Case Report: Identification of Maternal Low-Level Mosaicism in the Dystrophin Gene by Droplet Digital Polymerase Chain Reaction.

Germline mosaicism should be suspected when the same de novo mutations are identified in a second pregnancy with asymptomatic parents. Our study aims to find a feasible approach to reveal the existence of germline mosaicism. Multiplex Ligation-dependent Probe Amplification was performed on a Duchenne muscular dystrophy affected pedigree to detect deletion mutations. Then gap-polymerase chain reaction was performed to amplify the breakpoints junction sequence. Droplet digital polymerase chain reaction was utilized to identify the mutation frequencies in healthy parents. The same deletion in the exon 51 of the dystrophin gene, which was 50,035 bp in size, was detected in the proband and the fetus but not in their parents. Droplet digital polymerase chain reaction analysis of peripheral blood samples revealed mutant alleles of 3.53% in maternal blood cells. We here report a case of maternal low-level mosaicism confirmed by droplet digital polymerase chain reaction in peripheral blood samples, which reveals the existence of germline mosaicism. Gap-polymerase chain reaction combined with droplet digital polymerase chain reaction provide insights into the detection of germline mosaicism.

    Germline mosaicism
    GENETICS

 should be suspected when the

    same de novo mutations are identified in a second pregnancy with asymptomatic parents
    FAMILY

. Our study aims to find a feasible approach to reveal the existence of

    germline mosaicism
    GENETICS

.

    Multiplex Ligation-dependent Probe Amplification
    PARACLINICAL

 was performed on a

    Duchenne muscular dystrophy
    DIAGNOSIS

 affected pedigree to detect

    deletion mutations
    GENETICS

. Then

    gap-polymerase chain reaction
    PARACLINICAL

 was performed to

    amplify the breakpoints junction sequence
    PARACLINICAL

.

    Droplet digital polymerase chain reaction
    PARACLINICAL

 was utilized to identify the mutation frequencies in healthy parents. The

    same deletion in the exon 51 of the dystrophin gene, which was 50,035 bp in size, was detected in the proband and the fetus but not in their parents
    GENETICS

.

    Droplet digital polymerase chain reaction analysis of peripheral blood samples
    PARACLINICAL

 revealed

    mutant alleles of 3.53% in maternal blood cells
    GENETICS

. We here report a case of

    maternal low-level mosaicism
    GENETICS

 confirmed by

    droplet digital polymerase chain reaction in peripheral blood samples
    PARACLINICAL

, which reveals the existence of

    germline mosaicism
    GENETICS

.

    Gap-polymerase chain reaction combined with droplet digital polymerase chain reaction
    PARACLINICAL

 provide insights into the detection of

    germline mosaicism
    GENETICS

.


A symptomatic male carrier of Duchenne muscular dystrophy with Klinefelter's syndrome mimicking Becker muscular dystrophy.

Duchenne and Becker muscular dystrophy (DMD/BMD) are commonly inherited muscle disorders. We report a 31-year-old male who had muscle symptoms with left-right differences and intellectual disability. He was diagnosed with BMD at age 15 primarily based on muscle biopsy findings. A few years later, DMD gene analysis revealed that he was a heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation. A karyotype analysis was compatible with XXY Klinefelter's syndrome. The analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample revealed a skewed XCI pattern. This is the first reported case of a symptomatic male carrier of DMD caused by skewed XCI in Klinefelter's syndrome with a genetically proven heterozygous mutation of the DMD gene. The skewed XCI pattern could also explain the left-right differences in skeletal muscle symptoms observed in this patient.

    Duchenne and Becker muscular dystrophy (DMD/BMD)
    DIAGNOSIS

 are commonly

    inherited muscle disorders
    GENETICS

. We report a

    31-year-old
    AGE

    male
    GENDER

 who had

    muscle symptoms with left-right differences
    SYMPTOMS

 and

    intellectual disability
    SYMPTOMS

.

    He
    GENDER

 was diagnosed with

    BMD
    DIAGNOSIS

 at

    age 15
    AGE

 primarily based on

    muscle biopsy
    PARACLINICAL

 findings. A few years later,

    DMD gene analysis
    PARACLINICAL

 revealed that

    he
    GENDER

 was a

    heterozygous carrier of a normal copy of the gene and a mutated copy with an exon 45-54 deletion, which is expected to result in an out-of-frame mutation
    GENETICS

. A

    karyotype analysis
    PARACLINICAL

 was compatible with

    XXY Klinefelter's syndrome
    DIAGNOSIS

. The

    analysis of X-chromosome inactivation (XCI) using his skeletal muscle sample
    PARACLINICAL

 revealed a

    skewed XCI pattern
    GENETICS

. This is the first reported case of a symptomatic

    male
    GENDER

 carrier of

    DMD
    DIAGNOSIS

 caused by

    skewed XCI
    GENETICS

 in

    Klinefelter's syndrome
    DIAGNOSIS

 with a

    genetically proven heterozygous mutation of the DMD gene
    GENETICS

. The

    skewed XCI pattern
    GENETICS

 could also explain the

    left-right differences in skeletal muscle symptoms
    SYMPTOMS

 observed in this patient.


