The long dystrophin gene product Dp427 modulates retinal function and vascular morphology in response to age and retinal ischemia.

Mutations in dystrophin are the major cause of muscular dystrophies. Continuous muscular degeneration and late stage complications, including cardiomyopathy and respiratory insufficiency, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex. Multiple tissue-specific dystrophin gene products are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to secondary complications in non-muscular tissues. In this study, we evaluated the impact of the full-length dystrophin gene product, Dp427, on retinal homeostasis and angiogenesis. Based on the clinical case of a Duchenne muscular dystrophy (DMD) patient who developed severe fibrovascular changes in the retina in response to hypoxic stress, we hypothesized that defects in Dp427 make the retina more susceptible to stresses such as ageing and ischemia. To further study this, a mouse strain lacking Dp427 expression (Mdx) was studied during retinal development, ageing and in the oxygen-induced retinopathy (OIR) model. While retinal vascular morphology was normal during development and ageing, retinal function measured by electroretinography (ERG) was slightly reduced in young adult Mdx mice and deteriorated with age. Mdx mice also had increased retinal neovascularization in response to OIR and more pronounced long-term deterioration in retinal function following OIR. Based on these results, we suggest that DMD patients with a mutation in Dp427 may experience disturbed retinal homeostasis with increasing age and therefore be prone to develop excessive retinal neovascular changes in response to hypoxic stress. DMD patients in late disease stages should, thus, be regularly examined to detect asymptomatic retinal abnormalities and prevent visual impairment.

    Mutations in dystrophin
    GENETICS

 are the major cause of

    muscular dystrophies
    DIAGNOSIS

.

    Continuous muscular degeneration
    SYMPTOMS

 and

    late stage complications
    SYMPTOMS

, including

    cardiomyopathy
    SYMPTOMS

 and

    respiratory insufficiency
    SYMPTOMS

, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex.

    Multiple tissue-specific dystrophin gene products
    GENETICS

 are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to

    secondary complications in non-muscular tissues
    SYMPTOMS

. In this study, we evaluated the impact of the full-length dystrophin gene product

    , Dp427
    GENETICS

, on retinal homeostasis and

    angiogenesis
    SYMPTOMS

. Based on the clinical case of a

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patient who developed

    severe fibrovascular changes in the retina in response to hypoxic stress
    SYMPTOMS

, we hypothesized that

    defects in Dp427
    GENETICS

 make the retina more susceptible to stresses such as

    ageing
    SYMPTOMS

 and

    ischemia
    SYMPTOMS

. To further study this, a mouse strain

    lacking Dp427 expression
    GENETICS

 (

    Mdx
    GENDER

) was studied during retinal development, ageing and in the

    oxygen-induced retinopathy (
    DIAGNOSIS

OIR) model. While

    retinal vascular morphology was normal during development and ageing
    NEG_FINDINGS

,

    retinal function measured by electroretinography (ERG) was slightly reduced
    SYMPTOMS

 in

    young adult Mdx mice
    AGE

 and deteriorated with

    age
    AGE

.

    Mdx
    GENDER

 mice also had

    increased retinal neovascularization in response to OIR
    SYMPTOMS

 and

    more pronounced long-term deterioration in retinal function following OIR
    SYMPTOMS

. Based on these results, we suggest that

    DMD
    DIAGNOSIS

 patients with a

    mutation in Dp427
    GENETICS

 may experience

    disturbed retinal homeostasis
    SYMPTOMS

 with increasing age and therefore be prone to develop

    excessive retinal neovascular changes
    SYMPTOMS

 in response to

    hypoxic stress
    SYMPTOMS

.

    DMD
    DIAGNOSIS

 patients in late disease stages should, thus, be regularly examined to detect

    asymptomatic retinal abnormalities
    SYMPTOMS

 and prevent

    visual impairment
    SYMPTOMS

.

muscular dystrophies
Duchenne muscular dystrophy (DMD)
oxygen-induced retinopathy (
DMD
DMD


Skipping of an exon with a nonsense mutation in the DMD gene is induced by the conversion of a splicing enhancer to a splicing silencer.

Modulation of dystrophin pre-mRNA splicing is an attractive strategy to ameliorate the severe phenotype of Duchenne muscular dystrophy (DMD), although this requires a better understanding of the mechanism of splicing regulation. Aberrant splicing caused by gene mutations provides a good model to study splicing regulatory cis-elements and binding proteins. In this study, we identified skipping of in-frame exon 25 induced by a nonsense mutation (NM_004006.2:c.3340A > T;p.Lys1114*) in the DMD gene. Site-directed mutagenesis study in minigenes suggested that c.3340A > T converts an exonic splicing enhancer sequence (ESE) to a silencer element (ESS). Indeed, RNA pull-down and functional study provided evidence that c.3340A > T abolishes the binding of the splicing enhancer protein Tra2β and promotes interactions with the repressor proteins hnRNP A1, hnRNP A2, and hnRNP H. By carefully analyzing the sequence motif encompassing the mutation site, we concluded that the skipping of exon 25 was due to disruption of a Tra2β-dependent ESE and the creation of a new ESS associated with hnRNP A1 and hnRNP A2, which in turn increased the recruitment of hnRNP H to a nearby binding site. Finally, we demonstrated that c.3340A > T impairs the splicing of upstream intron 24 in a splicing minigene assay. In addition, we showed that the correct splicing of exon 25 is finely regulated by multiple splicing regulators that function in opposite directions by binding to closely located ESE and ESS. Our results clarify the detailed molecular mechanism of exon skipping induced by the nonsense mutation c.3340A > T and also provide information on exon 25 splicing.

Modulation of dystrophin pre-mRNA splicing is an attractive strategy to ameliorate the severe phenotype of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, although this requires a better understanding of the mechanism of splicing regulation.

    Aberrant splicing
    GENETICS

 caused by

    gene mutations
    GENETICS

 provides a good model to study splicing regulatory cis-elements and binding proteins. In this study, we identified

    skipping of in-frame exon 25
    GENETICS

 induced by a

    nonsense mutation (NM_004006.2:c.3340A > T;p.Lys1114*) in the DMD gene
    GENETICS

.

    Site-directed mutagenesis study in minigenes
    PARACLINICAL

 suggested that

    c.3340A > T converts an exonic splicing enhancer sequence (ESE) to a silencer element (ESS)
    GENETICS

. Indeed,

    RNA pull-down and functional study
    PARACLINICAL

 provided evidence that

    c.3340A > T abolishes the binding of the splicing enhancer protein Tra2β
    GENETICS

 and promotes interactions with the repressor proteins

    hnRNP A1, hnRNP A2
    BIOCHEMICAL

, and hnRNP H. By

    carefully analyzing the sequence motif encompassing the mutation site
    PARACLINICAL

, we concluded that the

    skipping of exon 25
    GENETICS

 was due to

    disruption of a Tra2β-dependent ESE and the creation of a new ESS associated with hnRNP A1 and hnRNP A2
    GENETICS

, which in turn increased the recruitment of hnRNP H to a nearby binding site. Finally, we demonstrated that

    c.3340A > T impairs the splicing of upstream intron 24
    GENETICS

 in a

    splicing minigene assay
    PARACLINICAL

. In addition, we showed that the

    correct splicing of exon 25
    GENETICS

 is finely regulated by multiple splicing regulators that function in opposite directions by binding to closely located ESE and ESS. Our results clarify the detailed molecular mechanism of

    exon skipping
    GENETICS

 induced by the

    nonsense mutation c.3340A > T
    GENETICS

 and also provide information on exon 25 splicing.


Rapidly Progressive Heart Failure in a Female Carrier of Becker Muscular Dystrophy with No Skeletal Muscle Symptoms.

Becker muscular dystrophy (BMD) carriers are at risk to developing cardiac dysfunction. The prevalence of female BMD carriers remains underestimated, and the disease progression varies. We herein report the case of a young female BMD carrier who developed dilated cardiomyopathy (DCM) and heart failure without any skeletal muscle signs. Her cardiac dysfunction progressed over a mere two months, resulting in the need for left ventricular assist device implantation. Her case demonstrates that progressive cardiomyopathy can be the only clinical manifestation in some BMD carriers, suggesting the need for a more aggressive implementation of genetic testing in female DCM patients.

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 carriers are at risk to developing

    cardiac dysfunction
    SYMPTOMS

. The prevalence of

    female
    GENDER

    BMD
    DIAGNOSIS

 carriers remains underestimated, and the disease progression varies. We herein report the case of a

    young
    AGE

    female
    GENDER

    BMD
    DIAGNOSIS

 carrier who developed

    dilated cardiomyopathy (DCM)
    DIAGNOSIS

 and

    heart failure
    SYMPTOMS

    without any skeletal muscle signs
    NEG_FINDINGS

.

    Her
    GENDER

    cardiac dysfunction progressed over a mere two months
    SYMPTOMS

, resulting in the need for

    left ventricular assist device implantation
    MEDICATION

.

    Her
    GENDER

 case demonstrates that

    progressive cardiomyopathy
    SYMPTOMS

 can be the only clinical manifestation in some

    BMD
    DIAGNOSIS

 carriers, suggesting the need for a more aggressive implementation of

    genetic testing
    PARACLINICAL

 in

    female
    GENDER

    DCM
    DIAGNOSIS

 patients.

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


A successful antibiotic treatment by a new administration route: a case report of a subcutaneous administration of ceftazidime and tobramycin.

When intramuscular or intravenous administrations of parenteral drugs are not possible, the use of other routes (e.g., subcutaneous route) should be considered. We report a patient with Duchenne muscular dystrophy, who was hospitalized for acute pneumonia due to antibiotic-resistant strains of bacteria. Our patient was successfully recovered with antimicrobial therapy by subcutaneous administration of ceftazidime and tobramycin, for which no safety and efficacy data are available in humans. To the best of our knowledge, this case is the first supporting the subcutaneous administration safety and potential efficacy of both ceftazidime and tobramycin in humans.

When

    intramuscular or intravenous administrations of parenteral drugs
    NEG_FINDINGS

 are not possible, the use of other routes (e.g., subcutaneous route) should be considered. We report a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

, who was hospitalized for

    acute pneumonia
    DIAGNOSIS

 due to

    antibiotic-resistant strains of bacteria
    SYMPTOMS

. Our patient was successfully recovered with

    antimicrobial therapy by subcutaneous administration of ceftazidime and tobramycin
    MEDICATION

, for which no safety and efficacy data are available in humans. To the best of our knowledge, this case is the first supporting the

    subcutaneous administration
    MEDICATION

 safety and potential efficacy

    of both ceftazidime and tobramycin
    MEDICATION

 in humans.

