symptoms of this disorder are gradually muscular weakness. The affected patients have inability to standing up and walking. Death is usually due to respiratory infection or cardiomyopathy. In this article, we have reported the discovery of a new nonsense mutation that creates abnormal stop codon in the dystrophin gene. This mutation was detected using Next Generation Sequencing (NGS) technique. The subject was a 17-year-old male with muscular dystrophy that who was suspected of having DMD. He was referred to Hakim medical genetics center of Neyshabur, IRAN.

    Duchenne Muscular Dystrophy (DMD
    DIAGNOSIS

;

    MIM 310200)
    DIAGNOSIS

 is one of the most common and severe type of

    hereditary muscular dystrophies
    DIAGNOSIS

. The disease is caused by

    mutations in the dystrophin gene
    GENETICS

. The

    dystrophin gene
    GENETICS

 is associated with

    X-linked recessive
    GENETICS

    Duchenne
    DIAGNOSIS

 and

    Becker muscular dystrophy
    DIAGNOSIS

. This disease occurs almost exclusively in

    males
    GENDER

. The clinical symptoms of

    muscle weakness
    SYMPTOMS

 usually begin at

    childhood
    AGE

. The main symptoms of this disorder are

    gradually muscular weakness
    SYMPTOMS

. The affected patients have

    inability to standing up and walking
    SYMPTOMS

.

    Death
    SYMPTOMS

 is usually due to

    respiratory infection
    SYMPTOMS

 or

    cardiomyopathy
    SYMPTOMS

. In this article, we have reported the discovery of a

    new nonsense mutation that creates abnormal stop codon in the dystrophin gene
    GENETICS

. This mutation was detected using

    Next Generation Sequencing (NGS) technique
    PARACLINICAL

. The subject was a

    17-year-old
    AGE

    male
    GENDER

 with

    muscular dystrophy
    DIAGNOSIS

 that who was suspected of having

    DMD
    DIAGNOSIS

.

    He
    GENDER

 was referred to Hakim medical genetics center of Neyshabur, IRAN.

Duchenne Muscular Dystrophy (DMD
MIM 310200)
hereditary muscular dystrophies
Duchenne
Becker muscular dystrophy
muscular dystrophy
DMD

muscle weakness
gradually muscular weakness
inability to standing up and walking
Death
respiratory infection
cardiomyopathy


Virtual 3D planning of tracheostomy placement and clinical applicability of 3D cannula design: a three-step study.

We aimed to investigate the potential of 3D virtual planning of tracheostomy tube placement and 3D cannula design to prevent tracheostomy complications due to inadequate cannula position.

3D models of commercially available cannula were positioned in 3D models of the airway. In study (1), a cohort that underwent tracheostomy between 2013 and 2015 was selected (n = 26). The cannula was virtually placed in the airway in the pre-operative CT scan and its position was compared to the cannula position on post-operative CT scans. In study (2), a cohort with neuromuscular disease (n = 14) was analyzed. Virtual cannula placing was performed in CT scans and tested if problems could be anticipated. Finally (3), for a patient with Duchenne muscular dystrophy and complications of conventional tracheostomy cannula, a patient-specific cannula was 3D designed, fabricated, and placed.

(1) The 3D planned and post-operative tracheostomy position differed significantly. (2) Three groups of patients were identified: (A) normal anatomy; (B) abnormal anatomy, commercially available cannula fits; and (C) abnormal anatomy, custom-made cannula, may be necessary. (3) The position of the custom-designed cannula was optimal and the trachea healed.

Virtual planning of the tracheostomy did not correlate with actual cannula position. Identifying patients with abnormal airway anatomy in whom commercially available cannula cannot be optimally positioned is advantageous. Patient-specific cannula design based on 3D virtualization of the airway was beneficial in a patient with abnormal airway anatomy.

We aimed to investigate the potential of

    3D virtual planning of tracheostomy tube placement
    PARACLINICAL

 and

    3D cannula design
    MEDICATION

 to prevent

    tracheostomy complications
    SYMPTOMS

 due to

    inadequate cannula position
    NEG_FINDINGS

.

    3D models of commercially available cannula
    MEDICATION

 were positioned in 3D

    models of the airway
    PARACLINICAL

. In study (1), a cohort that underwent

    tracheostomy
    MEDICATION

 between 2013 and 2015 was selected (n = 26). The cannula was

    virtually placed in the airway in the pre-operative CT scan
    PARACLINICAL

 and its position was compared to the cannula position on

    post-operative CT scans
    PARACLINICAL

. In study (2), a cohort with

    neuromuscular disease
    DIAGNOSIS

 (n = 14) was analyzed.

