Is heart transplantation a real option in patients with Duchenne syndrome? Inferences from a case report.

Duchenne muscular dystrophy (DMD) is the most frequent and severe form of MD. It firstly affects the skeletal muscles, causing severe disability, and subsequently the myocardium. The only two options to treat end-stage heart failure in these patients are either a left ventricular assist device (LVAD) implantation as destination therapy or a heart transplant. These hypotheses are still controversial, and data are very limited. We describe the case of an 18-year-old male patient, affected by DMD and in a wheelchair from the age of 11. He progressively developed dilated cardiomyopathy, and in 2016, at the age of 14 years, he underwent HeartWare LVAD implantation, as destination therapy, without post-operative complications. He has been followed up for 47 consecutive months; and 30 months after LVAD implantation, he developed an infection of the exit site, treated by antibiotics and surgical toilette. Following this event, on the basis of patient's good general conditions and willingness, we started to consider heart transplant as an option. Before the patient was listed, he underwent accurate workup, and we found higher values of forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow, compared with the predicted values of same-age DMD patients. The patient have neither scoliosis nor need for non-invasive mechanical ventilation, and finally, he was always treated with steroids with stable thoraco-abdominal function over the years. According to these considerations, the patient was listed for heart transplant. In 12 February 2020, at the age of 18 years, the patient underwent heart transplant with no post-operative complications. Cardiac transplantation is not considered a valid option for DMD patients, because of the shortage of donor availability and the systemic nature of DMD disease. Considering that this patient had already experienced an LVAD-related complication and he had better general condition than his DMD peers, we listed him for a heart transplant. We described the case of a DMD patient who underwent successful heart transplantation after 47 months of HeartWare LVAD assistance. Three months' follow-up is uneventful.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most frequent and severe form of

    MD
    DIAGNOSIS

. It firstly

    affects the skeletal muscles
    SYMPTOMS

, causing

    severe disability
    SYMPTOMS

, and subsequently the

    myocardium
    SYMPTOMS

. The only two options to treat

    end-stage heart failure
    DIAGNOSIS

 in these patients are either a

    left ventricular assist device (LVAD) implantation as destination therapy
    MEDICATION

 or a

    heart transplant
    MEDICATION

. These hypotheses are still controversial, and data are very limited. We describe the case of an

    18-year-old
    AGE

    male
    GENDER

 patient, affected by

    DMD
    DIAGNOSIS

 and in

    a wheelchair from the age of 11
    MEDICATION

.

    He
    GENDER

 progressively developed

    dilated cardiomyopathy
    DIAGNOSIS

, and in 2016, at the

    age of 14 years
    AGE

,

    he
    GENDER

 underwent

    HeartWare LVAD implantation, as destination therapy
    MEDICATION

,

    without post-operative complications
    NEG_FINDINGS

.

    He
    GENDER

 has been followed up for 47 consecutive months; and 30 months after

    LVAD implantation
    MEDICATION

,

    he
    GENDER

 developed an

    infection of the exit site
    SYMPTOMS

, treated by

    antibiotics and surgical toilette
    MEDICATION

. Following this event, on the basis of patient's good general conditions and willingness, we started to consider

    heart transplant
    MEDICATION

 as an option. Before the patient was listed,

    he
    GENDER

 underwent

    accurate workup
    PARACLINICAL

, and we found

    higher values of forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow
    SYMPTOMS

, compared with the predicted values of same-age

    DMD
    DIAGNOSIS

 patients. The patient have

    neither scoliosis nor need for non-invasive mechanical ventilation
    NEG_FINDINGS

, and finally,

    he
    GENDER

 was always

    treated with steroids
    MEDICATION

 with

    stable thoraco-abdominal function over the years
    SYMPTOMS

. According to these considerations, the patient was listed for

    heart transplant
    MEDICATION

. In 12 February 2020, at the

    age of 18 years
    AGE

, the patient underwent

    heart transplant
    MEDICATION

 with

    no post-operative complications
    NEG_FINDINGS

.

    Cardiac transplantation
    MEDICATION

 is not considered a valid option for

    DMD
    DIAGNOSIS

 patients, because of the shortage of donor availability and the systemic nature of

    DMD disease
    DIAGNOSIS

. Considering that this patient had already experienced an

    LVAD-related complication
    SYMPTOMS

 and

    he
    GENDER

 had better general condition than his

    DMD
    DIAGNOSIS

 peers, we listed

    him
    GENDER

 for a

    heart transplant
    MEDICATION

. We described the case of a

    DMD
    DIAGNOSIS

 patient who underwent

    successful heart transplantation
    MEDICATION

 after

    47 months of HeartWare LVAD assistance
    MEDICATION

. Three months' follow-up is uneventful.

Duchenne muscular dystrophy (DMD)
MD
end-stage heart failure
DMD
dilated cardiomyopathy
DMD
DMD
DMD disease
DMD
DMD


Rare intronic mutation between Exon 62 and 63 (c.9225-285A>G) of the dystrophin gene associated with atypical BMD phenotype.

Dystrophinopathies are predominantly caused by deletions, duplications and point mutations in the coding regions of the dystrophin gene with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a 17-year-old male with a Becker muscular dystrophy diagnosis and mental disability due to an intron mutation that led to aberrant splicing and formation of an additional exon. Histopathological analysis of muscle tissue revealed signs of muscular dystrophy and reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan. Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene did not identify a mutation in the coding regions. However, next generation sequencing revealed an intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame. We report a functional consequence of this mutation as an increased intracellular-weighted sodium signal (assessed by 23Na-magnetic resonance imaging) in leg muscles.

    Dystrophinopathies
    DIAGNOSIS

 are predominantly caused by

    deletions, duplications and point mutations in the coding regions of the dystrophin gene
    GENETICS

 with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a

    17-year-old
    AGE

    male
    GENDER

 with a

    Becker muscular dystrophy
    DIAGNOSIS

 diagnosis and

    mental disability
    SYMPTOMS

 due to an

    intron mutation that led to aberrant splicing and formation of an additional exon
    GENETICS

.

    Histopathological analysis of muscle tissue
    PARACLINICAL

 revealed

    signs of muscular dystrophy
    SYMPTOMS

 and

    reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan
    BIOCHEMICAL

.

    Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene
    PARACLINICAL

    did not identify a mutation in the coding regions
    NEG_FINDINGS

. However,

    next generation sequencing
    PARACLINICAL

 revealed an

    intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame
    GENETICS

. We report a functional consequence of this mutation as an

    increased intracellular-weighted sodium signal
    SYMPTOMS

 (assessed by

    23Na-magnetic resonance imaging
    PARACLINICAL

)

    in leg muscles
    SYMPTOMS

.

Dystrophinopathies
Becker muscular dystrophy


Severe cardiac involvement with preserved truncated dystrophin expression in Becker muscular dystrophy by +1G>A DMD splice-site mutation: a case report.

Becker muscular dystrophy (BMD) is caused by specific mutations in the DMD gene that causes progressive muscle weakness and primarily affects skeletal and cardiac muscle. Although cardiac involvement is a significant cause of mortality in BMD, the genetic-phenotype correlation for skeletal and cardiac muscles has not been elucidated. Here, we described a 39-year-old man with BMD, who presented with subtle skeletal muscle weakness in the right leg in his 20s and underwent left ventricular restoration for severe dilated cardiomyopathy at the age of 29. He had difficulty climbing stairs after the age of 35. Neither duplication nor deletion of exons was detected by multiplex ligation-dependent probe amplification. A hemizygous c.264 + 1G>A mutation in intron 4 of the DMD was identified by next-generation sequencing. Furthermore, exon 4 skipping of the DMD was confirmed in both skeletal and cardiac muscles evaluated by reverse transcriptase PCR. Endomyocardial and skeletal muscle biopsies revealed dystrophic pathology characterized by muscle fiber atrophy and hypertrophy with a mild degree of interstitial fibrosis. Interestingly, dystrophin immunohistochemistry demonstrated patchy and faint staining of the skeletal muscle membranes but almost normal staining of the cardiac muscle membranes. Western blot analysis revealed a decreased amount of truncated dystrophin in skeletal muscle but surprisingly almost normal amount in cardiac muscle. This case indicates that BMD patients may have severe cardiac dysfunction despite preserved cardiac truncated dystrophin expression.

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 is caused by

    specific mutations in the DMD gene
    GENETICS

 that causes

    progressive muscle weakness
    SYMPTOMS

 and

    primarily affects skeletal and cardiac muscle
    SYMPTOMS

. Although

    cardiac involvement
    SYMPTOMS

 is a significant cause of mortality in

    BMD
    DIAGNOSIS

, the genetic-phenotype correlation for skeletal and

    cardiac muscles
    SYMPTOMS

 has not been elucidated. Here, we described a

    39-year-old
    AGE

    man
    GENDER

 with

    BMD
    DIAGNOSIS

, who presented with

    subtle skeletal muscle weakness in the right leg
    SYMPTOMS

 in

    his 20s
    AGE

 and underwent

    left ventricular restoration
    MEDICATION

 for

    severe dilated cardiomyopathy
    DIAGNOSIS

 at the

    age of 29
    AGE

.

    He
    GENDER

 had

    difficulty climbing stairs
    NEG_FINDINGS

    after the age of 35
    AGE

.

    Neither duplication nor deletion of exons was detected
    NEG_FINDINGS

 by

    multiplex ligation-dependent probe amplification
    PARACLINICAL

. A

    hemizygous c.264 + 1G>A mutation in intron 4 of the DMD
    GENETICS

 was identified by

    next-generation sequencing
    PARACLINICAL

. Furthermore,

    exon 4 skipping of the DMD
    GENETICS

 was confirmed in both

    skeletal and cardiac muscles
    SYMPTOMS

 evaluated by

    reverse transcriptase PCR
    PARACLINICAL

.

    Endomyocardial and skeletal muscle biopsies
    PARACLINICAL

 revealed

    dystrophic pathology
    SYMPTOMS

 characterized by

    muscle fiber atrophy and hypertrophy
    SYMPTOMS

 with a

    mild degree of interstitial fibrosis
    SYMPTOMS

. Interestingly,

    dystrophin immunohistochemistry
    PARACLINICAL

 demonstrated

    patchy and faint staining of the skeletal muscle membranes
    SYMPTOMS

 but

    almost normal staining of the cardiac muscle membranes
    NEG_FINDINGS

.

    Western blot analysis
    PARACLINICAL

 revealed a

    decreased amount of truncated dystrophin in skeletal muscle
    BIOCHEMICAL

 but

    surprisingly almost normal amount in cardiac muscle
    NEG_FINDINGS

. This case indicates that

    BMD
    DIAGNOSIS

 patients may have

    severe cardiac dysfunction
    SYMPTOMS

    despite preserved cardiac truncated dystrophin expression
    NEG_FINDINGS

.

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


Rehabilitation Following Fracture in Dystrophinopathy, A Case Series.

Boys with dystrophinopathies (DMD) are at increased risk of low bone mineral density and fracture. Femoral fracture is the most common extremity fracture and is accompanied by significant risk of functional loss. Care considerations for DMD have stressed that aggressive management may be needed to maintain ambulation and that surgical fixation allows early mobilization.

Describe 5 cases of femoral fracture in ambulatory boys with DMD and the course of care undertaken to optimize function.

Five boys with DMD median age 15y (12-16) who were independently ambulatory. Median 10m walk speed prior to their first fracture was 8 sec (7-17.37) and 4 of 5 were less than the 9 seconds predictive of 2 year ambulation retention. Three of the cases had a single incident causing fracture; the remaining cases had 2 and 3 incidents respectively representing a total of 8 fractures 6 of which were surgically stabilized.