Duchenne muscular dystrophy
acute pneumonia


Therapeutic approach with Ataluren in Duchenne symptomatic carriers with nonsense mutations in dystrophin gene. Results of a 9-month follow-up in a case report.

Duchenne muscular Dystrophy (DMD) is a X-linked degenerative disorder affecting skeletal muscles and myocardium caused by mutations in the dystrophin gene, mainly deletions and duplications. Point-mutations account for 13% and stop codon mutations are even more unfrequent. A drug treatment for patients with DMD caused by stop codon gene mutations and still ambulant, has become recently available, based on the clear demonstration of its efficacy in slowing the course of the disease. The drug is able to read through the stop codon; furthermore it has the advantage of an oral administration and a better patient's compliance. We report a case of a still ambulant 27 year-old DMD symptomatic carrier with a stop-codon mutation in exon 53 (c.7792C > T; p.Gln2598Stop), who started the treatment with Ataluren at a dosage of 2,250 mg/die, reporting a prompt subjective improvement in muscle strength. Unfortunately two months after, the patient discontinued taking the drug for a traumatic femur fracture requiring surgical repair and prolonged rehabilitation. With the resumption of the drug intake in February 2018, the patient reported almost immediately an improvement in motor skills, including the possibility of recovering walking, first with support and then unsupported. These results seem even more encouraging, as Duchenne patients hardly recover the ability to walk following a fracture at this age and extend the possibility to treat with ataluren also the symptomatic Duchenne carriers who have nonsense dystrophin gene mutations. Furthermore the case here reported supports the concept that symptomatic DMD female carriers must enjoy the same therapeutic opportunities offered to males.

    Duchenne muscular Dystrophy (DMD)
    DIAGNOSIS

 is a

    X-linked
    GENETICS

    degenerative disorder
    DIAGNOSIS

    affecting skeletal muscles and myocardium
    SYMPTOMS

 caused by

    mutations in the dystrophin gene
    GENETICS

, mainly

    deletions and duplications
    GENETICS

.

    Point-mutations
    GENETICS

 account for 13% and

    stop codon mutations
    GENETICS

 are even more unfrequent. A drug treatment for patients with

    DMD
    DIAGNOSIS

 caused by

    stop codon gene mutations
    GENETICS

 and still ambulant, has become recently available, based on the clear demonstration of its efficacy in slowing the course of the disease. The drug is able to read through the stop codon; furthermore it has the advantage of an

    oral administration
    MEDICATION

 and a better patient's compliance. We report a case of a

    still ambulant
    AGE

    27 year-old
    AGE

    DMD
    DIAGNOSIS

 symptomatic carrier with a

    stop-codon mutation in exon 53 (c.7792C > T; p.Gln2598Stop)
    GENETICS

, who started the

    treatment with Ataluren at a dosage of 2,250 mg/die
    MEDICATION

, reporting a

    prompt subjective improvement in muscle strength
    SYMPTOMS

. Unfortunately two months after, the patient

    discontinued taking the drug for a traumatic femur fracture requiring surgical repair and prolonged rehabilitation
    NEG_FINDINGS

. With the

    resumption of the drug intake
    MEDICATION

 in February 2018, the patient reported almost immediately an

    improvement in motor skills, including the possibility of recovering walking, first with support and then unsupported
    SYMPTOMS

. These results seem even more encouraging, as

    Duchenne
    DIAGNOSIS

 patients

    hardly recover the ability to walk following a fracture
    NEG_FINDINGS

 at

    this age
    AGE

 and extend the possibility to treat with

    ataluren
    MEDICATION

 also the symptomatic

    Duchenne
    DIAGNOSIS

 carriers who have

    nonsense dystrophin gene mutations
    GENETICS

. Furthermore the case here reported supports the concept that symptomatic

    DMD
    DIAGNOSIS

    female
    GENDER

 carriers must enjoy the same therapeutic opportunities offered to

    males
    GENDER

.

Duchenne muscular Dystrophy (DMD)
degenerative disorder
DMD
DMD
Duchenne
Duchenne
DMD


Application whole exome sequencing for the clinical molecular diagnosis of patients with Duchenne muscular dystrophy; identification of four novel nonsense mutations in four unrelated Chinese DMD patients.

Duchenne muscular dystrophy (DMD) is the most common form of inherited muscular dystrophy. Germline mutations in dystrophin (DMD) gene cause DMD, with a X-linked recessive mode of inheritance. Patients with DMD are usually characterized by weakness of muscle, usually started since childhood and gradually the patient will unable to stand and walk.

In our present study, we identified four unrelated Chinese patients with DMD from four Chinese families. Whole exome sequencing was performed for genetic molecular analysis for these probands.

Whole exome sequencing and confirmatory Sanger sequencing identified four novel nonsense mutations in these four unrelated Chinese patients, respectively. All these four mutations lead to the formation of a truncated DMD protein by formation of a premature stop codon. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG), these four novel nonsense mutations are categorized as "likely pathogenic" variants.

Our present finding not only identified four novel loss-of-function mutations in dystrophin (DMD) gene but also strongly emphasized the significance of whole exome sequencing as the most efficient way of identifying the candidate genes and mutations which enables us for easy and rapid clinical diagnosis, follow-up, and management of DMD patients.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common form of

    inherited muscular dystrophy
    DIAGNOSIS

.

    Germline mutations in dystrophin (DMD) gene
    GENETICS

 cause

    DMD
    DIAGNOSIS

, with a

    X-linked recessive mode of inheritance
    GENETICS

. Patients with

    DMD
    DIAGNOSIS

 are usually characterized by

    weakness of muscle
    SYMPTOMS

, usually started since

    childhood
    AGE

 and gradually the patient will

    unable to stand and walk
    NEG_FINDINGS

.

In our present study, we identified four unrelated

    Chinese
    ETHNICITY

 patients with

    DMD
    DIAGNOSIS

 from four

    Chinese
    ETHNICITY

 families.

    Whole exome sequencing
    PARACLINICAL

 was performed for

    genetic molecular analysis
    PARACLINICAL

 for these probands.

    Whole exome sequencing and confirmatory Sanger sequencing
    PARACLINICAL

 identified four

    novel nonsense mutations
    GENETICS

 in these four unrelated

    Chinese
    ETHNICITY

 patients, respectively. All these four mutations lead to the formation of a

    truncated DMD protein by formation of a premature stop codon
    GENETICS

. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG), these four

    novel nonsense mutations
    GENETICS

 are categorized as "likely pathogenic" variants.

Our present finding not only identified

    four novel loss-of-function mutations in dystrophin (DMD) gene
    GENETICS

 but also strongly emphasized the significance of

    whole exome sequencing
    PARACLINICAL

 as the most efficient way of identifying the candidate genes and mutations which enables us for easy and rapid clinical diagnosis, follow-up, and management of

    DMD
    DIAGNOSIS

 patients.

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


First familial Becker muscular dystrophy in Tanzania: Clinical and genetic features.

In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders.

In

    African
    ETHNICITY

 neurological practice,

    muscle disorders
    DIAGNOSIS

 are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common

    neurological disorders
    DIAGNOSIS

. In this report we describe the first

    Tanzanian
    ETHNICITY

 patient with genetically confirmed

    Becker muscular dystrophy
    DIAGNOSIS

.

    His
    GENDER

 phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his

    progressive weakness of the legs
    SYMPTOMS

 with

    difficulty in walking only after a fall
    SYMPTOMS

. We demonstrate that

    muscular dystrophies
    DIAGNOSIS

 occur in

    sub-Saharan Africa
    ETHNICITY

.

    Neurologists
    PARACLINICAL

 must however be aware that patients are likely to delay seeking medical care for

    muscle disorders
    DIAGNOSIS

.

muscle disorders
neurological disorders
Becker muscular dystrophy
muscular dystrophies
muscle disorders

progressive weakness of the legs
difficulty in walking only after a fall


The intracellular Ca2+ concentration is elevated in cardiomyocytes differentiated from hiPSCs derived from a Duchenne muscular dystrophy patient.

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy. The major symptoms of this condition are walking difficulties, dyspnea caused by progressive skeletal muscle weakness, and cardiomyopathy. Recent advances in ventilator support devices have dramatically decreased mortality caused by respiratory distress. Consequently, cardiomyopathy resulting in heart failure is currently the major cause of death among DMD patients. One mechanism by which skeletal muscle is damaged in DMD patients involves elevation of the intracellular Ca2+ concentration. By contrast, the mechanisms underlying the development of cardiomyopathy are unclear. To investigate this, we examined the intracellular Ca2+ concentration and calcium transients in cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs). hiPSCs were derived from a DMD patient (DMD-hiPSCs), in whom exon 44 of the gene encoding dystrophin was deleted, and from his parents (control-hiPSCs), who did not carry this mutation. The intracellular Ca2+ concentration was measured using the fluorescent indicator indo-1. The fluorescence ratio (410/490 nm) of indo-1 at rest (R0), the peak of this ratio (Rmax), and the amplitude (Rmax-R0) were significantly higher in cardiomyocytes differentiated from DMD-hiPSCs than in those differentiated from control-hiPSCs. Moreover, mechanical stretching significantly increased the intracellular Ca2+ concentration in cardiomyocytes differentiated from DMD-hiPSCs, but not in those differentiated from control-hiPSCs. These findings indicate that elevation of the intracellular Ca2+ concentration can cause cardiac damage leading to cardiomyopathy in DMD patients.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common and severe form of

    muscular dystrophy
    DIAGNOSIS

. The major symptoms of this condition are

    walking difficulties
    SYMPTOMS

,

    dyspnea
    SYMPTOMS

 caused by

    progressive skeletal muscle weakness
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

. Recent advances in

    ventilator support devices
    MEDICATION

 have dramatically decreased mortality caused by

    respiratory distress
    SYMPTOMS

. Consequently,

    cardiomyopathy
    DIAGNOSIS

 resulting in

    heart failure
    SYMPTOMS

 is currently the major cause of

    death
    SYMPTOMS

 among

    DMD
    DIAGNOSIS

 patients. One mechanism by which

    skeletal muscle is damaged
    SYMPTOMS

 in

    DMD
    DIAGNOSIS

 patients involves

    elevation of the intracellular Ca2+ concentration
    BIOCHEMICAL

. By contrast, the mechanisms underlying the development of

    cardiomyopathy
    DIAGNOSIS

 are unclear. To investigate this, we examined the intracellular Ca2+ concentration and calcium transients in

    cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs)
    MICROSCOPIC

.

    hiPSCs
    MICROSCOPIC

 were derived from a

    DMD
    DIAGNOSIS

 patient (DMD-hiPSCs), in whom

    exon 44 of the gene encoding dystrophin was deleted
    GENETICS

, and from his parents (control-hiPSCs), who

    did not carry this mutation
    FAMILY

. The intracellular Ca2+ concentration was measured using the fluorescent indicator indo-1. The fluorescence ratio (410/490 nm) of indo-1 at rest (R0), the peak of this ratio (Rmax), and the amplitude (Rmax-R0) were significantly higher in

    cardiomyocytes differentiated from DMD-hiPSCs
    MICROSCOPIC

 than in those differentiated from control-hiPSCs. Moreover,

    mechanical stretching
    MEDICATION

 significantly

    increased the intracellular Ca2+ concentration
    BIOCHEMICAL

 in

    cardiomyocytes differentiated from DMD-hiPSCs
    MICROSCOPIC

, but not in those differentiated from control-hiPSCs. These findings indicate that

    elevation of the intracellular Ca2+ concentration
    BIOCHEMICAL

 can cause

    cardiac damage
    SYMPTOMS

 leading to

    cardiomyopathy
    DIAGNOSIS

 in

    DMD
    DIAGNOSIS

 patients.