    Virtual cannula placing was performed in CT scans
    PARACLINICAL

 and tested if problems could be anticipated. Finally (3), for a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 and

    complications of conventional tracheostomy cannula
    NEG_FINDINGS

, a

    patient-specific cannula was 3D designed, fabricated, and placed
    MEDICATION

.

(1) The 3D planned and post

    -operative tracheostomy
    MEDICATION

 position differed significantly. (2) Three groups of patients were identified: (A) normal anatomy; (B) abnormal anatomy,

    commercially available cannula fits
    MEDICATION

; and (C) abnormal anatomy,

    custom-made cannula
    MEDICATION

, may be necessary. (3) The position

    of the custom-designed cannula
    MEDICATION

 was optimal and the

    trachea healed
    SYMPTOMS

.

    Virtual planning of the tracheostomy
    PARACLINICAL

 did not correlate with actual cannula position. Identifying patients with

    abnormal airway anatomy
    SYMPTOMS

 in whom

    commercially available cannula cannot be optimally positioned
    NEG_FINDINGS

 is advantageous.

    Patient-specific cannula design
    MEDICATION

 based on

    3D virtualization of the airway
    PARACLINICAL

 was beneficial in a patient with

    abnormal airway anatomy
    SYMPTOMS

.

tracheostomy complications
trachea healed
abnormal airway anatomy
abnormal airway anatomy

neuromuscular disease
Duchenne muscular dystrophy


Duchenne muscular dystrophy with platypnea-orthodeoxia from Chilaiditi syndrome.

Chilaiditi syndrome is a rare pathophysiology in which the colon or other organs are interposed between the diaphragm and liver, and respiratory or digestive symptoms sometimes manifest. Although there have been some cases of Chilaiditi syndrome complicating neuromuscular disorders, none have described resulting respiratory or digestive symptoms.

Our patient was a 20-year-old man with DMD who had been receiving noninvasive positive-pressure ventilation during the night. He experienced respiratory distress when changing from a supine to sitting position. Ventilator adjustment did not relieve the respiratory distress. Abdominal computed tomography revealed marked constipation and interposition of the transverse colon between the diaphragm and liver, indicating Chilaiditi syndrome. The right side of the diaphragm was elevated by the interposed transverse colon when the respiratory distress was present on chest radiograph, but not when symptoms were absent. The patient was diagnosed with platypnea-orthodeoxia attributed to Chilaiditi syndrome. The respiratory distress was improved by the relief of constipation, in addition to the usage of the ventilator throughout the day.

The rare symptoms and pathophysiology of DMD complicated by Chilaiditi syndrome are reported and discussed herein.

    Chilaiditi syndrome
    DIAGNOSIS

 is a rare pathophysiology in which

    the colon or other organs are interposed between the diaphragm and liver
    SYMPTOMS

, and

    respiratory or digestive symptoms
    SYMPTOMS

 sometimes manifest. Although there have been some cases of

    Chilaiditi syndrome
    DIAGNOSIS

 complicating

    neuromuscular disorders
    DIAGNOSIS

, none have described

    resulting respiratory or digestive symptoms
    SYMPTOMS

.

Our patient was a

    20-year-old
    AGE

    man
    GENDER

 with

    DMD
    DIAGNOSIS

 who had been receiving

    noninvasive positive-pressure ventilation during the night
    MEDICATION

.

    He
    GENDER

 experienced

    respiratory distress
    SYMPTOMS

 when changing from a

    supine to sitting position
    MEDICATION

.

    Ventilator adjustment did not relieve the respiratory distress
    NEG_FINDINGS

.

    Abdominal computed tomography
    PARACLINICAL

 revealed

    marked constipation
    SYMPTOMS

 and

    interposition of the transverse colon between the diaphragm and liver
    SYMPTOMS

, indicating

    Chilaiditi syndrome
    DIAGNOSIS

.

    The right side of the diaphragm was elevated by the interposed transverse colon
    SYMPTOMS

 when the

    respiratory distress
    SYMPTOMS

 was present on

    chest radiograph
    PARACLINICAL

, but

    not when symptoms were absent
    NEG_FINDINGS

. The patient was diagnosed with

    platypnea-orthodeoxia
    SYMPTOMS

 attributed to

    Chilaiditi syndrome
    DIAGNOSIS

. The

    respiratory distress
    SYMPTOMS

 was improved by the

    relief of constipation
    MEDICATION

, in addition to the

    usage of the ventilator throughout the day
    MEDICATION

.