Following the first fracture, all 5 subjects regained some form of ambulation. Three patients regained independent ambulation and 2 with hand held support or contact guard. Two subjects went on to have additional falls with associated fracture. No patient regained the ability to rise from the floor and only one of the 5 regained the ability to climb steps and all demonstrated a decline in walking speed.

Prompt orthopedic intervention, early mobility, and intensive rehabilitation even in the end stage ambulatory patient, were factors in helping preserve function in these patients with dystrophinopathies.

    Boys
    GENDER

 with

    dystrophinopathies (DMD)
    DIAGNOSIS

 are at increased risk of

    low bone mineral density
    SYMPTOMS

 and

    fracture
    SYMPTOMS

.

    Femoral fracture
    SYMPTOMS

 is the most common

    extremity fracture
    SYMPTOMS

 and is accompanied by significant risk of

    functional loss
    SYMPTOMS

. Care considerations for

    DMD
    DIAGNOSIS

 have stressed that

    aggressive management
    MEDICATION

 may be needed to

    maintain ambulation
    MEDICATION

 and that

    surgical fixation
    MEDICATION

 allows

    early mobilization
    MEDICATION

.

Describe 5 cases of

    femoral fracture
    DIAGNOSIS

 in

    ambulatory boys
    AGE

 with

    DMD
    DIAGNOSIS

 and the

    course of care undertaken
    MEDICATION

 to optimize function.

Five

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

    median age 15y (12-16)
    AGE

 who were

    independently ambulatory
    SYMPTOMS

.

    Median 10m walk speed prior to their first fracture was 8 sec (7-17.37)
    SYMPTOMS

 and 4 of 5 were

    less than the 9 seconds predictive of 2 year ambulation retention
    SYMPTOMS

. Three of the cases had a single

    incident causing fracture
    SYMPTOMS

; the remaining cases had 2 and 3 incidents respectively representing a total of 8 fractures 6 of which were

    surgically stabilized
    MEDICATION

.

    Following the first fracture
    MEDICATION

, all 5 subjects

    regained some form of ambulation
    SYMPTOMS

. Three patients

    regained independent ambulation
    SYMPTOMS

 and 2

    with hand held support or contact guard
    MEDICATION

. Two subjects went on to have

    additional falls with associated fracture
    SYMPTOMS

.

    No patient regained the ability to rise from the floor
    NEG_FINDINGS

 and only one of the 5

    regained the ability to climb steps
    NEG_FINDINGS

 and all demonstrated a

    decline in walking speed
    SYMPTOMS

.

    Prompt orthopedic intervention
    MEDICATION

,

    early mobility
    MEDICATION

, and

    intensive rehabilitation
    MEDICATION

 even in the

    end stage ambulatory patient
    MEDICATION

, were factors in helping preserve function in these patients with

    dystrophinopathies
    DIAGNOSIS

.

dystrophinopathies (DMD)
DMD
femoral fracture
DMD
DMD
dystrophinopathies

aggressive management
maintain ambulation
surgical fixation
early mobilization
course of care undertaken
surgically stabilized
Following the first fracture
with hand held support or contact guard
Prompt orthopedic intervention
early mobility
intensive rehabilitation
end stage ambulatory patient


Co-Transplantation of Bone Marrow-MSCs and Myogenic Stem/Progenitor Cells from Adult Donors Improves Muscle Function of Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with a progressive deficiency of dystrophin that leads to skeletal muscle degeneration. In this study, we tested the hypothesis that a co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle can improve the skeletal muscle function of DMD patients. Three patients diagnosed with DMD, confirmed by the dystrophin gene mutation, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015). Stem/progenitor cells collected from bone marrow and skeletal muscles of related healthy donors, based on HLA matched antigens, were expanded in a closed MC3 cell culture system. A simultaneous co‑transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii (two patients) and gastrocnemius (one patient). During a six‑month follow‑up, the patients were examined with electromyography (EMG) and monitored for blood kinase creatine level. Muscle biopsies were examined with histology and assessed for dystrophin at the mRNA and protein level. A panel of 27 cytokines was analysed with multiplex ELISA. We did not observe any adverse effects after the intramuscular administration of cells. The efficacy of BM‑MSC and SM‑SPC application was confirmed through an EMG assessment by an increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index. The beneficial effect of cellular therapy was confirmed by a decrease in creatine kinase levels and a normalised profile of pro-inflammatory cytokines. BM-MSCs may support the pro-regenerative potential of SM-SPCs thanks to their trophic, paracrine, and immunomodulatory activity. Both applied cell populations may fuse with degenerating skeletal muscle fibres in situ, facilitating skeletal muscle recovery. However, further studies are required to optimise the dose and timing of stem/progenitor cell delivery.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 associated with a progressive

    deficiency of dystrophin
    BIOCHEMICAL

 that leads to

    skeletal muscle degeneration
    SYMPTOMS

. In this study, we tested the hypothesis that a

    co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle
    MEDICATION

 can

    improve the skeletal muscle function
    SYMPTOMS

 of

    DMD
    DIAGNOSIS

 patients. Three patients diagnosed with

    DMD
    DIAGNOSIS

, confirmed by the

    dystrophin gene mutation
    GENETICS

, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015).

    Stem/progenitor cells collected from bone marrow and skeletal muscles
    MICROSCOPIC

 of related healthy donors, based on HLA matched antigens, were

    expanded in a closed MC3 cell culture system
    MEDICATION

. A

    simultaneous co‑transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii
    MEDICATION

 (two patients)

    and gastrocnemius
    MEDICATION

 (one patient). During a six‑month follow‑up, the patients were examined with

    electromyography (EMG)
    PARACLINICAL

 and

    monitored for blood kinase creatine level
    PARACLINICAL

.

    Muscle biopsies were examined with histology
    PARACLINICAL

 and

    assessed for dystrophin at the mRNA and protein level
    PARACLINICAL

. A

    panel of 27 cytokines was analysed with multiplex ELISA
    PARACLINICAL

. We

    did not observe any adverse effects after the intramuscular administration of cells
    NEG_FINDINGS

. The efficacy of

    BM‑MSC and SM‑SPC application
    MEDICATION

 was confirmed through an

    EMG assessment
    PARACLINICAL

 by an

    increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index
    SYMPTOMS

. The beneficial effect of

    cellular therapy
    MEDICATION

 was confirmed by a

    decrease in creatine kinase levels
    BIOCHEMICAL

 and a

    normalised profile of pro-inflammatory cytokines
    BIOCHEMICAL

.

    BM-MSCs
    MEDICATION

 may support the

    pro-regenerative potential of SM-SPCs
    SYMPTOMS

 thanks to their

    trophic, paracrine, and immunomodulatory activity
    SYMPTOMS

. Both applied

    cell populations may fuse with degenerating skeletal muscle fibres in situ
    MICROSCOPIC

, facilitating

    skeletal muscle recovery
    SYMPTOMS

. However, further studies are required to optimise the dose and timing of

    stem/progenitor cell delivery
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
DMD
DMD

genetic disorder
dystrophin gene mutation


Generation of the Becker muscular dystrophy patient derived induced pluripotent stem cell line carrying the DMD splicing mutation c.1705-8 T>C.

Becker Muscular dystrophy (BMD) is an X-linked syndrome characterized by progressive muscle weakness. BMD is generally less severe than Duchenne Muscular Dystrophy. BMD is caused by mutations in the dystrophin gene that normally give rise to the production of a truncated but partially functional dystrophin protein. We generated an induced pluripotent cell line from dermal fibroblasts of a BMD patient carrying a splice mutation in the dystrophin gene (c.1705-8 T>C). The iPSC cell-line displayed the characteristic pluripotent-like morphology, expressed pluripotency markers, differentiated into cells of the three germ layers and had a normal karyotype.

    Becker Muscular dystrophy (BMD)
    DIAGNOSIS

 is an

    X-linked syndrome
    GENETICS

 characterized by

    progressive muscle weakness
    SYMPTOMS

.

    BMD
    DIAGNOSIS

 is generally less severe than

    Duchenne Muscular Dystrophy
    DIAGNOSIS

.

    BMD
    DIAGNOSIS

 is caused by

    mutations in the dystrophin gene
    GENETICS

 that normally give rise to the production of a

    truncated but partially functional dystrophin protein
    BIOCHEMICAL

. We generated an

    induced pluripotent cell line from dermal fibroblasts
    MICROSCOPIC

 of a

    BMD
    DIAGNOSIS

 patient carrying a

    splice mutation in the dystrophin gene (c.1705-8 T>C)
    GENETICS

. The

    iPSC cell-line
    MICROSCOPIC

 displayed the

    characteristic pluripotent-like morphology
    MICROSCOPIC

,

    expressed pluripotency markers
    GENETICS

,

    differentiated into cells of the three germ layers
    MICROSCOPIC

 and had a

    normal karyotype
    NEG_FINDINGS

.

Becker Muscular dystrophy (BMD)
BMD
Duchenne Muscular Dystrophy
BMD
BMD


Exon skipping in Duchenne Muscle dystrophy due to a silent p.Ser443= mutation in the DMD gene.

Duchenne Muscle dystrophy (DMD) is a X-linked inherited disease predominantly caused by severe mutations in DMD gene leading to absence of dystrophin protein. Here we report a 14-year-old Mongolian boy suffering from proximal muscle weakness, pseudohypertrophic deltoid and gastrocnemius muscles since early childhood. Lactate dehydrogenase (LDH) and creatine kinase (CK) levels were elevated. Mutation analysis including MLPA and sequencing of the DMD gene revealed a hemizygous silent variant, c.1329C>T (p.Ser443=) in exon 11. This silent mutation, listed in the SNP database (rs1060502631), was described as a variant of unknown significance (VUS) in ClinVar database. cDNA analysis demonstrated partial skipping of exon 11 due to this mutation. Although silent mutations are usually considered non-pathogenic, our case emphasizes that silent mutations can be potentially pathogenic. Hence, if silent variants are not annotated in database or not known to be benign, they should be analysed further at cDNA level.

    Duchenne Muscle dystrophy (DMD)
    DIAGNOSIS

 is a

    X-linked inherited disease
    GENETICS

 predominantly caused by

    severe mutations in DMD gene
    GENETICS

 leading to

    absence of dystrophin protein
    BIOCHEMICAL

. Here we report a

    14-year-old
    AGE

    Mongolian
    ETHNICITY

    boy
    GENDER

 suffering from

    proximal muscle weakness
    SYMPTOMS

,

    pseudohypertrophic deltoid and gastrocnemius muscles
    SYMPTOMS

    since early childhood
    AGE

.

    Lactate dehydrogenase (LDH) and creatine kinase (CK) levels were elevated
    BIOCHEMICAL

.

    Mutation analysis including MLPA and sequencing of the DMD gene
    PARACLINICAL

 revealed a

    hemizygous silent variant, c.1329C>T (p.Ser443=) in exon 11
    GENETICS

. This

    silent mutation, listed in the SNP database (rs1060502631)
    GENETICS

, was described as a

    variant of unknown significance (VUS)
    NEG_FINDINGS

 in ClinVar database.

    cDNA analysis
    PARACLINICAL

 demonstrated

    partial skipping of exon 11 due to this mutation
    GENETICS

. Although

    silent mutations
    GENETICS

 are usually considered non-pathogenic, our case emphasizes that

    silent mutations
    GENETICS

 can be potentially pathogenic. Hence, if silent variants are not annotated in database or not known to be benign, they should be analysed further at cDNA level.