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

walking difficulties
dyspnea
progressive skeletal muscle weakness
cardiomyopathy
respiratory distress
heart failure
death
skeletal muscle is damaged
cardiac damage

ventilator support devices
mechanical stretching


Levosimendan as Rescue Therapy for Acute Heart Failure in a Patient with Duchenne Muscular Dystrophy.

The longer survival of patients with Duchenne muscular dystrophy due to advances in clinical care has increased the incidence of Duchenne muscular dystrophy-associated cardiomyopathy, a nearly consistent feature in the third decade of life. A 26-year-old patient with Duchenne muscular dystrophy experienced severe acute heart failure triggered by pneumonia. Levosimendan was effective in improving heart function.

The longer survival of patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 due to advances in clinical care has increased the incidence of

    Duchenne muscular dystrophy-associated cardiomyopathy
    DIAGNOSIS

, a nearly consistent feature in the

    third decade of life
    AGE

. A

    26-year-old
    AGE

 patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 experienced

    severe acute heart failure
    SYMPTOMS

 triggered by

    pneumonia
    SYMPTOMS

.

    Levosimendan
    MEDICATION

 was effective in

    improving heart function
    SYMPTOMS

.

severe acute heart failure
pneumonia
improving heart function


Use of home telemedicine for critical illness rehabilitation: an Indian success story.

One-fifth of healthcare beneficiaries in developed nations get discharged from hospitals to physician supervised skilled nursing care facilities. In low-income and middle-income countries like India, postdischarge skilled nursing facilities are at a very nascent stage and largely underequipped in terms of infrastructure, skilled nursing and physician staff to manage complicated patients. Hence the responsibility of management of such patients lies largely with their families. We present a case where a 26-year-old man with Duchenne Muscular Dystrophy who became ventilator dependent following major surgeries was weaned off his ventilator and rehabilitated back to his prehospital state. This was done at his home with visiting nurses and rehabilitation services under telemedicine supervision by a critical care specialist. Use of telemedicine services could be a viable and cost-effective option to ensure adherence to evidence-based medicine and standardisation of care in resource limited countries such as India.

One-fifth of healthcare beneficiaries in developed nations get

    discharged from hospitals to physician supervised skilled nursing care facilities
    MEDICATION

. In low-income and middle-income countries like

    India
    ETHNICITY

,

    postdischarge skilled nursing facilities
    MEDICATION

 are at a very nascent stage and largely underequipped in terms of infrastructure, skilled nursing and physician staff to manage complicated patients. Hence the responsibility of management of such patients lies largely with their families. We present a case where a

    26-year-old
    AGE

    man
    GENDER

 with

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 who became

    ventilator dependent
    MEDICATION

 following

    major surgeries
    MEDICATION

 was

    weaned off his ventilator and rehabilitated back to his prehospital state
    MEDICATION

. This was done at his

    home with visiting nurses and rehabilitation services
    MEDICATION

 under

    telemedicine supervision
    MEDICATION

 by a

    critical care specialist
    PARACLINICAL

. Use of

    telemedicine services
    MEDICATION

 could be a viable and cost-effective option to ensure adherence to evidence-based medicine and standardisation of care in resource limited countries such as

    India
    ETHNICITY

.


Coexistence of a CAV3 mutation and a DMD deletion in a family with complex muscular diseases.

Whole-exome sequencing (WES) can comprehensively detect both pathogenic single nucleotide variants and copy number variants, enabling identification of a coexistence of two or more genetic etiologies. Here we report a family consisting of individuals with Becker muscular dystrophy and rippling muscle disease. The proband, a 12-year-old boy, was diagnosed with Becker muscular dystrophy with exon 45-55 DMD deletions at age 4. He had myalgia and muscle stiffness. Interestingly, percussion-induced muscle mounding (PIMM), which is a characteristic of rippling muscle disease, was also observed. The father also showed muscle stiffness, myalgia, fatigability, muscle rippling and PIMM. WES revealed a missense CAV3 mutation (NM_033337.2:c.80G>A) in the proband, the father, the oldest sister and the grandmother, who had an elevated serum creatine kinase (CK) level. The c.80G>A mutation was considered pathogenic according to ACMG guidelines. The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation and had normal CK. Using two programs for copy number analysis with WES data, we successfully identified the DMD deletion in the proband, the older sister and the mother. We revealed the coexistence of the CAV3 mutation and the DMD deletion in a family with complex muscular diseases and confirmed the usefulness of WES for elucidating such etiology.

    Whole-exome sequencing (WES)
    PARACLINICAL

 can comprehensively detect both

    pathogenic single nucleotide variants and copy number variants
    GENETICS

, enabling identification of a coexistence of two or more

    genetic etiologies
    GENETICS

. Here we report a family consisting of individuals with

    Becker muscular dystrophy
    DIAGNOSIS

 and

    rippling muscle disease
    DIAGNOSIS

. The

    proband
    GENDER

, a

    12-year-old
    AGE

    boy
    GENDER

, was diagnosed with

    Becker muscular dystrophy
    DIAGNOSIS

 with

    exon 45-55 DMD deletions
    GENETICS

 at

    age 4
    AGE

.

    He
    GENDER

 had

    myalgia
    SYMPTOMS

 and

    muscle stiffness
    SYMPTOMS

. Interestingly,

    percussion-induced muscle mounding (PIMM)
    SYMPTOMS

, which is a characteristic of

    rippling muscle disease
    SYMPTOMS

, was also observed. The

    father
    GENDER

 also showed

    muscle stiffness
    SYMPTOMS

,

    myalgia
    SYMPTOMS

,

    fatigability
    SYMPTOMS

,

    muscle rippling
    SYMPTOMS

 and

    PIMM
    SYMPTOMS

.

    WES
    PARACLINICAL

 revealed a

    missense CAV3 mutation (NM_033337.2:c.80G>A)
    GENETICS

    in the proband, the father, the oldest sister and the grandmother
    FAMILY

, who had an

    elevated serum creatine kinase (CK) level
    BIOCHEMICAL

. The

    c.80G>A mutation
    GENETICS

 was considered pathogenic according to ACMG guidelines.

    The second older sister, the mother and the paternal grandfather did not have the CAV3 mutation
    FAMILY

 and

    had normal CK
    NEG_FINDINGS

. Using

    two programs for copy number analysis with WES data
    PARACLINICAL

, we successfully identified

    the DMD deletion in the proband, the older sister and the mother
    FAMILY

. We revealed the

    coexistence of the CAV3 mutation and the DMD deletion
    GENETICS

 in a

    family with complex muscular diseases
    FAMILY

 and confirmed the usefulness of

    WES
    PARACLINICAL

 for elucidating such etiology.

Becker muscular dystrophy
rippling muscle disease
Becker muscular dystrophy


[Two cases of rare diseases with abnormalities of X chromosome].

To explore the clinical features and genetic diagnosis of two cases with rare diseases and X chromosome abnormalities.

Multiple ligation-dependent probe amplification (MLPA) and karyotype analysis were carried out on an 8-year-old girl who was diagnosed with Duchenne muscular dystrophy. Karyotype analysis and PCR assay for SRY and AZF genes were carried out for a-2-month-old male infant with short penis.

The girl, who featured short stature and cubitus valgus, was diagnosed as Turner syndrome with a karyotype of 46,X,i(Xq). The male infant was detected with a karyotype of 45,X, with presence of SRY gene but absence of AZF gene.

Both cases may be associated with abnormalities of X chromosome. Genetic testing can facilitate early diagnosis and clinical intervention for such patients.

To explore the clinical features and

    genetic diagnosis
    PARACLINICAL

 of two cases with

    rare diseases
    DIAGNOSIS

 and

    X chromosome abnormalities
    GENETICS

.

    Multiple ligation-dependent probe amplification (MLPA)
    PARACLINICAL

 and

    karyotype analysis
    PARACLINICAL

 were carried out on an

    8-year-old
    AGE

    girl
    GENDER

 who was diagnosed with

    Duchenne muscular dystrophy
    DIAGNOSIS

.

    Karyotype analysis
    PARACLINICAL

 and

    PCR assay for SRY and AZF genes
    PARACLINICAL

 were carried out for a-2-month-old

    male
    GENDER

    infant
    AGE

 with

    short penis
    SYMPTOMS

.

The

    girl
    GENDER

, who featured

    short stature
    SYMPTOMS

 and

    cubitus valgus
    SYMPTOMS

, was diagnosed as

    Turner syndrome
    DIAGNOSIS

 with a

    karyotype of 46,X,i(Xq)
    GENETICS

. The

    male
    GENDER

    infant
    AGE

 was detected with a

    karyotype of 45,X
    GENETICS

, with

    presence of SRY gene
    GENETICS

 but

    absence of AZF gene
    GENETICS

.

Both cases may be associated with

    abnormalities of X chromosome
    GENETICS

.

    Genetic testing
    PARACLINICAL

 can facilitate early diagnosis and

    clinical intervention
    MEDICATION

 for such patients.

rare diseases
Duchenne muscular dystrophy
Turner syndrome

X chromosome abnormalities
karyotype of 46,X,i(Xq)
karyotype of 45,X
presence of SRY gene
absence of AZF gene
abnormalities of X chromosome

short penis
short stature
cubitus valgus


DP71 and SERCA2 alteration in human neurons of a Duchenne muscular dystrophy patient.