The rare symptoms and pathophysiology of

    DMD
    DIAGNOSIS

    complicated by Chilaiditi syndrome
    DIAGNOSIS

 are reported and discussed herein.

Chilaiditi syndrome
Chilaiditi syndrome
neuromuscular disorders
DMD
Chilaiditi syndrome
Chilaiditi syndrome
DMD
complicated by Chilaiditi syndrome


Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD.

A

    broad mutational spectrum in the dystrophin (DMD) gene
    GENETICS

, from

    large deletions/duplications to point mutations
    GENETICS

, causes

    Duchenne/Becker muscular dystrophy (D/BMD)
    DIAGNOSIS

.

    Comprehensive genotyping
    PARACLINICAL

 is particularly relevant considering the mutation-centered therapies for

    dystrophinopathies
    DIAGNOSIS

. We report the genetic characterization of a patient with disease onset at

    age 13 years
    AGE

,

    elevated creatine kinase levels
    BIOCHEMICAL

 and

    reduced dystrophin labeling
    BIOCHEMICAL

, where

    multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants
    PARACLINICAL

.

    Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing)
    PARACLINICAL

 were used to characterize the mutation. An

    aberrant transcript
    GENETICS

 was identified,

    containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene
    GENETICS

. This corresponded to the

    partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame
    GENETICS

. Further characterization identified a

    complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51
    GENETICS

.

    Haplotyping and segregation analysis
    PARACLINICAL

 demonstrated that the

    mutation had a de novo origin
    GENETICS

. Besides underscoring the importance of

    mRNA studies
    PARACLINICAL

 in genetically unsolved cases, this is the first report of a

    disease-causing fully intronic LINE-1 element
    GENETICS

 in

    DMD
    DIAGNOSIS

, adding to the diversity of mutational events that give rise to

    D/BMD
    DIAGNOSIS

.

elevated creatine kinase levels
reduced dystrophin labeling


Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy.

Duchenne muscular dystrophy is the most common muscle disease found in male children. Currently, there is no effective therapy available for Duchenne muscular dystrophy patients. Therefore, it is essential to make a prenatal diagnosis and provide genetic counseling to reduce the birth of such boys. We report a case of preimplantation genetic diagnosis associated with Duchenne muscular dystrophy. The couple E.P.R., 38-year-old, symptomatic patient heterozygous for a 2 to 47 exon deletion mutation in DMD gene and G.T.S., 39-year-old, sought genetic counseling about preimplantation genetic diagnosis process. They have had a 6-year-old son who died due to Duchenne muscular dystrophy complications. The couple underwent four cycles of intracytoplasmic sperm injection (ICSI) and eight embryos biopsies were analyzed by polymerase chain reaction (PCR) for specific mutation analysis, followed by microarray-based comparative genomic hybridisation (array CGH) for aneuploidy analysis. Preimplantation genetic diagnosis revealed that two embryos had inherited the maternal DMD gene mutation, one embryo had a chromosomal alteration and five embryos were normal. One blastocyst was transferred and resulted in successful pregnancy. The other embryos remain vitrified. We concluded that embryo analysis using associated techniques of PCR and array CGH seems to be safe for embryo selection in cases of X-linked disorders, such as Duchenne muscular dystrophy.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is the most common

    muscle disease
    DIAGNOSIS

 found in

    male
    GENDER

    children
    AGE

. Currently, there is no effective therapy available for

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients. Therefore, it is essential to make a

    prenatal diagnosis
    PARACLINICAL

 and provide

    genetic counseling
    MEDICATION

 to reduce the birth of such

    boys
    GENDER

. We report a case of

    preimplantation genetic diagnosis
    MEDICATION

 associated with

    Duchenne muscular dystrophy
    DIAGNOSIS

. The

    couple
    GENDER

 E.P.R.,

    38-year-old
    AGE

, symptomatic patient

    heterozygous for a 2 to 47 exon deletion mutation in DMD gene
    GENETICS

 and G.T.S.,

    39-year-old
    AGE

, sought

    genetic counseling
    MEDICATION

 about

    preimplantation genetic diagnosis process
    MEDICATION

.