Laparoscopic gynecological surgery in an adult woman with Becker muscular dystrophy performed with sevoflurane with cisatracurium anesthesia: A case report.

Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are progressive neuromuscular disorders caused by mutations in the dystrophin gene. The management of anesthesia in patients with BMD is complicated because they are highly sensitive to the conventional anesthetics such as volatile anesthetics and muscle relaxants. It is reported that anesthesia in patients with DMD is associated with several complications. However, a few case reports have been published on adult patients with BMD undergoing surgery with general anesthesia. Reports indicate that children with BMD may experience some serious complications with flurane-inhaled anesthesia. However, no study has yet shown that the use of flurane-induced anesthesia in adults with DMD carries high risks.

We describe a 56-year-old woman with BMD who was scheduled for laparoscopic hysterectomy and bilateral adnexectomy under general anesthesia due to a mass in the uterus. The patient was diagnosed with BMD 20 years back and reported that during this period, she was able to walk slowly with help during her daily life. Additionally, she also had a history of hypertension since 4 years and type 2 diabetes mellitus since 2 years.

The patient was postmenopausal and presented with abnormal uterine bleeding and elevated CA125. Abdominal ultrasonography revealed diffuse enlargement of the uterus and hypoechoic internal echoes. These findings were suggestive of diffuse adenomyosis with multiple uterine leiomyomas, which would have adverse effects later in her life. Therefore, the patient required surgery to address the symptoms and further confirm the diagnosis. The final diagnosis was confirmed by histopathological analysis.

The patient was scheduled for laparoscopic hysterectomy and bilateral adnexectomy. Anesthesia was induced and maintained by a combination of intravenous and inhalation anesthetic agents, particularly cisatracurium besilate and inhaled. sevoflurane.

The duration of anesthesia and postoperative period were uneventful. At the end of the operation, the patient had normal vital signs and was fully conscious. The patient was followed up for 8 months and no complications were noted during this period.

The combination of sevoflurane and cisatracurium besilate is a safe and effective method for the anesthetic management of adult patients with BMD scheduled for laparoscopic gynecological surgery. On the other hand, it is important to be aware of even rare complications of procedures, so that necessary precautions can be undertaken. Further investigations are necessary to determine the safe dosage of volatile anesthetics specifically for this clinical scenario so that anesthesiologists can use this combination method more accurately and precisely.

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 and

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 are

    progressive neuromuscular disorders
    DIAGNOSIS

 caused by

    mutations in the dystrophin gene
    GENETICS

. The management of

    anesthesia
    MEDICATION

 in patients with

    BMD
    DIAGNOSIS

 is complicated because they are highly sensitive to the conventional anesthetics such as

    volatile anesthetics and muscle relaxants
    MEDICATION

. It is reported that

    anesthesia
    MEDICATION

 in patients with

    DMD
    DIAGNOSIS

 is associated with several complications. However, a few case reports have been published on

    adult
    AGE

 patients with

    BMD
    DIAGNOSIS

 undergoing

    surgery with general anesthesia
    MEDICATION

. Reports indicate that

    children
    AGE

 with

    BMD
    DIAGNOSIS

 may experience some

    serious complications
    SYMPTOMS

 with

    flurane-inhaled anesthesia
    MEDICATION

. However, no study has yet shown that the use of

    flurane-induced anesthesia
    MEDICATION

 in

    adults
    AGE

 with

    DMD
    DIAGNOSIS

 carries high risks.

We describe a

    56-year-old
    AGE

    woman
    GENDER

 with

    BMD
    DIAGNOSIS

 who was scheduled for

    laparoscopic hysterectomy and bilateral adnexectomy under general anesthesia
    MEDICATION

 due to a

    mass in the uterus
    SYMPTOMS

. The patient was diagnosed with

    BMD
    DIAGNOSIS

 20 years back and reported that during this period,

    she
    GENDER

 was

    able to walk slowly
    SYMPTOMS

 with help during her daily life. Additionally,

    she
    GENDER

 also had a history of

    hypertension since 4 years
    SYMPTOMS

 and

    type 2 diabetes mellitus
    DIAGNOSIS

    since 2 years
    AGE

.

The patient was

    postmenopausal
    GENDER

 and presented with

    abnormal uterine bleeding
    SYMPTOMS

 and

    elevated CA125
    BIOCHEMICAL

.

    Abdominal ultrasonography
    PARACLINICAL

 revealed

    diffuse enlargement of the uterus
    SYMPTOMS

 and

    hypoechoic internal echoes
    SYMPTOMS

. These findings were suggestive of

    diffuse adenomyosis
    DIAGNOSIS

 with

    multiple uterine leiomyomas
    SYMPTOMS

, which would have

    adverse effects
    SYMPTOMS

 later in her life. Therefore, the patient required

    surgery
    MEDICATION

 to address the symptoms and further confirm the diagnosis. The final diagnosis was confirmed by

    histopathological analysis
    PARACLINICAL

.

The patient was scheduled for

    laparoscopic hysterectomy and bilateral adnexectomy
    MEDICATION

.

    Anesthesia
    MEDICATION

 was

    induced and maintained by a combination of intravenous and inhalation anesthetic agents, particularly cisatracurium besilate and inhaled. sevoflurane
    MEDICATION

.

The duration of anesthesia and postoperative period were

    uneventful
    NEG_FINDINGS

. At the end of the operation, the patient had

    normal vital signs
    NEG_FINDINGS

 and was

    fully conscious
    SYMPTOMS

. The patient was followed up for 8 months and

    no complications
    NEG_FINDINGS

 were noted during this period.

The

    combination of sevoflurane and cisatracurium besilate
    MEDICATION

 is a safe and effective method for the

    anesthetic management
    MEDICATION

 of

    adult
    AGE

 patients with

    BMD
    DIAGNOSIS

 scheduled for

    laparoscopic gynecological surgery
    MEDICATION

. On the other hand, it is important to be aware of even rare complications of procedures, so that necessary precautions can be undertaken. Further investigations are necessary to determine the safe dosage of

    volatile anesthetics
    MEDICATION

 specifically for this clinical scenario so that anesthesiologists can use this

    combination method
    MEDICATION

 more accurately and precisely.

Becker muscular dystrophy (BMD)
Duchenne muscular dystrophy (DMD)
progressive neuromuscular disorders
BMD
DMD
BMD
BMD
DMD
BMD
BMD
type 2 diabetes mellitus
diffuse adenomyosis
BMD

serious complications
mass in the uterus
able to walk slowly
hypertension since 4 years
abnormal uterine bleeding
diffuse enlargement of the uterus
hypoechoic internal echoes
multiple uterine leiomyomas
adverse effects
fully conscious

uneventful
normal vital signs
no complications


Duchenne Muscular Dystrophy: the Heart of the Matter.

Duchenne muscular dystrophy is one of many neuromuscular disorders, but it frequently causes severe disability early in life and early death. Cardiac involvement is an important cause of morbidity and mortality.

Heart disease in Duchenne muscular dystrophy can include a cardiomyopathy leading to end-stage heart failure along with associated supraventricular and ventricular arrhythmias. This article reviews the diagnosis and treatment of heart disease in Duchenne muscular dystrophy as well as emerging therapies.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is one of many

    neuromuscular disorders
    DIAGNOSIS

, but it frequently causes

    severe disability
    SYMPTOMS

    early in life
    AGE

 and

    early death
    SYMPTOMS

.

    Cardiac involvement
    SYMPTOMS

 is an important cause of morbidity and mortality.

    Heart disease
    DIAGNOSIS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

 can include a

    cardiomyopathy
    DIAGNOSIS

 leading to

    end-stage heart failure
    SYMPTOMS

 along with associated

    supraventricular and ventricular arrhythmias
    SYMPTOMS

. This article reviews the diagnosis and treatment of

    heart disease
    DIAGNOSIS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

 as well as emerging therapies.

Duchenne muscular dystrophy
neuromuscular disorders
Heart disease
Duchenne muscular dystrophy
cardiomyopathy
heart disease
Duchenne muscular dystrophy


Glucocorticoid-Associated Demise of a Patient With Duchenne Muscular Dystrophy.

We describe the clinical deterioration of a 26-yr-old man with Duchenne muscular dystrophy on oral daily high-dose deflazacort. Although this daily regimen was targeted to benefit ambulation and respiration, it resulted in premature death with lethal sequelae from liver failure, decubiti, diabetes mellitus, and morbid obesity. This case illustrates the need for further research weighing risk versus benefit of daily glucocorticoid therapy, specifically deflazacort, in Duchenne muscular dystrophy patients. Thus, curtailment of daily dosing to eliminate dire sequelae in patients living longer into adulthood than ever before is recommended.

We describe the clinical deterioration of a

    26-yr-old
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 on

    oral daily high-dose deflazacort
    MEDICATION

. Although this

    daily regimen
    MEDICATION

 was targeted to

    benefit ambulation and respiration
    MEDICATION

, it resulted in

    premature death
    SYMPTOMS

 with

    lethal sequelae
    SYMPTOMS

 from

    liver failure
    SYMPTOMS

,

    decubiti
    SYMPTOMS

,

    diabetes mellitus
    SYMPTOMS

, and

    morbid obesity
    SYMPTOMS

. This case illustrates the need for further research weighing risk versus benefit of

    daily glucocorticoid therapy, specifically deflazacort
    MEDICATION

, in

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients. Thus,

    curtailment of daily dosing
    MEDICATION

 to eliminate dire sequelae in patients living longer into

    adulthood
    AGE

 than ever before is recommended.

Duchenne muscular dystrophy
Duchenne muscular dystrophy

premature death
lethal sequelae
liver failure
decubiti
diabetes mellitus
morbid obesity


46,XX Testicular Disorders of Sex Development With DMD Gene Mutation: First Case Report Identified Prenatally by Integrated Analyses in China.

The present study describes the first prenatally diagnosed 46,XX testicular disorders of sex development (46,XX testicular DSD) case with DMD gene mutation by integrated analyses in a Chinese pedigree. Chromosome karyotype G-banding analysis of the proband showed a 46,XX karyotype, but B-ultrasound analysis demonstrated the existence of scrotum, testis and penis which inferred a male sexual differentiation. Aneuploidy and copy number variation (CNV) detection by low-coverage single-end whole genome sequencing (WGS) revealed a de novo SRY (sex-determining region Y) gene positive fragment of 224.34 kb length (chrY:2,649,472-2,873,810) which explained the gonadal/genital-chromosomal inconsistency in the proband. Additionally, targeted-region-capture-based DMD gene sequencing and Sanger verification confirmed a widely reported pathogenic heterozygous nonsense mutation (NM_004006, c.9100C>T, p.Arg3034Ter) in the dystrophin-coding gene named DMD. This study emphasizes that integrated analyses of the imaging results, cytogenetics, and molecular features can play an important role in prenatal diagnosis. It requires the combination of more detection techniques with higher resolution than karyotyping to determine the genetic and biological sex of fetuses in prenatal diagnosis. To conclusively determine both the biological and genetic sex of the fetus at the time of prenatal diagnosis particularly in cases that involve X-linked conditions is of vital importance, which would crucially influence the decision-making regarding abortions. This study will help in prenatal diagnosis of DMD in future, also providing a new perspective that enables the genetic diagnosis of sex reversal in pregnancy. Moreover, genetic counseling/analysis for early diagnosis and pre-symptom interventions are warranted.