Cognitive deficit has been identified in one third of patients affected by Duchenne Muscular Dystrophy, primarily attributed to loss of the short Dp71 dystrophin, the major brain dystrophin isoform. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in human neurons obtained by differentiation from induced pluripotent stem cell line of a patient affected by cognitive impairment. We found structural and molecular alterations in both pluripotent stem cell and derived neurons, reduced Dp71 expression, and a Ca2+ cytoplasmic overload in neurons coupled with increased expression of the SERCA2 pump in the dystrophic neurons. These results suggest that the reduction of Dp71 protein in the Duchenne muscular dystrophy neurons leads to alterations in SERCA2 and to elevated cytosolic Ca2+ concentration with consequent potential disruption of the dystrophin proteins and Dp71-associated proteins.

    Cognitive deficit
    SYMPTOMS

 has been identified in one third of patients affected by

    Duchenne Muscular Dystrophy
    DIAGNOSIS

, primarily attributed to

    loss of the short Dp71 dystrophin, the major brain dystrophin isoform
    GENETICS

. In this study, we investigated for the first time the Dp71 and Dp71-associated proteins cellular localization and expression in

    human neurons
    MICROSCOPIC

 obtained by

    differentiation from induced pluripotent stem cell line
    MICROSCOPIC

 of a patient affected by

    cognitive impairment
    SYMPTOMS

. We found

    structural and molecular alterations in both pluripotent stem cell and derived neurons
    MICROSCOPIC

,

    reduced Dp71 expression
    BIOCHEMICAL

, and a

    Ca2+ cytoplasmic overload in neurons
    MICROSCOPIC

 coupled with

    increased expression of the SERCA2 pump in the dystrophic neurons
    MICROSCOPIC

. These results suggest that the

    reduction of Dp71 protein
    BIOCHEMICAL

 in the

    Duchenne muscular dystrophy
    DIAGNOSIS

    neurons
    MICROSCOPIC

 leads to

    alterations in SERCA2
    GENETICS

 and to

    elevated cytosolic Ca2+ concentration
    BIOCHEMICAL

 with consequent potential

    disruption of the dystrophin proteins and Dp71-associated proteins
    BIOCHEMICAL

.

Duchenne Muscular Dystrophy
Duchenne muscular dystrophy


Mosaicism in carrier of Duchenne muscular dystrophy mutation - Implication for prenatal diagnosis.

Duchenne muscular dystrophy (DMD) is a severe disorder caused by mutation in the X-linked dystrophin gene, therefor carrier testing is required for all female family members. However, there are cases mutation analysis cannot detect any mutation due to a phenomenon called mosaicism. The case report describes a case of mosaicism in a DMD carrier and discusses the approach in diagnosis and counseling of familial disorder.

The proband was diagnosed with DMD at age six. Sequencing of Dystrophin gene identified a 2-nucleotide deletion c.2032_2033delCA, p.Q678DfsX41. Family investigation suggested that the mother was an obligate carrier of Dystrophin mutation. Sequencing of DNA sample from the mother's peripheral blood did not reveal any mutation, there for we take sample from hair follicle for analysis. The result indicated that the mother was a carrier but was masked from initial analysis by mosaicsism.

We suggested that more care need to be taken in identifying cases when no mutation was detected in probable or obligate carrier and prenatal diagnosis should remain an option.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    severe disorder
    DIAGNOSIS

 caused by

    mutation in the X-linked dystrophin gene
    GENETICS

, therefor

    carrier testing
    PARACLINICAL

 is required for all

    female
    GENDER

 family members. However, there are cases

    mutation analysis cannot detect any mutation
    NEG_FINDINGS

 due to a phenomenon called

    mosaicism
    GENETICS

. The case report describes a case of

    mosaicism
    DIAGNOSIS

 in a

    DMD
    DIAGNOSIS

 carrier and discusses the approach in diagnosis and counseling of

    familial disorder
    DIAGNOSIS

.

The proband was diagnosed with

    DMD
    DIAGNOSIS

 at

    age six
    AGE

.

    Sequencing of Dystrophin gene
    PARACLINICAL

 identified a

    2-nucleotide deletion c.2032_2033delCA, p.Q678DfsX41
    GENETICS

.

    Family investigation
    PARACLINICAL

 suggested that the

    mother was an obligate carrier of Dystrophin mutation
    FAMILY

.

    Sequencing of DNA sample from the mother's peripheral blood
    PARACLINICAL

    did not reveal any mutation
    NEG_FINDINGS

, there for we take

    sample from hair follicle for analysis
    PARACLINICAL

. The result indicated that the

    mother was a carrier
    FAMILY

 but was

    masked from initial analysis by mosaicsism
    NEG_FINDINGS

.

We suggested that more care need to be taken in identifying cases when

    no mutation was detected in probable or obligate carrier
    NEG_FINDINGS

 and

    prenatal diagnosis
    PARACLINICAL

 should remain an option.

Duchenne muscular dystrophy (DMD)
severe disorder
mosaicism
DMD
familial disorder
DMD


Caudal epidural block instead of general anesthesia in an adult with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD), first described in 1834, is an X-linked dystrophinopathy, leading to early onset skeletal muscle weakness. Life expectancy is reduced to early adulthood as a result of involvement of voluntary skeletal muscles with respiratory failure, orthopedic deformities, and associated cardiomyopathy. Given its multisystem involvement, surgical intervention may be required to address the sequelae of the disease process. We present a 36-year-old adult with DMD, who required anesthetic care during surgical debridement of an ischial pressure sore. Given his significant respiratory muscle involvement, ultrasound-guided caudal epidural anesthesia was used instead of general during the surgical procedure. The technique and its applications are discussed, with particular emphasis on the feasibility and safety of using regional anesthetic techniques in patients with DMD.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, first described in 1834, is an

    X-linked
    GENETICS

    dystrophinopathy
    DIAGNOSIS

, leading to

    early onset skeletal muscle weakness
    SYMPTOMS

. Life expectancy is reduced to

    early adulthood
    AGE

 as a result of

    involvement of voluntary skeletal muscles
    SYMPTOMS

 with

    respiratory failure
    SYMPTOMS

,

    orthopedic deformities
    SYMPTOMS

, and associated

    cardiomyopathy
    SYMPTOMS

. Given its

    multisystem involvement
    SYMPTOMS

,

    surgical intervention
    MEDICATION

 may be required to address the sequelae of the disease process. We present a

    36-year-old
    AGE

    adult
    GENDER

 with

    DMD
    DIAGNOSIS

, who required

    anesthetic care
    MEDICATION

 during

    surgical debridement of an ischial pressure sore
    MEDICATION

. Given his

    significant respiratory muscle involvement
    SYMPTOMS

,

    ultrasound-guided caudal epidural anesthesia
    MEDICATION

 was used

    instead of general during the surgical procedure
    MEDICATION

. The technique and its applications are discussed, with particular emphasis on the feasibility and safety of using

    regional anesthetic techniques
    MEDICATION

 in patients with

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
dystrophinopathy
DMD
DMD


Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.

The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further.

To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months.

On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies.

We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months.

Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria.

We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).A multicentre controlled study added eplerenone or placebo to 42 patients with DMD with early cardiomyopathy but preserved left ventricular function already established on ACEI or ARB therapy. Results showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months (eplerenone group median 1.0%, interquartile range (IQR) 0.3 to -2.2; placebo group median 2.2%, IQR 1.3 to -3.1%; P = 0.020). The median decline in LVEF over the same period was also less in the eplerenone group (-1.8%, IQR -2.9 to 6.0) than in the placebo group (-3.7%, IQR -10.8 to 1.0; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision. Serious adverse events were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).A randomised placebo-controlled study of subcutaneous growth hormone in 16 participants with DMD or BMD showed an increase in left ventricular mass after three months' treatment but no significant improvement in cardiac function. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were no clinically significant adverse events (very low-certainty evidence).Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the prophylactic use of perindopril for cardioprotection ahead of detectable cardiomyopathy, and for lisinopril or losartan plus eplerenone once cardiomyopathy is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice.

Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.

The

    dystrophinopathies
    DIAGNOSIS

 include

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

,

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

, and

    X-linked dilated cardiomyopathy (XLDCM)
    DIAGNOSIS

. In recent years, co-ordinated

    multidisciplinary management
    MEDICATION

 for these diseases has improved the quality of care, with

    early corticosteroid use
    MEDICATION

 prolonging

    independent ambulation
    MEDICATION

, and the routine use of

    non-invasive ventilation
    MEDICATION

 signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of

    cardiac involvement
    SYMPTOMS

 and so prolong survival further.

To assess the effects of interventions for preventing or treating

    cardiac involvement
    SYMPTOMS

 in

    DMD
    DIAGNOSIS

,

    BMD
    DIAGNOSIS

, and

    XLDCM
    DIAGNOSIS

, using

    measures of change in cardiac function over six months
    PARACLINICAL

.

We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which

    follow-up lasted for at least six months
    PARACLINICAL

.