    They
    GENDER

    have had a 6-year-old
    FAMILY

    son who died
    FAMILY

 due to

    Duchenne muscular dystrophy complications
    SYMPTOMS

. The

    couple
    GENDER

 underwent

    four cycles of intracytoplasmic sperm injection (ICSI)
    MEDICATION

 and

    eight embryos biopsies
    PARACLINICAL

 were

    analyzed by polymerase chain reaction (PCR) for specific mutation analysis
    PARACLINICAL

, followed by

    microarray-based comparative genomic hybridisation (array CGH) for aneuploidy analysis
    PARACLINICAL

.

    Preimplantation genetic diagnosis
    PARACLINICAL

 revealed that

    two embryos had inherited the maternal DMD gene mutation
    GENETICS

, one

    embryo had a chromosomal alteration
    FAMILY

 and five

    embryos were normal
    NEG_FINDINGS

.

    One blastocyst was transferred and resulted in successful pregnancy
    MEDICATION

.

    The other embryos remain vitrified
    MEDICATION

. We concluded that

    embryo analysis
    PARACLINICAL

 using associated techniques

    of PCR and array CGH
    PARACLINICAL

 seems to be safe for

    embryo selection
    MEDICATION

 in cases of

    X-linked disorders
    GENETICS

, such as

    Duchenne muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy
muscle disease
Duchenne muscular dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy


Surface EMG signals in very late-stage of Duchenne muscular dystrophy: a case study.

Robotic arm supports aim at improving the quality of life for adults with Duchenne muscular dystrophy (DMD) by augmenting their residual functional abilities. A critical component of robotic arm supports is the control interface, as is it responsible for the human-machine interaction. Our previous studies showed the feasibility of using surface electromyography (sEMG) as a control interface to operate robotic arm supports in adults with DMD (22-24 years-old). However, in the biomedical engineering community there is an often raised skepticism on whether adults with DMD at the last stage of their disease have sEMG signals that can be measured and used for control.

In this study sEMG signals from Biceps and Triceps Brachii muscles were measured for the first time in a 37 year-old man with DMD (Brooke 6) that lost his arm function 15 years ago. The sEMG signals were measured during maximal and sub-maximal voluntary isometric contractions and evaluated in terms of signal-to-noise ratio and co-activation ratio. Beyond the profound deterioration of the muscles, we found that sEMG signals from both Biceps and Triceps muscles were measurable in this individual, although with a maximum signal amplitude 100 times lower compared to sEMG from healthy subjects. The participant was able to voluntarily modulate the required level of muscle activation during the sub-maximal voluntary isometric contractions. Despite the low sEMG amplitude and a considerable level of muscle co-activation, simulations of an elbow orthosis using the measured sEMG as driving signal indicated that the sEMG signals of the participant had the potential to provide control of elbow movements.

To the best of our knowledge this is the first time that sEMG signals from a man with DMD at the last-stage of the disease were measured, analyzed and reported. These findings offer promising perspectives to the use of sEMG as an intuitive and natural control interface for robotic arm supports in adults with DMD until the last stage of the disease.

    Robotic arm supports
    MEDICATION

 aim at improving the quality of life for

    adults
    AGE

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 by augmenting their

    residual functional abilities
    SYMPTOMS

. A critical component of

    robotic arm supports
    MEDICATION

 is the control interface, as is it responsible for the

    human-machine interaction
    MEDICATION

. Our previous studies showed the feasibility of using

    surface electromyography (sEMG) as a control interface
    PARACLINICAL

 to operate

    robotic arm supports
    MEDICATION

 in

    adults
    AGE

 with

    DMD
    DIAGNOSIS

    (22-24 years-old
    AGE

). However, in the biomedical engineering community there is an often raised skepticism on whether

    adults
    AGE

 with

    DMD
    DIAGNOSIS

 at the last stage of their disease have sEMG signals that can be measured and used for control.