The present study describes the first prenatally diagnosed

    46,XX testicular disorders of sex development
    DIAGNOSIS

    (46,XX testicular DSD)
    DIAGNOSIS

 case with

    DMD gene mutation
    GENETICS

 by

    integrated analyses
    PARACLINICAL

 in a

    Chinese
    ETHNICITY

 pedigree.

    Chromosome karyotype G-banding analysis
    PARACLINICAL

 of the proband showed a

    46,XX karyotype
    GENETICS

, but

    B-ultrasound analysis
    PARACLINICAL

 demonstrated the

    existence of scrotum, testis and penis
    SYMPTOMS

 which inferred a

    male sexual differentiation
    SYMPTOMS

.

    Aneuploidy and copy number variation (CNV) detection by low-coverage single-end whole genome sequencing (WGS)
    PARACLINICAL

 revealed a

    de novo SRY (sex-determining region Y) gene positive fragment of 224.34 kb length (chrY:2,649,472-2,873,810)
    GENETICS

 which explained the

    gonadal/genital-chromosomal inconsistency
    SYMPTOMS

 in the proband. Additionally,

    targeted-region-capture-based DMD gene sequencing and Sanger verification
    PARACLINICAL

 confirmed a

    widely reported pathogenic heterozygous nonsense mutation (NM_004006, c.9100C>T, p.Arg3034Ter) in the dystrophin-coding gene named DMD
    GENETICS

. This study emphasizes that

    integrated analyses of the imaging results, cytogenetics, and molecular features
    PARACLINICAL

 can play an important role in

    prenatal diagnosis
    PARACLINICAL

. It requires the combination of more detection techniques with higher resolution than

    karyotyping
    PARACLINICAL

 to determine the genetic and biological sex of fetuses in

    prenatal diagnosis
    PARACLINICAL

. To conclusively determine both the biological and genetic sex of the fetus at the time of

    prenatal diagnosis
    PARACLINICAL

 particularly in cases that involve

    X-linked conditions
    GENETICS

 is of vital importance, which would crucially influence the decision-making regarding

    abortions
    MEDICATION

. This study will help in prenatal diagnosis of

    DMD
    DIAGNOSIS

 in future, also providing a new perspective that enables the genetic diagnosis of

    sex reversal
    DIAGNOSIS

 in

    pregnancy
    DIAGNOSIS

. Moreover,

    genetic counseling/analysis
    MEDICATION

 for early diagnosis and

    pre-symptom interventions
    MEDICATION

 are warranted.

abortions
genetic counseling/analysis
pre-symptom interventions


Fatal liver failure after therapeutic doses of paracetamol in a patient with Duchenne muscular dystrophy and atypical pharmacogenetic profile of drug-metabolizing enzymes.

Paracetamol has a good safety profile, but pharmacogenetic differences in drug-metabolizing enzymes may have an impact on its risk of hepatotoxicity. We present a case of fatal acute liver failure (ALF) after therapeutic doses of paracetamol in a patient with Duchenne muscular dystrophy, where pharmacogenetic screening was conducted. This 30-year-old man was electively admitted for a tracheostomy. A total of 14.5 g paracetamol was given over four days. He developed a severe ALF and died 11 days after admission. Pharmacogenetic screening showed absent CYP2D6 metabolism and increased CYP1A2 activity, which may have increased the formation of toxic intermediate metabolite, N-acetyl-p-benzo-quinone imine (NAPQI). He also had decreased function of UGT2B15, which increases the amount of paracetamol available for metabolism to NAPQI. Having a reduced muscle mass and thus a reduced glutathione levels to detoxify produced NAPQI may add to the risk of toxicity. This case may indicate that pharmacogenetic variability is of potential relevance for the risk of paracetamol-induced hepatotoxicity in patients with neuromuscular diseases. Further studies should investigate if pharmacogenetic screening could be a tool to detect potentially increased risk of hepatotoxicity in these patients at therapeutic doses of paracetamol and hence provide information for selection of analgesic treatment.

    Paracetamol
    MEDICATION

 has a good safety profile, but

    pharmacogenetic differences in drug-metabolizing enzymes
    GENETICS

 may have an impact on its risk of

    hepatotoxicity
    DIAGNOSIS

. We present a case of

    fatal acute liver failure (ALF)
    DIAGNOSIS

 after

    therapeutic doses of paracetamol
    MEDICATION

 in a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

, where

    pharmacogenetic screening
    PARACLINICAL

 was conducted. This

    30-year-old
    AGE

    man
    GENDER

 was

    electively admitted for a tracheostomy
    MEDICATION

. A

    total of 14.5 g paracetamol was given over four days
    MEDICATION

.

    He
    GENDER

 developed a

    severe ALF
    DIAGNOSIS

 and

    died
    SYMPTOMS

 11 days after admission.

    Pharmacogenetic screening
    PARACLINICAL

 showed

    absent CYP2D6 metabolism
    BIOCHEMICAL

 and

    increased CYP1A2 activity
    BIOCHEMICAL

, which may have increased the

    formation of toxic intermediate metabolite, N-acetyl-p-benzo-quinone imine (NAPQI)
    MICROSCOPIC

.

    He
    GENDER

 also had

    decreased function of UGT2B15
    BIOCHEMICAL

, which

    increases the amount of paracetamol available for metabolism to NAPQI
    BIOCHEMICAL

. Having a

    reduced muscle mass
    SYMPTOMS

 and thus a

    reduced glutathione levels to detoxify produced NAPQI
    BIOCHEMICAL

 may add to the risk of

    toxicity
    SYMPTOMS

. This case may indicate that

    pharmacogenetic variability
    GENETICS

 is of potential relevance for the risk of

    paracetamol-induced hepatotoxicity
    DIAGNOSIS

 in patients with

    neuromuscular diseases
    DIAGNOSIS

. Further studies should investigate if

    pharmacogenetic screening
    PARACLINICAL

 could be a tool to detect potentially increased risk of

    hepatotoxicity
    DIAGNOSIS

 in these patients at

    therapeutic doses of paracetamol
    MEDICATION

 and hence provide information for selection of

    analgesic treatment
    MEDICATION

.

hepatotoxicity
fatal acute liver failure (ALF)
Duchenne muscular dystrophy
severe ALF
paracetamol-induced hepatotoxicity
neuromuscular diseases
hepatotoxicity


Anesthetic management of a patient with a continuous-flow left ventricular assist device for video-assisted thoracoscopic surgery: a case report.

As patients with left ventricular assist device (LVAD) have long expected survival, the incidence of noncardiac surgery in this patient population is increasing. Here, we present the anesthetic management of a patient with a continuous-flow LVAD who underwent video-assisted thoracic surgery (VATS).

A 37-year-old man with LVAD was scheduled to undergo VATS because of repeated spontaneous pneumothorax. Generally, patients with these devices have marginal right heart function; therefore, it is important to avoid factors that worsen pulmonary vascular resistance (PVR). However, VATS requires one-lung ventilation (OLV) and it tends to cause increase in PVR, leading to right heart failure. In the present case, when the patient was set in a lateral decubitus position and progressive hypoxia was observed during OLV, transesophageal echocardiography demonstrated a dilated right ventricle and a temporally flattened interventricular septum, and the central venous pressure increased to approximately 20 mmHg. Because we anticipated deterioration of right heart function, dobutamine and milrinone were administered and/or respirator settings were changed to decrease PVR for maintaining LVAD performance. Finally, resection of a bulla was completed, and the patient was discharged in stable condition on postoperative day 37.

The anesthetic management of a patient with LVAD during VATS is challenging because the possible hemodynamic changes induced by hypoxia associated with OLV affect LVAD performance and right heart function. In our experience, VATS that requires OLV will be well tolerated in a patient with LVAD with preserved right heart function, and a multidisciplinary approach to maintain right heart function will be needed.

As patients with

    left ventricular assist device (LVAD)
    MEDICATION

 have long expected survival, the incidence of

    noncardiac surgery
    MEDICATION

 in this patient population is increasing. Here, we present the

    anesthetic management
    MEDICATION

 of a patient with a

    continuous-flow LVAD
    MEDICATION

 who underwent

    video-assisted thoracic surgery (VATS)
    MEDICATION

.

A

    37-year-old
    AGE

    man
    GENDER

 with

    LVAD
    MEDICATION

 was scheduled to undergo

    VATS
    MEDICATION

 because of

    repeated spontaneous pneumothorax
    SYMPTOMS

. Generally, patients with these devices have

    marginal right heart function
    SYMPTOMS

; therefore, it is important to avoid factors that

    worsen pulmonary vascular resistance (PVR)
    SYMPTOMS

. However,

    VATS
    MEDICATION

 requires

    one-lung ventilation (OLV)
    MEDICATION

 and it tends to cause

    increase in PVR
    SYMPTOMS

, leading to

    right heart failure
    SYMPTOMS

. In the present case, when the patient was

    set in a lateral decubitus position
    MEDICATION

 and

    progressive hypoxia
    SYMPTOMS

 was observed during

    OLV
    MEDICATION

,

    transesophageal echocardiography
    PARACLINICAL

 demonstrated a

    dilated right ventricle and a temporally flattened interventricular septum
    SYMPTOMS

, and the

    central venous pressure increased to approximately 20 mmHg
    SYMPTOMS

. Because we anticipated

    deterioration of right heart function
    SYMPTOMS

,

    dobutamine and milrinone
    MEDICATION

 were administered and/or

    respirator settings were changed to decrease PVR
    MEDICATION

 for

    maintaining LVAD performance
    MEDICATION

. Finally,

    resection of a bulla
    MEDICATION

 was completed, and the patient was discharged in stable condition on postoperative day 37.

The

    anesthetic management
    MEDICATION

 of a patient with

    LVAD
    MEDICATION

 during

    VATS
    MEDICATION

 is challenging because the

    possible hemodynamic changes induced by hypoxia associated with OLV
    SYMPTOMS

 affect

    LVAD performance and right heart function
    SYMPTOMS

. In our experience,

    VATS that requires OLV
    MEDICATION

 will be well tolerated in a patient with

    LVAD
    MEDICATION

 with

    preserved right heart function
    SYMPTOMS

, and a

    multidisciplinary approach to maintain right heart function
    MEDICATION

 will be needed.


Recurrent hypotension induced by sacubitril/valsartan in cardiomyopathy secondary to Duchenne muscular dystrophy: A case report.

Duchenne muscular dystrophy (DMD), which is caused by a mutation/deletion in the dystrophin gene on the X-chromosome, is the most common type of neuromuscular disorder in pediatrics. Skeletal muscle weakness progressively develops in DMD patients and usually leads to respiratory failure in the early adolescent years. Cardiac muscle is frequently affected in DMD patients, which leads to a high burden of cardiomyopathy and heart failure. In the era of improved respiratory care, cardiac deaths are becoming the major cause of mortality in DMD patients.

We report the case of a 15-year-old boy who presented to the hospital due to recurrent orthopnea for 6 mo and palpitations for 4 mo. He was diagnosed with progressive muscular dystrophy at the age of 3 years and was confined to a wheelchair at 12 years. He was prescribed diuretics and digoxin at the outpatient clinic; however, his symptoms did not resolve. Sacubitril/valsartan was added 1 mo prior to presentation, but he experienced recurrent episodes of palpitations. The electrocardiogram showed atrial tachycardia with a heart rate of 201 bpm, and he was then hospitalized. Hypotension was found following the administration of sacubitril/valsartan tablets; he could not tolerate even a small dose, always developing tachyarrhythmia. His symptoms were relieved after discontinuing sacubitril/valsartan, and his heart rate was controlled by a small dose of metoprolol tartrate and digoxin. Atrial tachycardia spontaneously converted in this patient, and his symptoms attenuated in the following 6 mo, without palpitation episodes.