We included five studies (N = 205) in the review; four studies included participants with

    DMD
    DIAGNOSIS

 only, and one study included participants with

    DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

. All studied different interventions, and meta-analysis was not possible. We found no studies for

    XLDCM
    DIAGNOSIS

. None of the trials reported

    cardiac function as improved or stable cardiac versus deteriorated
    SYMPTOMS

.The randomised first part of a two-part study of

    perindopril (N = 28) versus placebo (N = 27)
    MEDICATION

 in

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 with

    normal heart function at baseline
    NEG_FINDINGS

 showed

    no
    NEG_FINDINGS

 difference in the number of participants with a

    left ventricular ejection fraction (LVEF%) of less than 45%
    SYMPTOMS

 after

    three years of therapy
    MEDICATION

 (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who

    had received placebo from the beginning
    MEDICATION

 had

    reduced LVEF% (less than 45%)
    SYMPTOMS

. Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing

    treatment with lisinopril versus losartan
    MEDICATION

 in 23

    boys
    GENDER

 newly diagnosed with

    Duchenne cardiomyopathy
    DIAGNOSIS

 showed that

    after 12 months
    MEDICATION

, both were equally effective

    in preserving or improving LVEF%
    SYMPTOMS

 (

    lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19)
    MEDICATION

; mean difference

    (MD) -0.60% CI -6.67 to 5.47
    SYMPTOMS

: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the

    losartan group
    MEDICATION

 were withdrawn due to

    adverse events
    SYMPTOMS

: one participant

    developed an allergic reaction
    SYMPTOMS

, and a second exceeded the safety standard with a

    fall in ejection fraction greater than 10%
    SYMPTOMS

. Authors reported

    no other adverse events related to the medication
    NEG_FINDINGS

 (N = 22; very low-certainty evidence).A study comparing

    idebenone versus placebo
    MEDICATION

 in 21

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 showed

    little or no difference in mean change in cardiac function
    NEG_FINDINGS

 between the two groups from baseline

    to 12 months
    PARACLINICAL

; for

    fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6)
    SYMPTOMS

 in the placebo group (

    MD -0.20%, 95% CI -3.07 to 2.67
    SYMPTOMS

, N = 21), and for

    ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5)
    SYMPTOMS

 in the placebo group (

    MD -2.30%, 95% CI -9.18 to 4.58
    SYMPTOMS

, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).A multicentre controlled study

    added eplerenone or placebo
    MEDICATION

 to 42 patients with

    DMD
    DIAGNOSIS

 with

    early cardiomyopathy
    DIAGNOSIS

 but

    preserved left ventricular function
    SYMPTOMS

    already established on ACEI or ARB therapy
    NEG_FINDINGS

. Results showed that

    eplerenone
    MEDICATION

    slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months
    SYMPTOMS

 (

    eplerenone group median 1.0%, interquartile range (IQR) 0.3 to -2.2
    MEDICATION

;

    placebo group median 2.2%, IQR 1.3 to -3.1%
    MEDICATION

; P = 0.020). The

    median decline in LVEF over the same period was also less in the eplerenone group (-1.8%, IQR -2.9 to 6.0)
    SYMPTOMS

 than in the placebo group

    (-3.7%, IQR -10.8 to 1.0
    BIOCHEMICAL

; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision.

    Serious adverse events
    SYMPTOMS

 were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).A

    randomised placebo-controlled study of subcutaneous growth hormone
    MEDICATION

 in 16 participants with

    DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

 showed an

    increase in left ventricular mass
    SYMPTOMS

    after three months' treatment
    MEDICATION

 but

    no significant improvement in cardiac function
    NEG_FINDINGS

. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were

    no clinically significant adverse events
    NEG_FINDINGS

 (very low-certainty evidence).Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the

    prophylactic use of perindopril
    MEDICATION

 for

    cardioprotection
    MEDICATION

 ahead of

    detectable cardiomyopathy
    DIAGNOSIS

, and for

    lisinopril or losartan plus eplerenone
    MEDICATION

 once

    cardiomyopathy
    DIAGNOSIS

 is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice.

Based on the available evidence from RCTs,

    early treatment with ACE inhibitors or ARBs
    MEDICATION

 may be comparably beneficial for people with a

    dystrophinopathy
    DIAGNOSIS

; however, the certainty of evidence is very low. Very low-certainty evidence indicates that

    adding eplerenone
    MEDICATION

 might give additional benefit when

    early cardiomyopathy
    SYMPTOMS

 is detected.

    No clinically meaningful
    NEG_FINDINGS

 effect was seen for

    growth hormone or idebenone
    NEG_FINDINGS

, although the certainty of the evidence is also very low.

dystrophinopathies
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
X-linked dilated cardiomyopathy (XLDCM)
DMD
BMD
XLDCM
DMD
DMD
BMD
XLDCM
DMD
Duchenne cardiomyopathy
DMD
DMD
early cardiomyopathy
DMD
BMD
detectable cardiomyopathy
cardiomyopathy
dystrophinopathy


Identification of Duchenne/Becker muscular dystrophy mosaic carriers through a combined DNA/RNA analysis.

The Duchenne/Becker muscular dystrophy (DMD) carrier screening includes the evaluation of mutations in DMD gene, and the most widely used analysis is the multiplex ligation-dependent probe amplification (MLPA) for the DMD deletions/duplications detection. The high frequency of de novo mutations permits to estimate a risk up to 20% of mosaicisms for mothers of sporadic DMD children. The purpose of this study is to evaluate alternative analytical strategy for the detection of mosaics carrier women, in order to improve the recurrence risk estimation.

Different DNA and RNA analyses were conducted on samples from a woman that conceived a DMD fetus without previous family history of dystrophynopathy.

Standard MLPA analysis failed to identify mosaicism, even if MLPA doses suggested it. Electrophoresis and direct sequencing conducted on RNA permitted to detect two different amplicons of cDNAs, demonstrating the presence of somatic mosaicism. Subsequent detection of a second affected fetus confirmed the mosaic status on the mother.

The implementation of RNA analysis in diagnostic algorithm can increase the sensitivity of carrier test for mothers of sporadic affected patients, permitting detection of mosaic status. A revision of analytical guidelines is needed in order to improve the recurrence risk estimation and support prenatal genetic counseling.

The

    Duchenne/Becker muscular dystrophy (DMD)
    DIAGNOSIS

    carrier screening
    PARACLINICAL

 includes the

    evaluation of mutations in DMD gene
    PARACLINICAL

, and the most widely used analysis is the

    multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

 for the

    DMD deletions/duplications detection
    GENETICS

. The high frequency of

    de novo mutations
    GENETICS

 permits to estimate a risk up to 20% of

    mosaicisms
    GENETICS

 for mothers of

    sporadic DMD children
    FAMILY

. The purpose of this study is to evaluate alternative analytical strategy for the detection of mosaics carrier

    women
    GENDER

, in order to improve the recurrence risk estimation.

    Different DNA and RNA analyses
    PARACLINICAL

 were conducted on samples from a

    woman
    GENDER

 that

    conceived a DMD fetus
    MEDICATION

    without previous family history of dystrophynopathy
    NEG_FINDINGS

.

    Standard MLPA analysis failed to identify mosaicism
    NEG_FINDINGS

, even if

    MLPA doses
    NEG_FINDINGS

 suggested it.

    Electrophoresis and direct sequencing conducted on RNA
    PARACLINICAL

 permitted to detect two different

    amplicons of cDNAs
    GENETICS

, demonstrating the presence of

    somatic mosaicism
    GENETICS

. Subsequent detection of a

    second affected fetus confirmed the mosaic status on the mother
    FAMILY

.

The implementation of

    RNA analysis
    PARACLINICAL

 in diagnostic algorithm can increase the sensitivity of carrier test for mothers of sporadic affected patients, permitting detection of

    mosaic status
    GENETICS

. A revision of analytical guidelines is needed in order to improve the recurrence risk estimation and support

    prenatal genetic counseling
    MEDICATION

.

DMD deletions/duplications detection
de novo mutations
mosaicisms
amplicons of cDNAs
somatic mosaicism
mosaic status

conceived a DMD fetus
prenatal genetic counseling


[Cerebral embolism in Duchenne muscular dystrophy after respiratory tract infection - Report of two cases].

We report cerebral embolism in 2 patients with Duchenne muscular dystrophy (DMD) after respiratory tract infection. A 31-year-old man (Case 1) was admitted to the hospital because of an upper respiratory tract infection, then suddenly developed left-sided hemiparesis. Transthoracic echocardiography revealed an intracardiac thrombus in the left ventricle, and, under assumption of cardioembolic stroke, oral anticoagulation was initiated. Case 2 was a 36-year-old man who developed dysphasia after increasing sputum. Based on brain CT scan findings, we confirmed a diagnosis of cerebral infarction. There was no recurrence in either case. Both cases developed cerebral infarction due to embolism after mild upper respiratory tract infections. DMD patients have various risk factors for thrombus and embolus, while physicians should also be aware of possible cerebral infarction and other coagulation disorders irrespective of respiratory and cardiac therapy.

We report

    cerebral embolism
    SYMPTOMS

 in 2 patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 after

    respiratory tract infection
    SYMPTOMS

. A

    31-year-old
    AGE

    man
    GENDER

 (Case 1) was admitted to the hospital because of an

    upper respiratory tract infection
    SYMPTOMS

, then suddenly developed

    left-sided hemiparesis
    SYMPTOMS

.

    Transthoracic echocardiography
    PARACLINICAL

 revealed an

    intracardiac thrombus in the left ventricle
    SYMPTOMS

, and, under assumption of

    cardioembolic stroke
    SYMPTOMS

,

    oral anticoagulation
    MEDICATION

 was initiated. Case 2 was a

    36-year-old
    AGE

    man
    GENDER

 who developed

    dysphasia
    SYMPTOMS

 after

    increasing sputum
    SYMPTOMS

. Based on

    brain CT scan findings
    PARACLINICAL

, we confirmed a diagnosis of

    cerebral infarction
    SYMPTOMS

. There was

    no recurrence
    NEG_FINDINGS

 in either case. Both cases developed

    cerebral infarction
    SYMPTOMS

 due to

    embolism
    SYMPTOMS

 after

    mild upper respiratory tract infections
    SYMPTOMS

.

    DMD
    DIAGNOSIS

 patients have various risk factors for

    thrombus and embolus
    SYMPTOMS

, while physicians should also be aware of possible

    cerebral infarction
    SYMPTOMS

 and other

    coagulation disorders
    SYMPTOMS

    irrespective of respiratory and cardiac therapy
    NEG_FINDINGS

.


Myoglobinuria in two patients with Duchenne muscular dystrophy after treatment with zoledronate: a case-report and call for caution.

Rhabdomyolysis with myoglobinuria is a recognized complication of dystrophinopathies. It can be triggered by infections, exercise or volatile anesthetics. To our knowledge, it has never been reported in boys with Duchenne muscular dystrophy (DMD) after the administration of bisphosphonates. We report two patients with DMD who presented an apparent transient rhabdomyolysis with myoglobinuria after zoledronate administration. Possible mechanisms could involve hypophosphatemia, a known dose-dependent side effect of bisphosphonates, and/or direct myotoxicity of biphosphonates. Physicians and families should be aware of rhabdomyolysis with myoglobinuria as a potential uncommon side effect of bisphosphonates in DMD, in particular of zoledronate.