In this study

    sEMG signals from Biceps and Triceps Brachii muscles
    PARACLINICAL

 were measured for the first time in a

    37 year-old
    AGE

    man
    GENDER

 with

    DMD (Brooke 6)
    DIAGNOSIS

 that

    lost his arm function
    SYMPTOMS

 15 years ago. The

    sEMG signals were measured during maximal and sub-maximal voluntary isometric contractions
    PARACLINICAL

 and evaluated in terms of signal-to-noise ratio and co-activation ratio. Beyond the

    profound deterioration of the muscles
    SYMPTOMS

, we found that

    sEMG signals from both Biceps and Triceps muscles
    SYMPTOMS

 were measurable in this individual, although with a

    maximum signal amplitude 100 times lower compared to sEMG
    SYMPTOMS

 from healthy subjects. The participant was able to

    voluntarily modulate the required level of muscle activation during the sub-maximal voluntary isometric contractions
    SYMPTOMS

. Despite the

    low sEMG amplitude and a considerable level of muscle co-activation
    NEG_FINDINGS

,

    simulations of an elbow orthosis
    MEDICATION

 using the

    measured sEMG
    PARACLINICAL

 as driving signal indicated that the sEMG signals of the participant had the potential to provide

    control of elbow movements
    MEDICATION

.

To the best of our knowledge this is the first time that

    sEMG signals
    PARACLINICAL

 from a

    man
    GENDER

 with

    DMD
    DIAGNOSIS

 at the last-stage of the disease were measured, analyzed and reported. These findings offer promising perspectives to the use of

    sEMG
    MEDICATION

 as an intuitive and natural control interface for

    robotic arm supports
    MEDICATION

 in

    adults
    AGE

 with

    DMD
    DIAGNOSIS

 until the last stage of the disease.

Robotic arm supports
robotic arm supports
human-machine interaction
robotic arm supports
simulations of an elbow orthosis
control of elbow movements
sEMG
robotic arm supports

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD (Brooke 6)
DMD
DMD


DMD and West syndrome.

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients.

    Duchenne Muscular Dystrophy (DMD)
    DIAGNOSIS

 is the most frequent

    muscular dystrophy
    DIAGNOSIS

 in

    childhood
    AGE

, with a worldwide incidence of one in 5000 live

    male
    GENDER

 births. It is due to

    mutations in the dystrophin gene
    GENETICS

 leading to

    absence of full-length dystrophin protein
    BIOCHEMICAL

.

    Central nervous system involvement
    SYMPTOMS

 is well-known in

    Duchenne Muscular Dystrophy
    DIAGNOSIS

. The

    multiple dystrophin isoforms expressed in brain
    GENETICS

 have important roles in cerebral development and functioning. The association of

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 with

    seizures
    SYMPTOMS

 has been reported, and there is a higher prevalence of

    epilepsy
    DIAGNOSIS

 in

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%).

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 patients may present with

    focal seizures
    SYMPTOMS

,

    generalized tonic-clonic seizures
    SYMPTOMS

 or

    absences
    SYMPTOMS

. We report on two

    boys
    GENDER

 in whom

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 is associated with

    epileptic spasms
    SYMPTOMS

 and

    hypsarrhythmia
    SYMPTOMS

 that fulfil the criteria for

    West syndrome
    DIAGNOSIS

, thus extending the spectrum of

    seizure types
    SYMPTOMS

 described in

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 patients.

Duchenne Muscular Dystrophy (DMD)
muscular dystrophy
Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy
epilepsy
Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy
West syndrome
Duchenne Muscular Dystrophy

Central nervous system involvement
seizures
focal seizures
generalized tonic-clonic seizures
absences
epileptic spasms
hypsarrhythmia
seizure types


[Recurrent anorexia and pigmentation of skin for more than two months in an infant].

A 2-month-old boy presented with adrenal insufficiency, impaired liver function, hypertriglyceridemia, significantly elevated creatine kinase and electrolyte disturbance. Microarray comparative genomic hybridization (aCGH) analysis test showed a pathogenic 8.7 Mb deletion in the short arm of chromosome X (Xp21.3 - p21.1) and confirmed the diagnosis of complex glycerol kinase deficiency (cGKD). He was treated with hydrocortisone, coenzyme Q10 and L-carnitine and was subsequently followed up for 4 years. His serum cortisol levels returned to normal one week later after treatment, but the serum creatine kinase, triglyceride and aminotransferase levels were progressively increased along with mental retardation and decreased muscular strength. cGKD is also named as Xp21 contiguous gene syndrome. The clinical manifestations of this disease include hypertriglyceridemia, congenital adrenal hypoplasia (AHC), Duchenne muscular dystrophy, and mental retardation. This case highlights the necessity to screen the serum triglyceride and creatine kinase levels in infants with suspected adrenal insufficiency.

A

    2-month-old
    AGE

    boy
    GENDER

 presented with

    adrenal insufficiency
    SYMPTOMS

,

    impaired liver function
    SYMPTOMS

,

    hypertriglyceridemia
    BIOCHEMICAL

,

    significantly elevated creatine kinase
    BIOCHEMICAL

 and

    electrolyte disturbance
    BIOCHEMICAL

.