Blood pressure should be closely monitored in DMD patients with advanced heart failure when taking sacubitril/valsartan.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, which is caused by a

    mutation/deletion in the dystrophin gene on the X-chromosome
    GENETICS

, is the most common type of

    neuromuscular disorder
    DIAGNOSIS

 in

    pediatrics
    AGE

.

    Skeletal muscle weakness
    SYMPTOMS

 progressively develops in

    DMD
    DIAGNOSIS

 patients and usually leads to

    respiratory failure
    SYMPTOMS

 in the

    early adolescent years
    AGE

.

    Cardiac muscle
    SYMPTOMS

 is frequently affected in

    DMD
    DIAGNOSIS

 patients, which leads to a high burden of

    cardiomyopathy
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

. In the era of improved

    respiratory care
    MEDICATION

,

    cardiac deaths
    SYMPTOMS

 are becoming the major cause of mortality in

    DMD
    DIAGNOSIS

 patients.

We report the case of a

    15-year-old
    AGE

    boy
    GENDER

 who presented to the hospital due to

    recurrent orthopnea for 6 mo
    SYMPTOMS

 and

    palpitations for 4 mo
    SYMPTOMS

.

    He
    GENDER

 was diagnosed with

    progressive muscular dystrophy
    DIAGNOSIS

 at the

    age of 3 years
    AGE

 and was

    confined to a wheelchair
    MEDICATION

    at 12 years
    AGE

.

    He
    GENDER

 was prescribed

    diuretics and digoxin
    MEDICATION

 at the outpatient clinic; however, his

    symptoms did not resolve
    NEG_FINDINGS

.

    Sacubitril/valsartan was added
    MEDICATION

 1 mo prior to presentation, but

    he
    GENDER

 experienced

    recurrent episodes of palpitations
    SYMPTOMS

. The

    electrocardiogram
    PARACLINICAL

 showed

    atrial tachycardia with a heart rate of 201 bpm
    SYMPTOMS

, and

    he
    GENDER

 was then

    hospitalized
    MEDICATION

.

    Hypotension
    SYMPTOMS

 was found following the

    administration of sacubitril/valsartan tablets
    MEDICATION

;

    he
    GENDER

    could not tolerate even a small dose
    NEG_FINDINGS

, always developing

    tachyarrhythmia
    SYMPTOMS

. His symptoms were relieved after

    discontinuing sacubitril/valsartan
    MEDICATION

, and his

    heart rate
    SYMPTOMS

 was controlled by a

    small dose of metoprolol tartrate and digoxin
    MEDICATION

.

    Atrial tachycardia
    SYMPTOMS

 spontaneously converted in this patient, and his

    symptoms attenuated in the following 6 mo
    SYMPTOMS

,

    without palpitation episodes
    NEG_FINDINGS

.

    Blood pressure
    PARACLINICAL

 should be

    closely monitored
    PARACLINICAL

 in

    DMD
    AGE

 patients with

    advanced heart failure
    DIAGNOSIS

 when

    taking sacubitril/valsartan
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
neuromuscular disorder
DMD
DMD
DMD
progressive muscular dystrophy
advanced heart failure

symptoms did not resolve
could not tolerate even a small dose
without palpitation episodes


A Case Study With Symbihand: An sEMG-Controlled Electrohydraulic Hand Orthosis for Individuals With Duchenne Muscular Dystrophy.

With recent improvements in healthcare, individuals with Duchenne muscular dystrophy (DMD) have prolonged life expectancy, and it is therefore vital to preserve their independence. Hand function plays a central role in maintaining independence in daily living. This requires sufficient grip force and the ability to modulate it with no substantially added effort. Individuals with DMD have low residual grip force and its modulation is challenging and fatiguing. To assist their hand function, we developed a novel dynamic hand orthosis called SymbiHand, where the user's hand motor intention is decoded by means of surface electromyography, enabling the control of an electrohydraulic pump for actuation. Mechanical work is transported using hydraulic transmission and flexible structures to redirect interaction forces, enhancing comfort by minimizing shear forces. This paper outlines SymbiHand's design and control, and a case study with an individual with DMD. Results show that SymbiHand increased the participant's maximum grasping force from 2.4 to 8 N. During a grasping force-tracking task, muscular activation was decreased by more than 40% without compromising task performance. These results suggest that SymbiHand has the potential to decrease muscular activation and increase grasping force for individuals with DMD, adding to the hand a total mass of no more than 241 g. Changes in mass distributions and an active thumb support are necessary for improved usability, in addition to larger-scale studies for generalizing its assistive potential.

With recent improvements in healthcare, individuals with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 have prolonged life expectancy, and it is therefore vital to preserve their independence. Hand function plays a central role in maintaining independence in daily living. This requires sufficient grip force and the ability to modulate it with

    no substantially added effort
    NEG_FINDINGS

. Individuals with

    DMD
    DIAGNOSIS

 have

    low residual grip force
    NEG_FINDINGS

 and its modulation is challenging and

    fatiguing
    SYMPTOMS

. To assist their hand function, we developed a

    novel dynamic hand orthosis called SymbiHand
    MEDICATION

, where the

    user's hand motor intention is decoded by means of surface electromyography
    PARACLINICAL

, enabling the control of an

    electrohydraulic pump for actuation
    MEDICATION

.

    Mechanical work is transported using hydraulic transmission and flexible structures
    MEDICATION

 to redirect interaction forces, enhancing comfort by

    minimizing shear forces
    SYMPTOMS

. This paper outlines

    SymbiHand
    MEDICATION

's design and control, and a case study with an individual with

    DMD
    DIAGNOSIS

. Results show that

    SymbiHand
    MEDICATION

 increased the participant's maximum grasping force from 2.4 to 8 N. During a

    grasping force-tracking task
    PARACLINICAL

,

    muscular activation was decreased by more than 40%
    SYMPTOMS

    without compromising task performance
    NEG_FINDINGS

. These results suggest that

    SymbiHand
    MEDICATION

 has the potential to

    decrease muscular activation
    SYMPTOMS

 and

    increase grasping force
    MEDICATION

 for individuals with

    DMD
    DIAGNOSIS

, adding to the hand a total mass of no more than 241 g. Changes in mass distributions and an

    active thumb support
    MEDICATION

 are necessary for improved usability, in addition to larger-scale studies for generalizing its

    assistive
    MEDICATION

 potential.

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD

no substantially added effort
low residual grip force
without compromising task performance


Reprogramming of human Peripheral Blood Mononuclear Cell (PBMC) from a Chinese patient suffering Duchenne muscular dystrophy to iPSC line (SDQLCHi007-A) carrying deletion of 49-50 exons in the DMD gene.

Duchenne muscular dystrophy (DMD), an X-linked genetic disorder characterized by progressive muscle weakness and atrophies affecting skeletal and cardiac muscles, is caused by mutations in dystrophin (DMD) gene that spans 79 exons. Here, we generated iPSCs from a Chinese patient with 49-50 exons deletion in DMD gene by reprogramming peripheral blood mononuclear cells with non-integrating vectors. The generated iPSCs line (SDQLCHi007-A) carrying the identical deletion of 49-50 exons, expresses pluripotency markers, presents a normal karyotype and is able to differentiate into three germ layers.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, an

    X-linked genetic disorder
    GENETICS

 characterized by

    progressive muscle weakness
    SYMPTOMS

 and

    atrophies affecting skeletal and cardiac muscles
    SYMPTOMS

, is caused by

    mutations in dystrophin (DMD) gene that spans 79 exons
    GENETICS

. Here, we generated iPSCs from a

    Chinese
    ETHNICITY

 patient with

    49-50 exons deletion in DMD gene
    GENETICS

 by

    reprogramming peripheral blood mononuclear cells
    MICROSCOPIC

 with non-integrating vectors. The generated iPSCs line (SDQLCHi007-A) carrying the

    identical deletion of 49-50 exons
    GENETICS

,

    expresses pluripotency markers
    GENETICS

, presents a

    normal karyotype
    NEG_FINDINGS

 and is

    able to differentiate into three germ layers
    MICROSCOPIC

.


The Dystrophinopathies.

The dystrophinopathies are among the most common neuromuscular conditions, and they include Duchenne and Becker muscular dystrophies. This article reviews the epidemiology, clinical manifestations, genetic cause, management, and new and emerging therapies for this condition.

New studies have highlighted how oral corticosteroids have changed the natural history of the disease, prolonging ambulation in boys with Duchenne muscular dystrophy and reducing the risk of developing scoliosis and subsequent surgical correction, improving cardiac health, and increasing long-term survival. Additionally, recent publications have provided insights into how newer and emerging treatment options are becoming more common for this condition. With gene therapy being approved in the United States for the severe form, the dystrophinopathies represent model diseases to understand the personalization of genetic treatment.

Improvement in the standardization of care and the use of oral corticosteroids have increased the life expectancy of patients with dystrophinopathy and changed the natural history of the disease. This article presents a summary of clinical features, diagnostic testing, and new and emerging treatment strategies for the dystrophinopathies.

The

    dystrophinopathies
    DIAGNOSIS

 are among the most common

    neuromuscular conditions
    DIAGNOSIS

, and they include

    Duchenne
    DIAGNOSIS

 and

    Becker muscular dystrophies
    DIAGNOSIS

. This article reviews the epidemiology, clinical manifestations, genetic cause, management, and new and emerging therapies for this condition.

New studies have highlighted how

    oral corticosteroids
    MEDICATION

 have changed the natural history of the disease,

    prolonging ambulation
    MEDICATION

 in

    boys
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 and reducing the risk of developing

    scoliosis and subsequent surgical correction
    MEDICATION

,

    improving cardiac health
    SYMPTOMS

, and increasing long-term survival. Additionally, recent publications have provided insights into how newer and emerging treatment options are becoming more common for this condition. With

    gene therapy
    MEDICATION

 being approved in the United States for the severe form, the

    dystrophinopathies
    DIAGNOSIS

 represent model diseases to understand the personalization of

    genetic treatment
    MEDICATION

.

Improvement in the standardization of care and the use of

    oral corticosteroids
    MEDICATION

 have increased the life expectancy of patients with

    dystrophinopathy
    DIAGNOSIS

 and changed the natural history of the disease. This article presents a summary of clinical features, diagnostic testing, and new and emerging treatment strategies for the

    dystrophinopathies
    DIAGNOSIS

.

dystrophinopathies
neuromuscular conditions
Duchenne
Becker muscular dystrophies
Duchenne muscular dystrophy
dystrophinopathies
dystrophinopathy
dystrophinopathies


Identification of two novel insertion abnormal transcripts in two Chinese families affected with Dystrophinopathy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive inheritance muscle dystrophy disease, associated with pathogenic variants in the DMD gene. MLPA, DHPLC and DMD sequence studies fail to found the causative alteration in two cases. This study intends to evaluate the disease-causing mutations and explains the correlation genotype-phenotype.

The mRNA analysis and Long-range PCR with sequencing were used for molecular diagnosis.

In case one, an insertion of 78 nucleotides between exons 40 and 41 (r.5739_5740insMN602429:r415_492) was identified in case one. The insertion sequences were highly homologous to the intron 40 (NG_012232.1:g.1001760_g.1001837). Long-range PCR with sequencing analysis showed that a novel deep intronic DMD mutation (NG_012232.1:g.1001838A>G) was identified, generating a premature stop codon and terminating protein translation. The likely pathogenic mutation was detected in fetal sample. In case two, an insertion of 74 nucleotides which located inside the consensus sequence AG/GT was detected between exons 2 and 3 (r.93_94insMN584887:r61_134), which resulted in a premature stop codon. The insertion sequences were traceable in the intron 2 of DMD gene (NG_012232.1:g.415926_g.415999). We did not perform prenatal DMD gene diagnosis for case two due to lack of sufficient genetic information.