    Rhabdomyolysis
    DIAGNOSIS

 with

    myoglobinuria
    BIOCHEMICAL

 is a recognized complication of

    dystrophinopathies
    DIAGNOSIS

. It can be triggered by

    infections
    SYMPTOMS

,

    exercise
    MEDICATION

 or

    volatile anesthetics
    MEDICATION

. To our knowledge, it has never been reported in

    boys
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 after the

    administration of bisphosphonates
    MEDICATION

. We report two patients with

    DMD
    DIAGNOSIS

 who presented an apparent

    transient rhabdomyolysis
    SYMPTOMS

 with

    myoglobinuria
    BIOCHEMICAL

 after

    zoledronate administration
    MEDICATION

. Possible mechanisms could involve

    hypophosphatemia
    BIOCHEMICAL

, a known

    dose-dependent side effect of bisphosphonates
    SYMPTOMS

, and/or

    direct myotoxicity of biphosphonates
    SYMPTOMS

. Physicians and families should be aware of

    rhabdomyolysis with myoglobinuria
    SYMPTOMS

 as a potential uncommon side effect of

    bisphosphonates
    MEDICATION

 in

    DMD
    DIAGNOSIS

, in particular of

    zoledronate
    MEDICATION

.

Rhabdomyolysis
dystrophinopathies
Duchenne muscular dystrophy (DMD)
DMD
DMD

exercise
volatile anesthetics
administration of bisphosphonates
zoledronate administration
bisphosphonates
zoledronate


Importance of long-term motor function evaluation after prednisolone treatment for Duchenne muscular dystrophy.

[Purpose] Motor function evaluation by physical therapists is considered a valuable tool to assess the progression of muscular dystrophies. Few reports have described long-term motor function assessment during the administration of corticosteroids such as prednisolone (PSL) in these patients. This study examined the importance of long-term non-invasive motor function evaluation in a series of 3 cases. [Participants and Methods] Three boys with Duchenne muscular dystrophy who were administered an identical PSL dosage regimen were retrospectively evaluated, and motor function tests were compared in them before and after an increase in PSL dosage. Regular feedback was obtained from the patients' mothers regarding their impressions of their child's motor function after the introduction of PSL. [Results] Motor function was conserved or significantly improved after an increase in dosage in all cases. Interestingly, subjective assessment by mothers revealed a perceived improvement only in case 1 without any changes reported in cases 2 or 3. [Conclusion] PSL was demonstrably effective for 2.5-5 years after initiating PSL treatment, although parental impressions varied. Thus, long-term non-invasive evaluation by physical therapists may provide important objective data regarding medication efficacy and disease progression. Future studies should include long-term testing results as an essential component of the discontinuation criteria for PSL.

[Purpose]

    Motor function evaluation
    PARACLINICAL

 by

    physical therapists
    PARACLINICAL

 is considered a valuable tool to assess the progression of

    muscular dystrophies
    DIAGNOSIS

. Few reports have described

    long-term motor function assessment
    PARACLINICAL

 during the

    administration of corticosteroids such as prednisolone (PSL)
    MEDICATION

 in these patients. This study examined the importance of

    long-term non-invasive motor function evaluation
    PARACLINICAL

 in a series of 3 cases. [Participants and Methods] Three

    boys
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 who were administered an

    identical PSL dosage regimen
    MEDICATION

 were retrospectively evaluated, and

    motor function tests
    PARACLINICAL

 were compared in them before and after an

    increase in PSL dosage
    MEDICATION

. Regular feedback was obtained from the patients' mothers regarding their impressions of their child's motor function after the introduction of

    PSL
    MEDICATION

. [Results]

    Motor function was conserved or significantly improved
    SYMPTOMS

 after an

    increase in dosage
    MEDICATION

 in all cases. Interestingly, subjective assessment by mothers revealed a

    perceived improvement
    SYMPTOMS

 only in case 1 without any changes reported in cases 2 or 3. [Conclusion]

    PSL
    MEDICATION

 was demonstrably effective for 2.5-5 years after

    initiating PSL treatment
    MEDICATION

, although parental impressions varied. Thus,

    long-term non-invasive evaluation by physical therapists
    PARACLINICAL

 may provide important objective data regarding medication efficacy and disease progression. Future studies should include long-term testing results as an essential component of the discontinuation criteria for

    PSL
    MEDICATION

.

muscular dystrophies
Duchenne muscular dystrophy


Myocarditis in Duchenne Muscular Dystrophy After Changing Steroids.

Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). This case highlights the importance of steroids in treating cardiac complications of DMD and the dangers of discontinuing or switching between steroid classes.

To recognize the presentation of acute myocardial inflammation, or dystrophinitis, in DMD, which presents as myocarditis and to treat the myocardial inflammation and dilated cardiomyopathy associated with DMD through guideline-directed medical therapy, steroids, and serial surveillance for cardiac dysfunction.

A case report of an 18-year-old patient with DMD and with steroid withdrawal-induced myocarditis followed up for 3 years to observe for cardiac function recovery and the natural history of cardiomyopathy in DMD, who was hospitalized in the cardiac care unit and followed up between November 3, 2016, and March 27, 2017.

Switching from deflazacort to underdosed prednisone for 7 days.

Increased myocardial inflammation, edema, and fibrosis after stopping deflazacort abruptly.

An 18-year-old male patient with DMD presented to the emergency department with acute-onset chest pain. Ischemic changes were present on electrocardiogram, and elevated cardiac enzymes were detected. Depressed cardiac function and potential evidence of inflammation were seen on cardiac magnetic resonance (CMR) imaging, characterized by elevated T2 values and late gadolinium enhancement. These findings were all consistent with acute myocarditis but without a viral prodrome. Several days prior to presentation, the patient's deflazacort was abruptly discontinued and converted to an equivalent dose of prednisone. After restarting deflazacort, his symptoms improved, and subsequent CMR showed resolution of myocardial edema and improved left ventricular function.

This case highlights adverse effects associated with changing between corticosteroid classes in DMD cardiomyopathy and also demonstrates the utility of CMR in detecting myocardial inflammation and monitoring response to treatment.

    Cardiac dysfunction
    SYMPTOMS

 is a leading cause of morbidity and mortality in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. This case highlights the importance of

    steroids
    MEDICATION

 in treating

    cardiac complications
    SYMPTOMS

 of

    DMD
    DIAGNOSIS

 and the dangers of

    discontinuing or switching between steroid classes
    MEDICATION

.

To recognize the presentation of

    acute myocardial inflammation
    DIAGNOSIS

, or

    dystrophinitis
    DIAGNOSIS

, in

    DMD
    DIAGNOSIS

, which presents as

    myocarditis
    DIAGNOSIS

 and to treat the

    myocardial inflammation
    SYMPTOMS

 and

    dilated cardiomyopathy
    DIAGNOSIS

 associated with

    DMD
    DIAGNOSIS

 through

    guideline-directed medical therapy
    MEDICATION

,

    steroids
    MEDICATION

, and

    serial surveillance for cardiac dysfunction
    PARACLINICAL

.

A case report of an

    18-year-old
    AGE

 patient with

    DMD
    DIAGNOSIS

 and with

    steroid withdrawal-induced myocarditis
    DIAGNOSIS

 followed up for 3 years to observe for

    cardiac function recovery
    SYMPTOMS

 and the natural history of

    cardiomyopathy
    DIAGNOSIS

 in

    DMD
    DIAGNOSIS

, who was

    hospitalized in the cardiac care unit
    MEDICATION

 and followed up between November 3, 2016, and March 27, 2017.

    Switching from deflazacort to underdosed prednisone for 7 days
    MEDICATION

.

    Increased myocardial inflammation, edema, and fibrosis
    SYMPTOMS

 after

    stopping deflazacort abruptly
    MEDICATION

.

An

    18-year-old
    AGE

    male
    GENDER

 patient with

    DMD
    DIAGNOSIS

 presented to the emergency department with

    acute-onset chest pain
    SYMPTOMS

.

    Ischemic changes
    SYMPTOMS

 were present on

    electrocardiogram
    SYMPTOMS

, and

    elevated cardiac enzymes
    BIOCHEMICAL

 were detected.

    Depressed cardiac function
    SYMPTOMS

 and

    potential evidence of inflammation
    SYMPTOMS

 were seen on

    cardiac magnetic resonance (CMR) imaging
    PARACLINICAL

, characterized by

    elevated T2 values and late gadolinium enhancement
    SYMPTOMS

. These findings were all consistent with

    acute myocarditis
    DIAGNOSIS

 but

    without a viral prodrome
    NEG_FINDINGS

. Several days prior to presentation, the patient's

    deflazacort was abruptly discontinued and converted to an equivalent dose of prednisone
    MEDICATION

. After

    restarting deflazacort
    MEDICATION

, his

    symptoms improved
    SYMPTOMS

, and subsequent

    CMR
    PARACLINICAL

 showed

    resolution of myocardial edema
    SYMPTOMS

 and

    improved left ventricular function
    SYMPTOMS

.

This case highlights

    adverse effects associated with changing between corticosteroid classes
    SYMPTOMS

 in

    DMD cardiomyopathy
    DIAGNOSIS

 and also demonstrates the utility of

    CMR
    PARACLINICAL

 in detecting

    myocardial inflammation
    SYMPTOMS

 and monitoring response to treatment.

Duchenne muscular dystrophy (DMD)
DMD
acute myocardial inflammation
dystrophinitis
DMD
myocarditis
dilated cardiomyopathy
DMD
DMD
steroid withdrawal-induced myocarditis
cardiomyopathy
DMD
DMD
acute myocarditis
DMD cardiomyopathy


A novel mutation of dystrophin in a Becker muscular dystrophy family with severe cardiac involvement: from genetics to clinicopathology.

Dystrophin gene defects are the pathogenic molecular basis of Becker muscular dystrophy (BMD), characterised by skeletal myopathy and cardiomyopathy. Because of the broad phenotype spectrum, it was difficult to use the traditional diagnostic method to achieve an early accurate diagnosis of BMD-associated cardiomyopathy.

We applied an in-house gene panel testing and a gene-filtering strategy to investigate the genetic defect in a four-generation family with 73 members. The proband had a heart transplant due to heart failure; the explanted heart was subjected to a careful pathological analysis.

A novel small in-frame mutation (c.4998_5000 del CAG, p.1667 del Ala) of the dystrophin gene was identified and co-segregated in the affected family members. By using the image segmentation technology, we found the left ventricular free wall demonstrated severe fibrofatty replacement of cardiac myocytes from the epicardium to the endocardium.

We identified a novel dystrophin mutation (p.1667 del Ala), resulting in BMD-associated cardiomyopathy that demonstrated the pathological features of significant fibrofatty replacement in the sub-epicardial layer of the ventricle; further, the high-throughput sequencing is helpful for making an early diagnosis of BMD.