    Microarray comparative genomic hybridization (aCGH) analysis test
    PARACLINICAL

 showed a

    pathogenic 8.7 Mb deletion in the short arm of chromosome X (Xp21.3 - p21.1)
    GENETICS

 and confirmed the diagnosis of

    complex glycerol kinase deficiency (cGKD)
    DIAGNOSIS

.

    He
    GENDER

 was treated with

    hydrocortisone, coenzyme Q10 and L-carnitine
    MEDICATION

 and was subsequently followed up for 4 years. His

    serum cortisol levels returned to normal
    BIOCHEMICAL

 one week later after treatment, but the

    serum creatine kinase, triglyceride and aminotransferase levels were progressively increased
    BIOCHEMICAL

 along with

    mental retardation
    SYMPTOMS

 and

    decreased muscular strength
    SYMPTOMS

.

    cGKD
    DIAGNOSIS

 is also named as

    Xp21 contiguous gene syndrome
    DIAGNOSIS

. The clinical manifestations of this disease include

    hypertriglyceridemia
    BIOCHEMICAL

,

    congenital adrenal hypoplasia (AHC)
    DIAGNOSIS

,

    Duchenne muscular dystrophy
    DIAGNOSIS

, and

    mental retardation
    SYMPTOMS

. This case highlights the necessity to

    screen the serum triglyceride and creatine kinase levels
    PARACLINICAL

 in

    infants
    AGE

 with suspected

    adrenal insufficiency
    SYMPTOMS

.

adrenal insufficiency
impaired liver function
mental retardation
decreased muscular strength
mental retardation
adrenal insufficiency


Implantation of a left ventricular assist device to provide long-term support for end-stage Duchenne muscular dystrophy-associated cardiomyopathy.

A young man with Duchenne muscular dystrophy presented to the UT Southwestern Neuromuscular Cardiomyopathy Clinic with advanced heart failure. Despite maximal medical therapy, his cardiac function continued to decline requiring initiation of inotrope therapy. Given the patient's clinical deterioration, a left ventricular assist device (LVAD) was implanted as destination therapy after undergoing a multidisciplinary assessment. The patient tolerated the surgical implantation of the LVAD without any significant complications, and he has had a relatively unremarkable course 38 months post-LVAD implantation. A critical factor contributing to the long-term success of this patient was the decision to select an LVAD that would not disrupt the diaphragm and thus preserve the respiratory muscle strength. This case demonstrates that permanent mechanical LVADs should be considered for appropriately selected Duchenne muscular dystrophy patients with medically refractory end-stage cardiomyopathy.

A

    young
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 presented to the UT Southwestern

    Neuromuscular Cardiomyopathy
    DIAGNOSIS

 Clinic with

    advanced heart failure
    SYMPTOMS

.

    Despite maximal medical therapy
    NEG_FINDINGS

, his

    cardiac function continued to decline
    SYMPTOMS

 requiring

    initiation of inotrope therapy
    MEDICATION

. Given the patient's

    clinical deterioration
    SYMPTOMS

, a

    left ventricular assist device (LVAD) was implanted as destination therapy
    MEDICATION

 after undergoing a multidisciplinary assessment. The patient

    tolerated the surgical implantation of the LVAD
    MEDICATION

    without any significant complications
    NEG_FINDINGS

, and

    he
    GENDER

 has had a

    relatively unremarkable course
    SYMPTOMS

 38 months post

    -LVAD implantation
    MEDICATION

. A critical factor contributing to the long-term success of this patient was the decision to select an

    LVAD
    MEDICATION

 that would

    not disrupt the diaphragm and thus preserve the respiratory muscle strength
    NEG_FINDINGS

. This case demonstrates that

    permanent mechanical LVADs
    MEDICATION

 should be considered for appropriately selected

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients with

    medically refractory end-stage cardiomyopathy
    DIAGNOSIS

.

advanced heart failure
cardiac function continued to decline
clinical deterioration
relatively unremarkable course


Cholestasis and Hepatic Iron Deposition in an Infant With Complex Glycerol Kinase Deficiency.