These findings clarify importance of proceeding to the mRNA analysis when no causative mutations were found neither by MLPA/DHPLC nor gene sequencing so as to reach the molecular confirmation of DMD and carry out an accurate genetic assessment/ carrier status testing.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    X-linked recessive inheritance muscle dystrophy disease
    GENETICS

, associated with

    pathogenic variants in the DMD gene
    GENETICS

.

    MLPA
    PARACLINICAL

,

    DHPLC
    PARACLINICAL

 and

    DMD sequence studies
    PARACLINICAL

    fail to found the causative alteration
    NEG_FINDINGS

 in two cases. This study intends to evaluate the disease-causing mutations and explains the correlation genotype-phenotype.

    The mRNA analysis
    PARACLINICAL

 and

    Long-range PCR with sequencing
    PARACLINICAL

 were used for

    molecular diagnosis
    PARACLINICAL

.

In case one, an

    insertion of 78 nucleotides between exons 40 and 41 (r.5739_5740insMN602429:r415_492)
    GENETICS

 was identified in case one.

    The insertion sequences were highly homologous to the intron 40 (NG_012232.1:g.1001760_g.1001837)
    GENETICS

.

    Long-range PCR with sequencing analysis
    PARACLINICAL

 showed that a

    novel deep intronic DMD mutation (NG_012232.1:g.1001838A>G) was identified, generating a premature stop codon and terminating protein translation
    GENETICS

. The likely pathogenic mutation was detected in

    fetal sample
    PARACLINICAL

. In case two,

    an insertion of 74 nucleotides which located inside the consensus sequence AG/GT was detected between exons 2 and 3 (r.93_94insMN584887:r61_134), which resulted in a premature stop codon
    GENETICS

.

    The insertion sequences were traceable in the intron 2 of DMD gene (NG_012232.1:g.415926_g.415999)
    GENETICS

. We

    did not perform prenatal DMD gene diagnosis
    NEG_FINDINGS

 for case two due to lack of sufficient genetic information.

These findings clarify importance of proceeding to the

    mRNA analysis
    PARACLINICAL

 when

    no causative mutations were found neither by MLPA/DHPLC nor gene sequencing
    NEG_FINDINGS

 so as to reach the

    molecular confirmation
    PARACLINICAL

 of

    DMD
    DIAGNOSIS

 and carry out an

    accurate genetic assessment/ carrier status testing
    PARACLINICAL

.


Importance of muscle biopsy to establish pathogenicity of DMD missense and splice variants.

A precise genetic diagnosis of a dystrophinopathy has far-reaching implications for affected boys and their families. We present three boys with DMD single nucleotide variants associated with Becker muscular dystrophy presenting with myalgia, reduced exercise capacity, neurodevelopmental symptoms and elevated creatine kinase. The DMD variants were difficult to classify: AIII:1 a synonymous variant in exon 13 c.1602G>A, p.Lys534Lys; BIII:1 an essential splice-site variant in intron 33 c.4674+1G>A, and CII:1 a missense mutation within the cysteine-rich domain, exon 66 c.9619T>C, p.Cys3207Arg. Complementary DNA (cDNA) analysis using muscle-derived mRNA established splice-altering effects of variants for AIII:1 and BIII:1, and normal splicing in CII:1. Western blot analysis demonstrated mildly to moderately reduced dystrophin levels (17.6 - 36.1% the levels of controls), supporting dystrophinopathy as a probable diagnosis. These three cases highlight the diagnostic utility of muscle biopsy for mRNA studies and western blot to investigate DMD variants of uncertain pathogenicity, by exploring effects on splicing and dystrophin protein levels.

A precise genetic diagnosis of a

    dystrophinopathy
    DIAGNOSIS

 has far-reaching implications for affected

    boys
    GENDER

 and their families. We present three

    boys
    GENDER

 with

    DMD single nucleotide variants
    GENETICS

 associated with

    Becker muscular dystrophy
    DIAGNOSIS

 presenting with

    myalgia
    SYMPTOMS

,

    reduced exercise capacity
    SYMPTOMS

,

    neurodevelopmental symptoms
    SYMPTOMS

 and

    elevated creatine kinase
    BIOCHEMICAL

. The

    DMD variants
    GENETICS

 were difficult to classify:

    AIII:1 a synonymous variant in exon 13 c.1602G>A, p.Lys534Lys
    GENETICS

;

    BIII:1 an essential splice-site variant in intron 33 c.4674+1G>A
    GENETICS

, and

    CII:1 a missense mutation within the cysteine-rich domain, exon 66 c.9619T>C, p.Cys3207Arg
    GENETICS

.

    Complementary DNA (cDNA) analysis using muscle-derived mRNA
    PARACLINICAL

 established

    splice-altering effects of variants for AIII:1 and BIII:1
    GENETICS

, and

    normal splicing in CII:1
    GENETICS

.

    Western blot analysis
    PARACLINICAL

 demonstrated

    mildly to moderately reduced dystrophin levels (17.6 - 36.1% the levels of controls)
    BIOCHEMICAL

, supporting

    dystrophinopathy
    DIAGNOSIS

 as a probable diagnosis. These three cases highlight the diagnostic utility of

    muscle biopsy for mRNA studies
    PARACLINICAL

 and

    western blot
    PARACLINICAL

 to investigate

    DMD
    DIAGNOSIS

 variants of uncertain pathogenicity, by exploring effects on splicing and

    dystrophin protein levels
    BIOCHEMICAL

.

dystrophinopathy
Becker muscular dystrophy
dystrophinopathy
DMD

myalgia
reduced exercise capacity
neurodevelopmental symptoms


Large in-frame 5' deletions in DMD associated with mild Duchenne muscular dystrophy: Two case reports and a review of the literature.

Duchenne muscular dystrophy is caused by mutations in the dystrophin-encoding DMD gene. While Duchenne is most commonly caused by large intragenic deletions that cause frameshift and complete loss of dystrophin expression, in-frame deletions in DMD can result in the expression of internally truncated dystrophin proteins and may be associated with a milder phenotype. In this study, we describe two individuals with large in-frame 5' deletions (exon 3-23 and exon 3-28) that remove the majority of the N-terminal region, including part of the actin binding and central rod domains. Both patients had progressive muscle weakness during childhood but are observed to have a relatively mild disease course compared to typical Duchenne. We show that in muscle biopsies from both patients, truncated dystrophin is expressed at the sarcolemma. We have additionally developed a patient-specific fibroblast-derived cell model, which can be inducibly reprogrammed to form myotubes that largely recapitulate biopsy findings for the patient with the exon 3-23 deletion, providing a culture model for future investigation of this unusual case. We discuss these mutations in the context of previously reported 5' in-frame DMD deletions and relevant animal models, and review the spectrum of phenotypes associated with these deletions.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is caused by

    mutations in the dystrophin-encoding DMD gene
    GENETICS

. While

    Duchenne
    DIAGNOSIS

 is most commonly caused by

    large intragenic deletions
    GENETICS

 that cause

    frameshift and complete loss of dystrophin expression
    GENETICS

,

    in-frame deletions in DMD
    GENETICS

 can result in the expression of

    internally truncated dystrophin proteins
    BIOCHEMICAL

 and may be associated with a milder phenotype. In this study, we describe two individuals with

    large in-frame 5' deletions (exon 3-23 and exon 3-28) that remove the majority of the N-terminal region, including part of the actin binding and central rod domains
    GENETICS

. Both patients had

    progressive muscle weakness
    SYMPTOMS

    during childhood
    AGE

 but are observed to have a relatively mild disease course compared to typical

    Duchenne
    DIAGNOSIS

. We show that in

    muscle biopsies
    PARACLINICAL

 from both patients,

    truncated dystrophin is expressed at the sarcolemma
    MICROSCOPIC

. We have additionally developed a patient-specific

    fibroblast-derived cell model
    MICROSCOPIC

, which can be

    inducibly reprogrammed to form myotubes
    MICROSCOPIC

 that largely recapitulate biopsy findings for the patient with the

    exon 3-23 deletion
    GENETICS

, providing a culture model for future investigation of this unusual case. We discuss these mutations in the context of previously reported

    5' in-frame DMD deletions
    GENETICS

 and relevant animal models, and review the spectrum of phenotypes associated with these deletions.

Duchenne muscular dystrophy
Duchenne
Duchenne


A case report: X-linked dystrophin gene mutation causing severe isolated dilated cardiomyopathy.

X-linked dilated cardiomyopathy (XLDCM) is a rare but rapidly progressive cardiomyopathy caused by dystrophin gene mutation. Mutations are more often associated with Duchenne and Becker Muscular Dystrophy, which are characterized by skeletal muscle weakness or limb girdle dystrophy. However, patients with isolated XLDCM have normal skeletal muscle but complete dystrophin loss in cardiac muscle resulting in isolated myocardial involvement without overt signs of skeletal myopathy.

A previously well 16-year-old boy developed sudden onset dense left-sided weakness and facial droop. Computed tomography (CT) angiography and CT brain showed an occluded right internal carotid artery extending to the right middle cerebral artery. He underwent successful endovascular clot retrieval but developed frank pulmonary oedema and cardiogenic shock requiring inotropic support and intubation. Transthoracic echocardiography demonstrated severe left ventricular (LV) cardiomyopathy and an apical thrombus. Subsequent cardiac magnetic resonance (CMR) imaging confirmed the LV parameters and diffuse late gadolinium enhancement. Despite absence of skeletal manifestations, subsequent genetic testing revealed an X-linked dystrophin gene mutation [c.31+G>T (IVS1G>T)]. He was commenced on empirical heart failure therapy and underwent successful cardiac transplantation.

X-linked dilated cardiomyopathy is a rare, rapidly progressing cardiomyopathy. Patients show normal skeletal muscle dystrophin but absent expression in cardiac muscle, resulting fibrosis, and atrophy. About 20% of affected young males have significantly reduced survival and thus the diagnosis must be considered in cases of idiopathic cardiomyopathy with CMR and genetic testing key to the diagnosis. Whilst evidence exists for empirical heart failure medications, cardiac transplantation remains the definitive treatment.

    X-linked dilated cardiomyopathy (XLDCM)
    DIAGNOSIS

 is a rare but

    rapidly progressive cardiomyopathy
    DIAGNOSIS

 caused by

    dystrophin gene mutation
    GENETICS

. Mutations are more often associated with

    Duchenne
    DIAGNOSIS

 and

    Becker Muscular Dystrophy
    DIAGNOSIS

, which are characterized by

    skeletal muscle weakness
    SYMPTOMS

 or

    limb girdle dystrophy
    SYMPTOMS

. However, patients with

    isolated XLDCM
    DIAGNOSIS

 have

    normal skeletal muscle
    NEG_FINDINGS

 but

    complete dystrophin loss in cardiac muscle
    SYMPTOMS

 resulting in

    isolated myocardial involvement
    SYMPTOMS

    without overt signs of skeletal myopathy
    NEG_FINDINGS

.

A previously well

    16-year-old
    AGE

    boy
    GENDER

 developed

    sudden onset dense left-sided weakness
    SYMPTOMS

 and

    facial droop
    SYMPTOMS

.