    Dystrophin gene defects
    GENETICS

 are the pathogenic molecular basis of

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

, characterised by

    skeletal myopathy
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

. Because of the broad phenotype spectrum, it was difficult to use the traditional diagnostic method to achieve an early accurate diagnosis of

    BMD-associated cardiomyopathy
    DIAGNOSIS

.

We applied an

    in-house gene panel testing
    PARACLINICAL

 and a

    gene-filtering strategy
    PARACLINICAL

 to investigate the

    genetic defect
    GENETICS

 in a

    four-generation family with 73 members
    FAMILY

. The

    proband
    GENDER

 had a

    heart transplant
    MEDICATION

 due to

    heart failure
    SYMPTOMS

; the

    explanted heart
    PARACLINICAL

 was subjected to a

    careful pathological analysis
    PARACLINICAL

.

A

    novel small in-frame mutation (c.4998_5000 del CAG, p.1667 del Ala) of the dystrophin gene
    GENETICS

 was identified and

    co-segregated in the affected family members
    FAMILY

. By using the

    image segmentation technology
    PARACLINICAL

, we found the

    left ventricular free wall demonstrated severe fibrofatty replacement of cardiac myocytes from the epicardium to the endocardium
    SYMPTOMS

.

We identified a

    novel dystrophin mutation (p.1667 del Ala)
    GENETICS

, resulting in

    BMD-associated cardiomyopathy
    DIAGNOSIS

 that demonstrated the

    pathological features of significant fibrofatty replacement in the sub-epicardial layer of the ventricle
    SYMPTOMS

; further, the

    high-throughput sequencing
    PARACLINICAL

 is helpful for making an early diagnosis of

    BMD
    DIAGNOSIS

.

Becker muscular dystrophy (BMD)
BMD-associated cardiomyopathy
BMD-associated cardiomyopathy
BMD


Mutation Location and Cognitive Impairment in Duchenne Muscular Dystrophy.

Cognitive impairment is commonly seen in patients with Duchenne muscular dystrophy (DMD). Few studies have shown a correlation between loss of different isoforms of the DMD gene and cognitive impairment.

The objective of the study was to determine whether correlation exists in the location of mutation in DMD gene or loss of different isoforms and cognitive impairment in children with DMD in the Indian population.

Ten children were evaluated. Gene mutation analysis was done by multiplex ligation-dependent probe amplification method. The isoforms affected were inferred from mutation location in each of these patients. Binet Kamat Intelligence Test (BKT) and Bender Gestalt test (BGT) were administered.

All male patients were aged between 4 and 9 years. Genetic analysis showed deletion in all patients, with seven having deletion in "hotspot" regions (exon 43-52). Psychometric analysis by BGT and BKT showed mean score of 8.6 and mean IQ score of 85.5, respectively. Comparison between patients with hotspot mutations and mutations in other regions, for mean IQ score and BGT score, was statistically significant (P = 0.132 and P = 0.005, respectively). The difference in the IQ score between patients with isolated Dp427 loss (n = 3) and cumulative Dp427/Dp260/Dp140utr loss (n = 6) was statistically significant (P = 0.011). Visuomotor functioning was more impaired in patients with isolated Dp427 loss.

The role of cumulative loss of isoforms along with importance of loss of Dp140pc isoform was seen in our study. One patient with loss of Dp140utr isoform had intellectual impairment which is not commonly seen. Visuomotor functioning is more affected in more upstream mutations as shown in our study.

    Cognitive impairment
    SYMPTOMS

 is commonly seen in patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. Few studies have shown a correlation between

    loss of different isoforms of the DMD gene
    GENETICS

 and

    cognitive impairment
    SYMPTOMS

.

The objective of the study was to determine whether correlation exists in the

    location of mutation in DMD gene or loss of different isoforms
    GENETICS

 and

    cognitive impairment
    SYMPTOMS

 in

    children
    AGE

 with

    DMD
    DIAGNOSIS

 in the

    Indian
    ETHNICITY

 population.

Ten

    children
    AGE

 were evaluated.

    Gene mutation analysis
    PARACLINICAL

 was done by

    multiplex ligation-dependent probe amplification method
    PARACLINICAL

. The

    isoforms affected
    GENETICS

 were inferred from mutation location in each of these patients.

    Binet Kamat Intelligence Test (BKT) and Bender Gestalt test (BGT)
    PARACLINICAL

 were administered.

All

    male
    GENDER

 patients were

    aged between 4 and 9 years
    AGE

.

    Genetic analysis
    PARACLINICAL

 showed

    deletion
    GENETICS

 in all patients, with seven having

    deletion in "hotspot" regions (exon 43-52)
    GENETICS

.

    Psychometric analysis by BGT and BKT
    PARACLINICAL

 showed

    mean score of 8.6
    PARACLINICAL

 and

    mean IQ score of 85.5
    SYMPTOMS

, respectively. Comparison between patients with

    hotspot mutations
    GENETICS

 and

    mutations in other regions
    GENETICS

, for

    mean IQ score and BGT score
    PARACLINICAL

, was statistically significant (P = 0.132 and P = 0.005, respectively). The difference in the IQ score between patients with

    isolated Dp427 loss
    BIOCHEMICAL

 (n = 3) and

    cumulative Dp427/Dp260/Dp140utr loss
    SYMPTOMS

 (n = 6) was statistically significant (P = 0.011).

    Visuomotor functioning was more impaired
    SYMPTOMS

 in patients with

    isolated Dp427 loss
    BIOCHEMICAL

.

The role of

    cumulative loss of isoforms
    GENETICS

 along with importance of

    loss of Dp140pc isoform
    GENETICS

 was seen in our study. One patient with

    loss of Dp140utr isoform
    GENETICS

 had

    intellectual impairment
    SYMPTOMS

 which is not commonly seen.

    Visuomotor functioning
    SYMPTOMS

 is more affected in

    more upstream mutations
    GENETICS

 as shown in our study.


Noninvasive ventilatory support to reverse weight loss in Duchenne muscular dystrophy: A case series.

This case series of five patients with Duchenne muscular dystrophy demonstrates the nutritional advantages of instituting noninvasive intermittent positive pressure ventilatory support via 15mm angled mouthpieces to relieve tachypnea and provide more time to swallow food safely. In each case weight loss was reversed.

This case series of five patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 demonstrates the nutritional advantages of instituting

    noninvasive intermittent positive pressure ventilatory support via 15mm angled mouthpieces
    MEDICATION

 to

    relieve tachypnea
    SYMPTOMS

 and

    provide more time to swallow food safely
    MEDICATION

. In each case

    weight loss was reversed
    SYMPTOMS

.

relieve tachypnea
weight loss was reversed


Fat Embolism Syndrome in Duchenne Muscular Dystrophy Patients: Early Recognition and Aggressive Therapy.

We describe two pediatric patients with Duchenne muscular dystrophy that presented with acute neurologic deterioration and hypoxic respiratory failure requiring mechanical ventilation. These cases fulfill the clinical criteria for Fat Embolism Syndrome. Early recognition and aggressive supportive therapy with mechanical ventilation, right ventricular afterload reduction, and blood transfusion led to survival without any residual effects from the event. Fat Embolism Syndrome needs to be considered early in the course of patients with Duchenne muscular dystrophy who present with respiratory and neurological symptoms.

We describe two

    pediatric
    AGE

 patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 that presented with

    acute neurologic deterioration
    SYMPTOMS

 and

    hypoxic respiratory failure
    SYMPTOMS

 requiring

    mechanical ventilation
    MEDICATION

. These cases fulfill the clinical criteria for

    Fat Embolism Syndrome
    DIAGNOSIS

. Early recognition and

    aggressive supportive therapy with mechanical ventilation
    MEDICATION

,

    right ventricular afterload reduction
    MEDICATION

, and

    blood transfusion
    MEDICATION

 led to

    survival
    MEDICATION

    without any residual effects from the event
    NEG_FINDINGS

.

    Fat Embolism Syndrome
    DIAGNOSIS

 needs to be considered early in the course of patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

 who present with

    respiratory and neurological symptoms
    SYMPTOMS

.

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

acute neurologic deterioration
hypoxic respiratory failure
respiratory and neurological symptoms


Ketoacidosis in Duchenne muscular dystrophy: A report on 4 cases.

The longer survival in Duchenne dystrophy can be associated with previously unrecognised medical issues, in particular cardiac and nutritional problems, which provide new challenges in the management of these patients. We describe a series of patients who have DMD presenting with severe acid base abnormalities due to ketoacidosis. The cases described all developed the abnormalities in the context of decreased dietary intake. In all cases, the acid-base derangement resolved with intravenous glucose infusion. We conclude that decreased calorific intake for any reason can lead to very severe acid-base derangement in patients with DMD. The treatment is relatively simple once the problem has been identified. An awareness of this potential complication is important for all clinicians involved in the acute care of these patients.

The longer survival in

    Duchenne dystrophy
    DIAGNOSIS

 can be associated with previously unrecognised medical issues, in particular

    cardiac
    SYMPTOMS

 and

    nutritional problems
    SYMPTOMS

, which provide new challenges in the management of these patients. We describe a series of patients who have

    DMD
    DIAGNOSIS

 presenting with

    severe acid base abnormalities
    BIOCHEMICAL

 due to

    ketoacidosis
    BIOCHEMICAL

. The cases described all developed the abnormalities in the context of

    decreased dietary intake
    BIOCHEMICAL

. In all cases, the

    acid-base derangement
    BIOCHEMICAL

 resolved with

    intravenous glucose infusion
    MEDICATION

. We conclude that

    decreased calorific intake
    MEDICATION

 for any reason can lead to

    very severe acid-base derangement
    BIOCHEMICAL

 in patients with

    DMD
    DIAGNOSIS

. The treatment is relatively simple once the problem has been identified. An awareness of this potential complication is important for all clinicians involved in the acute care of these patients.

severe acid base abnormalities
ketoacidosis
decreased dietary intake
acid-base derangement
very severe acid-base derangement

intravenous glucose infusion
decreased calorific intake


Phenotypic Characterization of a Family With An In-frame Deletion in the DMD Gene and Variable Penetrance.