We present a 6-week-old male infant with persistent hyperbilirubinemia, hypertriglyceridemia, elevated creatine kinase levels, and transaminitis since the second week of life. When he developed hyperkalemia, clinical suspicion was raised for adrenal insufficiency despite hemodynamic stability. A full endocrine workup revealed nearly absent adrenocorticotropic hormone. Coupled with his persistent hypertriglyceridemia (peak of 811 mg/dL) and elevated creatine kinase levels (>20 000 U/L), his corticotropin level lead to a clinical diagnosis of complex glycerol kinase deficiency (GKD), also known as Xp21 deletion syndrome. This complex disorder encompasses the phenotype of Duchenne muscular dystrophy, GKD, and congenital adrenal hypoplasia due to the deletion of 3 contiguous genetic loci on the X chromosome. Our case exemplifies the presentation of this disorder and highlights the important lesson of distinguishing between adrenal hypoplasia congenita and congenital adrenal hyperplasia, as well as the sometimes subtle presentation of adrenal insufficiency. To our knowledge, it is also the first reported case of complex GKD deficiency with the additional finding of hepatic iron deposition, which may indicate a potential area for exploration regarding the pathogenesis of liver injury and cholestasis seen in cortisol-related endocrinopathies.

We present a

    6-week-old
    AGE

    male
    GENDER

    infant
    AGE

 with

    persistent hyperbilirubinemia
    BIOCHEMICAL

,

    hypertriglyceridemia
    BIOCHEMICAL

,

    elevated creatine kinase levels
    BIOCHEMICAL

, and

    transaminitis
    BIOCHEMICAL

    since the second week of life
    AGE

. When

    he
    GENDER

 developed

    hyperkalemia
    BIOCHEMICAL

, clinical suspicion was raised for

    adrenal insufficiency
    SYMPTOMS

    despite hemodynamic stability
    NEG_FINDINGS

. A

    full endocrine workup
    PARACLINICAL

 revealed

    nearly absent adrenocorticotropic hormone
    BIOCHEMICAL

. Coupled with his

    persistent hypertriglyceridemia (peak of 811 mg/dL)
    BIOCHEMICAL

 and

    elevated creatine kinase levels (>20 000 U/L)
    BIOCHEMICAL

, his

    corticotropin level
    BIOCHEMICAL

 lead to a clinical diagnosis of

    complex glycerol kinase deficiency (GKD)
    DIAGNOSIS

, also known as

    Xp21 deletion syndrome
    GENETICS

. This

    complex disorder
    DIAGNOSIS

 encompasses the phenotype of

    Duchenne muscular dystrophy
    DIAGNOSIS

,

    GKD
    DIAGNOSIS

, and

    congenital adrenal hypoplasia
    SYMPTOMS

 due to the

    deletion of 3 contiguous genetic loci on the X chromosome
    GENETICS

. Our case exemplifies the presentation of this disorder and highlights the important lesson of distinguishing between

    adrenal hypoplasia congenita
    DIAGNOSIS

 and

    congenital adrenal hyperplasia
    DIAGNOSIS

, as well as the sometimes subtle presentation of

    adrenal insufficiency
    SYMPTOMS

. To our knowledge, it is also the first reported case of

    complex GKD deficiency
    BIOCHEMICAL

 with the additional finding of

    hepatic iron deposition
    MICROSCOPIC

, which may indicate a potential area for exploration regarding the pathogenesis of

    liver injury
    SYMPTOMS

 and

    cholestasis
    SYMPTOMS

 seen in

    cortisol-related endocrinopathies
    DIAGNOSIS

.

adrenal insufficiency
congenital adrenal hypoplasia
adrenal insufficiency
liver injury
cholestasis


Sudden cardiac death of Duchenne muscular dystrophy with NT-proBNP in pericardial fluid as a useful biomarker for diagnosis of the cause of death: a case report.

Duchenne muscular dystrophy (DMD) is one of the most common and severest muscular dystrophies. Although it can be a cause of death when associated with cardiac muscle and/or respiratory muscles, no cases of sudden deaths in the setting of undiagnosed DMD with cardiac involvement have been reported in the literatures. Previous studies showed that N-terminal-proBNP (NT-proBNP) was a robust laboratory biomarker to diagnose and monitor cardiac failure in clinical situations, suggesting that it may be used as an auxiliary indicator for diagnosis on left ventricular dysfunction in sudden cardiac deaths in forensic settings. Here, we reported a case of 29-year-old man who died suddenly. Autopsy revealed that muscles of the body were almost replaced by fatty and fibrotic tissues. The heart was enlarged with disarray and degeneration of cardiomyocytes in cardiac muscle. Total absence of dystrophin was detected by immunohistochemical staining, which confirmed DMD. Postmortem biochemical test of pericardial fluid revealed a high level of NT-proBNP, indicating dysfunction of the left ventricle before death. The cause of death was certified as an early dilated cardiomyopathy (DCM)/dysfunction of the left ventricle secondary to DMD, suggesting that sudden cardiac death with cardiac dysfunction could be identified by immunohistochemical method in combination with pericardial fluid NT-proBNP determination after systemic autopsy.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is one of the most common and severest