    Computed tomography (CT) angiography
    PARACLINICAL

 and

    CT brain
    PARACLINICAL

 showed an

    occluded right internal carotid artery extending to the right middle cerebral artery
    SYMPTOMS

.

    He
    GENDER

 underwent

    successful endovascular clot retrieval
    MEDICATION

 but developed

    frank pulmonary oedema
    SYMPTOMS

 and

    cardiogenic shock
    SYMPTOMS

 requiring

    inotropic support and intubation
    MEDICATION

.

    Transthoracic echocardiography
    PARACLINICAL

 demonstrated

    severe left ventricular (LV) cardiomyopathy
    SYMPTOMS

 and an

    apical thrombus
    SYMPTOMS

. Subsequent

    cardiac magnetic resonance (CMR) imaging
    PARACLINICAL

 confirmed the

    LV parameters
    SYMPTOMS

 and

    diffuse late gadolinium enhancement
    SYMPTOMS

.

    Despite absence of skeletal manifestations
    NEG_FINDINGS

, subsequent

    genetic testing
    PARACLINICAL

 revealed an

    X-linked dystrophin gene mutation [c.31+G>T (IVS1G>T)]
    GENETICS

.

    He
    GENDER

 was

    commenced on empirical heart failure therapy
    MEDICATION

 and underwent

    successful cardiac transplantation
    MEDICATION

.

    X-linked
    GENETICS

    dilated cardiomyopathy
    DIAGNOSIS

 is a rare,

    rapidly progressing cardiomyopathy
    DIAGNOSIS

. Patients show

    normal skeletal muscle dystrophin
    NEG_FINDINGS

 but

    absent expression in cardiac muscle
    NEG_FINDINGS

, resulting

    fibrosis
    SYMPTOMS

, and

    atrophy
    SYMPTOMS

. About 20% of affected

    young
    AGE

    males
    GENDER

 have

    significantly reduced survival
    SYMPTOMS

 and thus the diagnosis must be considered in cases of

    idiopathic cardiomyopathy
    DIAGNOSIS

 with

    CMR
    PARACLINICAL

 and

    genetic testing
    PARACLINICAL

 key to the diagnosis. Whilst evidence exists for

    empirical heart failure medications
    MEDICATION

,

    cardiac transplantation
    MEDICATION

 remains the definitive treatment.

X-linked dilated cardiomyopathy (XLDCM)
rapidly progressive cardiomyopathy
Duchenne
Becker Muscular Dystrophy
isolated XLDCM
dilated cardiomyopathy
rapidly progressing cardiomyopathy
idiopathic cardiomyopathy


Preliminary Evidences of Safety and Efficacy of Flavonoids- and Omega 3-Based Compound for Muscular Dystrophies Treatment: A Randomized Double-Blind Placebo Controlled Pilot Clinical Trial.

Background: Nutritional compounds can exert both anti-inflammatory and anti-oxidant effects. Since these events exacerbate the pathophysiology of muscular dystrophies, we investigated nutraceutical supplementation as an adjuvant therapy in dystrophic patients, to low costs and easy route of administration. Moreover, this treatment could represent an alternative therapeutic strategy for dystrophic patients who do not respond to corticosteroid treatment. Objective: A 24 weeks randomized double-blind placebo-controlled clinical study was aimed at evaluating the safety and efficacy of daily oral administration of flavonoids- and omega3-based natural supplement (FLAVOMEGA) in patients affected by muscular dystrophy with recognized muscle inflammation. Design: We screened 60 patients diagnosed for Duchenne (DMD), Facioscapulohumeral (FSHD), and Limb Girdle Muscular Dystrophy (LGMD). Using a computer-generated random allocation sequence, we stratified patients in a 2:1:1 ratio (DMD:FSHD:LGMD) to one of two treatment groups: continuous FLAVOMEGA, continuous placebo. Of 29 patients included, only 24 completed the study: 15 were given FLAVOMEGA, 14 placebo. Results: FLAVOMEGA was well tolerated with no reported adverse events. Significant treatment differences in the change from baseline in 6 min walk distance (6MWD; secondary efficacy endpoint) (P = 0.033) and in isokinetic knee extension (P = 0.039) (primary efficacy endpoint) were observed in LGMD and FSHD subjects. Serum CK levels (secondary efficacy endpoint) decreased in all FLAVOMEGA treated groups with significant difference in DMD subjects (P = 0.039). Conclusions: Although the small number of patients and the wide range of disease severity among patients reduced statistical significance, we obtained an optimal profile of safety and tolerability for the compound, showing valuable data of efficacy in primary and secondary endpoints. Trial registration number: NCT03317171 Retrospectively registered 25/10/2017.

Background:

    Nutritional compounds
    MEDICATION

 can exert

    both anti-inflammatory and anti-oxidant effects
    SYMPTOMS

. Since these events exacerbate the pathophysiology of

    muscular dystrophies
    DIAGNOSIS

, we investigated

    nutraceutical supplementation
    MEDICATION

 as an

    adjuvant therapy
    MEDICATION

 in

    dystrophic
    DIAGNOSIS

 patients, to low costs and easy route of administration. Moreover, this treatment could represent an alternative therapeutic strategy for

    dystrophic
    DIAGNOSIS

 patients who do

    not respond to corticosteroid treatment
    NEG_FINDINGS

. Objective: A 24 weeks randomized double-blind placebo-controlled clinical study was aimed at evaluating the safety and efficacy of

    daily oral administration of flavonoids- and omega3-based natural supplement (FLAVOMEGA)
    MEDICATION

 in patients affected by

    muscular dystrophy
    DIAGNOSIS

 with

    recognized muscle inflammation
    SYMPTOMS

. Design: We screened 60 patients diagnosed for

    Duchenne (DMD), Facioscapulohumeral (FSHD)
    DIAGNOSIS

, and

    Limb Girdle Muscular Dystrophy (LGMD)
    DIAGNOSIS

. Using a computer-generated random allocation sequence, we stratified patients in a 2:1:1 ratio (

    DMD
    DIAGNOSIS

:

    FSHD
    DIAGNOSIS

:

    LGMD
    DIAGNOSIS

) to one of two treatment groups:

    continuous FLAVOMEGA, continuous placebo
    MEDICATION

. Of 29 patients included, only 24 completed the study: 15 were given

    FLAVOMEGA
    MEDICATION

, 14 placebo. Results:

    FLAVOMEGA
    MEDICATION

 was well tolerated with

    no reported adverse events
    NEG_FINDINGS

. Significant treatment differences in the change from baseline

    in 6 min walk distance (6MWD
    SYMPTOMS

; secondary efficacy endpoint) (P = 0.033) and

    in isokinetic knee extension
    SYMPTOMS

 (P = 0.039) (primary efficacy endpoint) were observed in

    LGMD
    DIAGNOSIS

 and

    FSHD
    DIAGNOSIS

 subjects.

    Serum CK levels
    BIOCHEMICAL

 (secondary efficacy endpoint)

    decreased
    BIOCHEMICAL

 in all

    FLAVOMEGA
    MEDICATION

 treated groups with significant difference in

    DMD
    DIAGNOSIS

 subjects (P = 0.039). Conclusions: Although the small number of patients and the wide range of disease severity among patients reduced statistical significance, we obtained an optimal profile of safety and tolerability for the compound, showing valuable data of efficacy in primary and secondary endpoints. Trial registration number: NCT03317171 Retrospectively registered 25/10/2017.

not respond to corticosteroid treatment
no reported adverse events


Recurrent Takotsubo syndrome in a boy with Duchenne muscular dystrophy: A case report.

Takotsubo syndrome is a rare cause of reversible ventricular dysfunction that imitate an acute coronary syndrome. The entity is unusual among pediatric populations and a recurrent episode is extremely rare. We report a case of recurrent takotsubo syndrome in an eight-year-old boy with Duchenne muscular dystrophy (DMD). His chest pain episodes were aggravated by a strong emotional stimuli. During episodes of chest pain, electrocardiograms (ECG) showed ST elevation while echocardiograms showed left ventricle apical ballooning; however, a coronary angiography was normal. Serial ECG and echocardiogram revealed a spontaneous resolution of ST elevation and normalized apical contraction which were compatible with the diagnosis of takotsubo syndrome. Interestingly, serial cardiac magnetic resonance imaging demonstrated increasing subepicardial enhancement which was compatible with progression of cardiac involvement in DMD. <Learning objective: Takotsubo syndrome should be considered in pediatric patients with acute chest pain. A recurrent episode of takotsubo syndrome is rare but is possible in pediatric populations. Patients with inherited muscular dystrophy could also develop takotsubo cardiomyopathy. A growing awareness of this syndrome may help physicians to diagnose and provide an early appropriate management of children with chest pain.>.

    Takotsubo syndrome
    DIAGNOSIS

 is a rare cause of

    reversible ventricular dysfunction
    SYMPTOMS

 that imitate an

    acute coronary syndrome
    SYMPTOMS

. The entity is unusual among

    pediatric
    AGE

 populations and a recurrent episode is extremely rare. We report a case of

    recurrent takotsubo syndrome
    DIAGNOSIS

 in an

    eight-year-old
    AGE

    boy
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. His

    chest pain episodes
    SYMPTOMS

 were

    aggravated by a strong emotional stimuli
    SYMPTOMS

. During

    episodes of chest pain
    SYMPTOMS

,

    electrocardiograms (ECG)
    PARACLINICAL

 showed

    ST elevation
    SYMPTOMS

 while

    echocardiograms
    PARACLINICAL

 showed

    left ventricle apical ballooning
    SYMPTOMS

; however, a

    coronary angiography was normal
    NEG_FINDINGS

.

    Serial ECG and echocardiogram
    PARACLINICAL

 revealed a

    spontaneous resolution of ST elevation
    SYMPTOMS

 and

    normalized apical contraction
    SYMPTOMS

 which were compatible with the diagnosis of

    takotsubo syndrome
    DIAGNOSIS

. Interestingly,

    serial cardiac magnetic resonance imaging
    PARACLINICAL

 demonstrated

    increasing subepicardial enhancement
    SYMPTOMS

 which was compatible with

    progression of cardiac involvement
    SYMPTOMS

 in

    DMD
    DIAGNOSIS

. <Learning objective:

    Takotsubo syndrome
    DIAGNOSIS

 should be considered in

    pediatric
    AGE

 patients with

    acute chest pain
    SYMPTOMS

. A

    recurrent episode of takotsubo syndrome
    DIAGNOSIS

 is rare but is possible in

    pediatric
    AGE

 populations. Patients with

    inherited muscular dystrophy
    DIAGNOSIS

 could also develop

    takotsubo cardiomyopathy
    DIAGNOSIS

. A growing awareness of this syndrome may help physicians to diagnose and provide an early appropriate management of

    children
    AGE

 with

    chest pain
    SYMPTOMS

.>.

Takotsubo syndrome
recurrent takotsubo syndrome
Duchenne muscular dystrophy (DMD)
takotsubo syndrome
DMD
Takotsubo syndrome
recurrent episode of takotsubo syndrome
inherited muscular dystrophy
takotsubo cardiomyopathy


Risk Factors for Cerebral Infarction in Duchenne Muscular Dystrophy: Review With our 2 Cases.

Although the incidence of cerebral infarction is higher in Duchenne muscular dystrophy (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for infarction in this disorder remain lacking.

We encountered 2 cases of Duchenne muscular dystrophy with cerebral infarction. To clarify risk factors for such infarction in Duchenne muscular dystrophy, we reviewed 20 cases, including our 2 patients.