Duchenne muscular dystrophy is a disorder with variable expression caused by framedisrupting mutations in the dystrophin gene. It is characterized by progressive muscle weakness and dilated cardiomyopathy. In-frame dystrophin mutations cause a clinically moderate disorder named Becker muscular dystrophy. Our aim was to study the clinical and genetic characteristics of a family with inherited cardiomyopathy and Becker muscular dystrophy. The index case was diagnosed with psychomotor retardation at 5 years of age. Asymmetric left ventricular hypertrophy and a long QT interval were evidenced at the age of 12. Mild muscular weakness was developed subsequently. Three genetic variants were identified in the index case: p.Arg891Alafs*160 in the MYBPC3 gene, p.Thr263Met in the KCNJ5 gene, and p.Ser2437_Ile2554delinsPhe in the DMD gene. The latter was expected to generate an in-frame deletion of exons 51 and 52 of the dystrophin gene. A family study revealed that the father and 3 uncles were carriers of the MYBPC3 mutation. The mother and a maternal grandfather were carriers of the other 2 variants. The 80-year-old grandfather, who had the dystrophin mutation, showed no sign of cardiomyopathy or muscular weakness. The deletion of exons 51 and 52 in the DMD gene, which has been proposed as one of the therapeutic strategies for Duchenne, is consistent with a normal life expectancy and the absence of myopathic symptoms in hemizygous males.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is a disorder with variable expression caused by

    framedisrupting mutations in the dystrophin gene
    GENETICS

. It is characterized by

    progressive muscle weakness
    SYMPTOMS

 and

    dilated cardiomyopathy
    SYMPTOMS

.

    In-frame dystrophin mutations
    GENETICS

 cause a clinically moderate disorder named

    Becker muscular dystrophy
    DIAGNOSIS

. Our aim was to study the clinical and genetic characteristics of a

    family with inherited cardiomyopathy
    FAMILY

 and

    Becker muscular dystrophy
    DIAGNOSIS

. The index case was diagnosed with

    psychomotor retardation
    SYMPTOMS

    at 5 years of age
    AGE

.

    Asymmetric left ventricular hypertrophy
    SYMPTOMS

 and a

    long QT interval
    SYMPTOMS

 were evidenced at the

    age of 12
    AGE

.

    Mild muscular weakness
    SYMPTOMS

 was developed subsequently.

    Three genetic variants
    GENETICS

 were identified in the index case:

    p.Arg891Alafs*160 in the MYBPC3 gene, p.Thr263Met in the KCNJ5 gene
    GENETICS

, and

    p.Ser2437_Ile2554delinsPhe in the DMD gene
    GENETICS

. The latter was

    expected to generate an in-frame deletion of exons 51 and 52 of the dystrophin gene
    GENETICS

. A

    family study
    PARACLINICAL

 revealed that

    the father and 3 uncles were carriers of the MYBPC3 mutation
    FAMILY

.

    The mother and a maternal grandfather were carriers of the other 2 variants
    FAMILY

. The

    80-year-old
    AGE

    grandfather, who had the dystrophin mutation
    FAMILY

, showed

    no sign of cardiomyopathy or muscular weakness
    NEG_FINDINGS

. The

    deletion of exons 51 and 52 in the DMD gene
    GENETICS

, which has been proposed as one of the therapeutic strategies for

    Duchenne
    DIAGNOSIS

, is consistent with a

    normal life expectancy
    NEG_FINDINGS

 and the

    absence of myopathic symptoms
    NEG_FINDINGS

 in

    hemizygous males
    GENETICS

.

Duchenne muscular dystrophy
Becker muscular dystrophy
Becker muscular dystrophy
Duchenne

progressive muscle weakness
dilated cardiomyopathy
psychomotor retardation
Asymmetric left ventricular hypertrophy
long QT interval
Mild muscular weakness


Muscular and cardiac manifestations in a Duchenne-carrier harboring a dystrophin deletion of exons 12-29.

Female carriers of mutations in the dystrophin gene (DMD-carriers) may manifest clinically in the skeletal muscle, the heart, or both. Cardiac involvement may manifest before, after, or together with the muscle manifestations. A 46y female developed slowly progressive weakness of the lower and upper limbs with left-sided predominance since age 26y. Muscle enzymes were repeatedly elevated and muscle biopsy showed absence of dystrophin. MLPA analysis revealed a deletion of exons 12-29. After starting steroids at age 39y, she developed palpitations and exertional dyspnoea. Cardiac MRI at age 41y revealed mildly reduced systolic function, a slightly enlarged left ventricle, mild hypokinesia of the entire myocardium, and focal, transmural late gadolinium enhancement (LGE) of the midventricular lateral wall. She did not tolerate beta-blockers but profited from ivabradine and lisinopril. In conclusion, muscle manifestations in DMD-carriers with deletions of exons 12-29 may start years before cardiac involvement becomes clinically apparent. Progressive worsening of systolic function in DMD-carriers is attributable to progressive myocardial fibrosis, as demonstrated by LGE. Steroids may trigger the development of cardiac disease in DMD-carriers.

    Female
    GENDER

 carriers of

    mutations in the dystrophin gene
    GENETICS

 (

    DMD-carriers
    GENETICS

) may manifest

    clinically in the skeletal muscle, the heart
    SYMPTOMS

, or both.

    Cardiac involvement
    SYMPTOMS

 may manifest before, after, or together with the

    muscle manifestations
    SYMPTOMS

. A

    46y
    AGE

    female
    GENDER

 developed

    slowly progressive weakness of the lower and upper limbs
    SYMPTOMS

    with left-sided predominance
    SYMPTOMS

 since

    age 26y
    AGE

.

    Muscle enzymes were repeatedly elevated
    BIOCHEMICAL

 and

    muscle biopsy
    PARACLINICAL

 showed

    absence of dystrophin
    BIOCHEMICAL

.

    MLPA analysis
    PARACLINICAL

 revealed a

    deletion of exons 12-29
    GENETICS

. After

    starting steroids
    MEDICATION

 at

    age 39y
    AGE

,

    she
    GENDER

 developed

    palpitations
    SYMPTOMS

 and

    exertional dyspnoea
    SYMPTOMS

.

    Cardiac MRI
    PARACLINICAL

 at

    age 41y
    AGE

 revealed

    mildly reduced systolic function
    SYMPTOMS

, a

    slightly enlarged left ventricle
    SYMPTOMS

,

    mild hypokinesia of the entire myocardium
    SYMPTOMS

, and

    focal, transmural late gadolinium enhancement (LGE) of the midventricular lateral wall
    SYMPTOMS

.

    She
    GENDER

    did not tolerate beta-blockers
    NEG_FINDINGS

 but profited from

    ivabradine and lisinopril
    MEDICATION

. In conclusion,

    muscle manifestations
    SYMPTOMS

 in

    DMD-carriers
    DIAGNOSIS

 with

    deletions of exons 12-29
    GENETICS

 may start years before

    cardiac involvement
    SYMPTOMS

 becomes clinically apparent.

    Progressive worsening of systolic function
    SYMPTOMS

 in

    DMD-carriers
    DIAGNOSIS

 is attributable to

    progressive myocardial fibrosis
    SYMPTOMS

, as demonstrated by

    LGE
    SYMPTOMS

.

    Steroids
    MEDICATION

 may trigger the development of

    cardiac disease
    DIAGNOSIS

 in

    DMD-carriers
    DIAGNOSIS

.

mutations in the dystrophin gene
DMD-carriers
deletion of exons 12-29
deletions of exons 12-29

Muscle enzymes were repeatedly elevated
absence of dystrophin

starting steroids
ivabradine and lisinopril
Steroids

DMD-carriers
DMD-carriers
cardiac disease
DMD-carriers


A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20.

Boys with Duchenne muscular dystrophy (DMD) have DMD gene mutations, with associated loss of the dystrophin protein and progressive muscle degeneration and weakness. Corticosteroids and palliative support are currently the best treatment options. The long-term benefits of recently approved compounds such as eteplirsen and ataluren remain to be seen. Dogs with naturally occurring dystrophinopathies show progressive disease akin to that of DMD. Accordingly, canine DMD models are useful for studies of pathogenesis and preclinical therapy development. A dystrophin-deficient, male border collie dog was evaluated at the age of 5 months for progressive muscle weakness and dysphagia.

Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L) were seen on a biochemistry panel. Histopathologic changes characteristic of dystrophinopathy were seen. Dystrophin was absent in the skeletal muscle on immunofluorescence microscopy and western blot. Whole genome sequencing, polymerase chain reaction, and Sanger sequencing revealed a frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream. Semen was archived for future line perpetuation.

This spontaneous canine dystrophinopathy occurred due to a novel mutation in the minor DMD mutation hotspot (between exons 2 through 20). Perpetuating this line could allow for preclinical testing of genetic therapies targeted to this area of the DMD gene.

    Boys
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 have

    DMD gene mutations
    GENETICS

, with associated

    loss of the dystrophin protein
    BIOCHEMICAL

 and

    progressive muscle degeneration
    SYMPTOMS

 and

    weakness
    SYMPTOMS

.

    Corticosteroids
    MEDICATION

 and

    palliative support
    MEDICATION

 are currently the best treatment options. The long-term benefits of recently approved compounds such as

    eteplirsen and ataluren
    MEDICATION

 remain to be seen. Dogs with naturally occurring

    dystrophinopathies
    DIAGNOSIS

 show

    progressive disease akin to that of DMD
    SYMPTOMS

. Accordingly, canine

    DMD
    DIAGNOSIS

 models are useful for studies of pathogenesis and preclinical therapy development. A

    dystrophin-deficient
    GENETICS

,

    male
    GENDER

 border collie dog was evaluated at the

    age of 5 months
    AGE

 for

    progressive muscle weakness
    SYMPTOMS

 and

    dysphagia
    SYMPTOMS

.

    Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L)
    BIOCHEMICAL

 were seen on a

    biochemistry panel
    PARACLINICAL

.

    Histopathologic changes characteristic of dystrophinopathy
    SYMPTOMS

 were seen.

    Dystrophin was absent in the skeletal muscle
    NEG_FINDINGS

 on

    immunofluorescence microscopy
    PARACLINICAL

 and

    western blot
    PARACLINICAL

.

    Whole genome sequencing, polymerase chain reaction, and Sanger sequencing
    PARACLINICAL

 revealed a

    frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream
    GENETICS

.

    Semen
    PARACLINICAL

 was archived for future line perpetuation.

This

    spontaneous canine dystrophinopathy
    DIAGNOSIS

 occurred due to a

    novel mutation in the minor DMD mutation hotspot (between exons 2 through 20)
    GENETICS

. Perpetuating this line could allow for preclinical testing of

    genetic therapies
    MEDICATION

 targeted to this area of the

    DMD gene
    GENETICS

.

Duchenne muscular dystrophy (DMD)
dystrophinopathies
DMD
spontaneous canine dystrophinopathy

Corticosteroids
palliative support
eteplirsen and ataluren
genetic therapies