    muscular dystrophies
    DIAGNOSIS

. Although it can be a cause of

    death
    SYMPTOMS

 when associated with

    cardiac muscle and/or respiratory muscles
    SYMPTOMS

, no cases of

    sudden deaths
    SYMPTOMS

 in the setting of undiagnosed

    DMD
    DIAGNOSIS

 with

    cardiac involvement
    SYMPTOMS

 have been reported in the literatures. Previous studies showed that

    N-terminal-proBNP (NT-proBNP)
    BIOCHEMICAL

 was a robust laboratory biomarker to diagnose and monitor

    cardiac failure
    SYMPTOMS

 in clinical situations, suggesting that it may be used as an auxiliary indicator for diagnosis on

    left ventricular dysfunction
    SYMPTOMS

 in

    sudden cardiac deaths
    SYMPTOMS

 in forensic settings. Here, we reported a case of

    29-year-old
    AGE

    man
    GENDER

 who

    died
    SYMPTOMS

    suddenly
    SYMPTOMS

.

    Autopsy
    PARACLINICAL

 revealed that

    muscles of the body were almost replaced by fatty and fibrotic tissues
    SYMPTOMS

. The

    heart was enlarged
    SYMPTOMS

 with

    disarray and degeneration of cardiomyocytes in cardiac muscle
    MICROSCOPIC

.

    Total absence of dystrophin
    BIOCHEMICAL

 was detected by

    immunohistochemical staining
    PARACLINICAL

, which confirmed

    DMD
    DIAGNOSIS

.

    Postmortem biochemical test of pericardial fluid
    PARACLINICAL

 revealed a

    high level of NT-proBNP
    BIOCHEMICAL

, indicating

    dysfunction of the left ventricle
    SYMPTOMS

 before

    death
    SYMPTOMS

. The cause of

    death
    SYMPTOMS

 was certified as an

    early dilated cardiomyopathy (DCM)/dysfunction of the left ventricle
    DIAGNOSIS

 secondary to

    DMD
    DIAGNOSIS

, suggesting that

    sudden cardiac death
    SYMPTOMS

 with

    cardiac dysfunction
    SYMPTOMS

 could be identified by

    immunohistochemical method
    PARACLINICAL

 in combination with

    pericardial fluid NT-proBNP determination
    PARACLINICAL

 after

    systemic autopsy
    PARACLINICAL

.

N-terminal-proBNP (NT-proBNP)
Total absence of dystrophin
high level of NT-proBNP


Electrical storm in a patient with Duchenne muscular dystrophy cardiomyopathy triggered by abrupt β-blocker interruption.

We present a case of a young man with Duchenne muscular dystrophy cardiomyopathy (DMDC) having an implantable cardioverter defibrillator for secondary prevention, who presented with electrical storm shortly after β-blocker interruption. The patient was stabilized and remained free of ventricular arrhythmias soon after reinitiating b-adrenoreceptor antagonists. The present case highlights the importance of sympathetic blockage in patients with DMDC due to existing pathophysiology of excess diastolic Ca2+ leak from sarcoplasmic reticulum as a result of ryanodine receptor dysfunction.

We present a case of a

    young
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy cardiomyopathy (DMDC)
    DIAGNOSIS

 having an

    implantable cardioverter defibrillator for secondary prevention
    MEDICATION

, who presented with

    electrical storm
    SYMPTOMS

 shortly after

    β-blocker interruption
    MEDICATION

. The patient was stabilized and remained

    free of ventricular arrhythmias
    NEG_FINDINGS

 soon after

    reinitiating b-adrenoreceptor antagonists
    MEDICATION

. The present case highlights the importance of

    sympathetic blockage
    MEDICATION

 in patients with

    DMDC
    DIAGNOSIS

 due to existing pathophysiology of

    excess diastolic Ca2+ leak from sarcoplasmic reticulum
    SYMPTOMS

 as a result of

    ryanodine receptor dysfunction
    SYMPTOMS

.