Age at onset of infarction ranged from 4 to 31 years (n = 19). Most patients were 16-21 years old (14 of 19; 73.7%). Eighteen patients (90%) had dilated cardiomyopathy (DCM), showing a higher frequency than in the age-matched general Duchenne muscular dystrophy population. Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%; n = 9). Detectable cardiac thrombus and atrial fibrillation were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively).

Presence of DCM with low LVEF seems to be the strongest risk factor for cerebral infarction in Duchenne muscular dystrophy.

Although the incidence of

    cerebral infarction
    SYMPTOMS

 is higher in

    Duchenne muscular dystrophy
    DIAGNOSIS

 (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for

    infarction
    SYMPTOMS

 in this disorder remain lacking.

We encountered 2 cases of

    Duchenne muscular dystrophy
    DIAGNOSIS

 with

    cerebral infarction
    SYMPTOMS

. To clarify risk factors for such

    infarction
    SYMPTOMS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

, we reviewed 20 cases, including our 2 patients.

    Age at onset of infarction
    AGE

    ranged from 4 to 31 years
    AGE

 (n = 19). Most patients were

    16-21 years old
    AGE

 (14 of 19; 73.7%). Eighteen patients (90%) had

    dilated cardiomyopathy (DCM)
    DIAGNOSIS

, showing a higher frequency than in the age-matched general

    Duchenne muscular dystrophy
    DIAGNOSIS

 population.

    Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%
    SYMPTOMS

; n = 9).

    Detectable cardiac thrombus
    SYMPTOMS

 and

    atrial fibrillation
    SYMPTOMS

 were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively).

    Presence of DCM with low LVEF
    SYMPTOMS

 seems to be the strongest risk factor for

    cerebral infarction
    SYMPTOMS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy
dilated cardiomyopathy (DCM)
Duchenne muscular dystrophy
Duchenne muscular dystrophy


Gigantic Stomach: A Rare Manifestation of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by degeneration and atrophy of skeletal, cardiac, and smooth muscles after a latent period of apparently normal development and function. The gastrointestinal manifestations start in the second decade of life and are mainly due to atrophy of smooth muscle layers. Refractory gastroparesis and chronic constipation can lead to severe gastric and small bowel dilatation, which can be life threatening. Here, we present a case of a 21-year-old male with a gigantic stomach secondary to DMD resolved with conservative management and no surgical intervention.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is characterized by

    degeneration and atrophy of skeletal, cardiac, and smooth muscles
    SYMPTOMS

 after a

    latent period of apparently normal development and function
    NEG_FINDINGS

. The

    gastrointestinal manifestations
    SYMPTOMS

 start in the

    second decade of life
    AGE

 and are mainly due to

    atrophy of smooth muscle layers
    SYMPTOMS

.

    Refractory gastroparesis
    SYMPTOMS

 and

    chronic constipation
    SYMPTOMS

 can lead to

    severe gastric and small bowel dilatation
    SYMPTOMS

, which can be

    life threatening
    SYMPTOMS

. Here, we present a case of a

    21-year-old
    AGE

    male
    GENDER

 with a

    gigantic stomach
    SYMPTOMS

 secondary to

    DMD
    DIAGNOSIS

 resolved with

    conservative management
    MEDICATION

 and

    no surgical intervention
    NEG_FINDINGS

.


Sonoelastography of the trunk and lower extremity muscles in a case of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder typically presenting with muscle weakness and reduced tone of trunk and lower extremities. The sonoelastographic properties of DMD are poorly understood. We describe sonoelastographic characteristics of a patient's trunk and lower extremity musculature. An 8-year-old male presented with a 5-year history of DMD. Sonoelastographic measures of the gluteus maximus and medius, lumbar erector spinae, rectus abdominis, rectus femoris, biceps femoris, tibialis anterior, medial and lateral gastrocnemius muscles were obtained. Sonoelastography demonstrated increased elasticity by elevated kiloPascals (kPa) across all muscles, except the lumbar erector spinae. Patient values were compared to an age-matched healthy control. These abnormal sonoelastographic findings reflected the pathological mechanical properties of DMD. Sonoelastography was valuable for characterizing the mechanical properties of normal and abnormal muscle tissue. There is limited information on the sonoelastography application to DMD. Sonoelastography may serve as a useful measure for diagnosis and monitoring clinical outcomes for DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    rare genetic disorder
    GENETICS

 typically presenting with

    muscle weakness
    SYMPTOMS

 and

    reduced tone of trunk and lower extremities
    SYMPTOMS

. The sonoelastographic properties of

    DMD
    DIAGNOSIS

 are poorly understood. We describe sonoelastographic characteristics of a patient's trunk

    and lower extremity musculature
    SYMPTOMS

. An

    8-year-old
    AGE

    male
    GENDER

 presented with a 5-year history of

    DMD
    DIAGNOSIS

.

    Sonoelastographic measures of the gluteus maximus and medius, lumbar erector spinae, rectus abdominis, rectus femoris, biceps femoris, tibialis anterior, medial and lateral gastrocnemius muscles
    PARACLINICAL

 were obtained.

    Sonoelastography
    PARACLINICAL

 demonstrated

    increased elasticity by elevated kiloPascals (kPa) across all muscles, except the lumbar erector spinae
    SYMPTOMS

. Patient values were compared to an age-matched healthy control. These

    abnormal sonoelastographic findings
    SYMPTOMS

 reflected the

    pathological mechanical properties
    SYMPTOMS

 of

    DMD
    DIAGNOSIS

.

    Sonoelastography
    PARACLINICAL

 was valuable for characterizing the mechanical properties of normal and

    abnormal muscle tissue
    SYMPTOMS

. There is limited information on the

    sonoelastography
    PARACLINICAL

 application to

    DMD
    DIAGNOSIS

.

    Sonoelastography
    PARACLINICAL

 may serve as a useful measure for diagnosis and monitoring clinical outcomes for

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD
DMD
DMD


[Respiratory failure and neurological impairment in a child with Duchenne muscular dystrophy following minor trauma].

Fat Embolism Syndrome (FES) is a rare and often lethal condition, associated with trauma or surgery. It is more serious than a typical fat embolism seen after a fracture in a long bone. FES is a triad of symtoms, including respiratory failure, abnormal neurology and petechial bleeding. FES is a diagnosis of exclusion. The incidence of FES is higher among adults compared to children. One possible explanation for this is the greater proportion of fat in the adult bone marrow. Children with Duchennes muscular dystrophy have a significantly increased risk of FES compared to both other children and adults. There is no specific treatment. Treatment is supportive until the respiratory and cardiovasculatory symtoms pass.

    Fat Embolism Syndrome (FES)
    DIAGNOSIS

 is a rare and often lethal condition, associated with

    trauma
    MEDICATION

 or

    surgery
    MEDICATION

. It is more serious than a typical

    fat embolism
    SYMPTOMS

 seen after a

    fracture in a long bone
    SYMPTOMS

.

    FES
    DIAGNOSIS

 is a triad of

    symtoms
    SYMPTOMS

, including

    respiratory failure
    SYMPTOMS

,

    abnormal neurology
    SYMPTOMS

 and

    petechial bleeding
    SYMPTOMS

.

    FES
    DIAGNOSIS

 is a diagnosis of exclusion. The incidence of

    FES
    DIAGNOSIS

 is higher among

    adults
    AGE

 compared to

    children
    AGE

. One possible explanation for this is the

    greater proportion of fat in the adult bone marrow
    MICROSCOPIC

.

    Children
    AGE

 with

    Duchennes muscular dystrophy
    DIAGNOSIS

 have a significantly increased risk of

    FES
    DIAGNOSIS

 compared to both other

    children
    AGE

 and

    adults
    AGE

. There is no specific treatment. Treatment is supportive until the

    respiratory and cardiovasculatory symtoms pass
    SYMPTOMS

.

Fat Embolism Syndrome (FES)
FES
FES
FES
Duchennes muscular dystrophy
FES


Urine mRNA to identify a novel pseudoexon causing dystrophinopathy.

In muscular dystrophies, identification of pathogenic pseudoexons involves sequencing of the target gene cDNA derived from muscle mRNA. Here we use a urine "liquid biopsy," droplet digital PCR, and sequencing of PCR products to identify a novel cryptic splice site in DMD intron 67 that causes dystrophinopathy. Pseudoexon inclusion is 35% in urine cells, 34% in urine extracellular RNA (exRNA), and 54% in muscle biopsy tissue, but absent in serum exRNA. Our results suggest that cryptic splice site use varies depending on the RNA source, and that urine RNA has the potential to substitute for muscle biopsies to identify DMD pseudoexons.

In

    muscular dystrophies
    DIAGNOSIS

, identification of

    pathogenic pseudoexons
    GENETICS

 involves

    sequencing of the target gene cDNA derived from muscle mRNA
    PARACLINICAL

. Here we use a

    urine "liquid biopsy
    PARACLINICAL

,"

    droplet digital PCR
    PARACLINICAL

, and

    sequencing of PCR products
    PARACLINICAL

 to identify a

    novel cryptic splice site in DMD intron 67
    GENETICS

 that causes

    dystrophinopathy
    DIAGNOSIS

.

    Pseudoexon inclusion is 35% in urine cells, 34% in urine extracellular RNA (exRNA), and 54% in muscle biopsy tissue
    MICROSCOPIC

, but

    absent in serum exRNA
    BIOCHEMICAL

. Our results suggest that cryptic splice site use varies depending on the RNA source, and that

    urine RNA
    PARACLINICAL

 has the potential to substitute for

    muscle biopsies
    PARACLINICAL

 to identify

    DMD pseudoexons
    GENETICS

.


Pneumothorax in neuromuscular disease associated with lung volume recruitment and mechanical insufflation-exsufflation.

A 25-year-old male with Duchenne muscular dystrophy and a 73-year-old male with motor neurone disease both presented with chest pain and increasing dyspnoea following routine mechanical insufflation-exsufflation or lung volume recruitment, on a background of long-term non-invasive ventilation. In each case, chest radiograph revealed a pneumothorax. In both cases the pneumothorax fully resolved following insertion of an intercostal catheter. There was no immediate recurrence and the patients were discharged home and ceased ongoing prophylactic respiratory therapy, although one person had recurrent pneumothoraces subsequently. This rare but serious complication highlights the need for careful risk/benefit analysis by clinicians prescribing these therapies.

A

    25-year-old
    AGE

    male
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 and a

    73-year-old
    AGE

    male
    GENDER

 with

    motor neurone disease
    DIAGNOSIS

 both presented with

    chest pain
    SYMPTOMS

 and

    increasing dyspnoea
    SYMPTOMS

 following

    routine mechanical insufflation-exsufflation or lung volume recruitment
    MEDICATION

, on a background of

    long-term non-invasive ventilation
    MEDICATION

. In each case,

    chest radiograph
    PARACLINICAL

 revealed a

    pneumothorax
    DIAGNOSIS

. In both cases the

    pneumothorax fully resolved
    SYMPTOMS

 following

    insertion of an intercostal catheter
    MEDICATION

. There was

    no immediate recurrence
    NEG_FINDINGS

 and the patients were

    discharged home
    MEDICATION

 and

    ceased ongoing prophylactic respiratory therapy
    NEG_FINDINGS

, although one person had

    recurrent pneumothoraces
    SYMPTOMS

 subsequently. This rare but serious complication highlights the need for careful risk/benefit analysis by clinicians prescribing these therapies.

Duchenne muscular dystrophy
motor neurone disease
pneumothorax

chest pain
increasing dyspnoea
pneumothorax fully resolved
recurrent pneumothoraces