Duchenne Muscular Dystrophy Successfully Treated with Aripiprazole in a Patient with Autism Spectrum Disorder Symptoms Including Irritability.

Duchenne muscular dystrophy (DMD) is associated with neuropsychiatric disorders, and patients often present with autism spectrum disorder (ASD). We herein report a case of DMD accompanied by ASD that was successfully treated with aripiprazole, an atypical antipsychotic that has been used for treating irritability in child and early adolescent patients with ASD. The patient was diagnosed as having DMD at 3 years of age. Although he developed severe psychotic symptoms including irritability, insomnia, hallucinations, and delusions at 17 years of age, all the symptoms were successfully treated with aripiprazole without any detectable side effects.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is associated with

    neuropsychiatric disorders
    DIAGNOSIS

, and patients often present with

    autism spectrum disorder (ASD)
    DIAGNOSIS

. We herein report a case of

    DMD
    DIAGNOSIS

 accompanied by

    ASD
    DIAGNOSIS

 that was successfully treated with

    aripiprazole
    MEDICATION

, an

    atypical antipsychotic
    MEDICATION

 that has been used for treating

    irritability
    DIAGNOSIS

 in

    child
    AGE

 and

    early adolescent
    AGE

 patients with

    ASD
    DIAGNOSIS

. The patient was diagnosed as having

    DMD
    DIAGNOSIS

    at 3 years of age
    AGE

. Although

    he
    GENDER

 developed

    severe psychotic symptoms
    SYMPTOMS

 including

    irritability, insomnia, hallucinations, and delusions
    SYMPTOMS

 at

    17 years of age
    AGE

, all the symptoms were successfully treated with

    aripiprazole
    MEDICATION

    without any detectable side effects
    NEG_FINDINGS

.

Duchenne muscular dystrophy (DMD)
neuropsychiatric disorders
autism spectrum disorder (ASD)
DMD
ASD
irritability
ASD
DMD

aripiprazole
atypical antipsychotic
aripiprazole


Corrigendum: Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

[This corrects the article DOI: 10.3389/fgene.2021.605611.].


Diagnosis of Duchenne Muscular Dystrophy in a Presymptomatic Infant Using Next-Generation Sequencing and Chromosomal Microarray Analysis: A Case Report.

Duchenne muscular dystrophy is a progressive and lethal X-linked recessive neuromuscular disease caused by mutations in the dystrophin gene. It has a high rate of diagnostic delay; early diagnosis and treatment are often not possible due to delayed recognition of muscle weakness and lack of effective treatments. Current treatments based on genetic therapy can improve clinical results, but treatment must begin as early as possible before significant muscle damage. Therefore, early diagnosis and rehabilitation of Duchenne muscular dystrophy are needed before symptom aggravation. Creatine kinase is a diagnostic marker of neuromuscular disorders. Herein, the authors report a case of an infant patient with Duchenne muscular dystrophy with a highly elevated creatine kinase level but no obvious symptoms of muscle weakness. The patient was diagnosed with Duchenne muscular dystrophy via next-generation sequencing and chromosomal microarray analysis to identify possible inherited metabolic and neuromuscular diseases related to profound hyperCKemia. The patient is enrolled in a rehabilitation program and awaits the approval of the genetic treatment in Korea. This is the first report of an infantile presymptomatic Duchenne muscular dystrophy diagnosis using next-generation sequencing and chromosomal microarray analysis.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is a

    progressive and lethal X-linked recessive
    DIAGNOSIS

    neuromuscular disease
    DIAGNOSIS

 caused by

    mutations in the dystrophin gene
    GENETICS

. It has a high rate of diagnostic delay; early diagnosis and treatment are often not possible due to delayed recognition of

    muscle weakness
    SYMPTOMS

 and lack of effective treatments. Current treatments based on

    genetic therapy
    MEDICATION

 can improve clinical results, but treatment must begin as early as possible before significant

    muscle damage
    SYMPTOMS

. Therefore, early diagnosis and

    rehabilitation
    MEDICATION

 of

    Duchenne muscular dystrophy
    DIAGNOSIS

 are needed before symptom aggravation.

    Creatine kinase
    BIOCHEMICAL

 is a diagnostic marker of

    neuromuscular disorders
    DIAGNOSIS

. Herein, the authors report a case of an

    infant
    AGE

 patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 with a

    highly elevated creatine kinase level
    BIOCHEMICAL

 but

    no obvious symptoms of muscle weakness
    NEG_FINDINGS

. The patient was diagnosed with

    Duchenne muscular dystrophy
    DIAGNOSIS

 via

    next-generation sequencing
    PARACLINICAL

 and

    chromosomal microarray analysis
    PARACLINICAL

 to identify possible

    inherited metabolic and neuromuscular diseases
    GENETICS

 related to

    profound hyperCKemia
    BIOCHEMICAL

. The patient is

    enrolled in a rehabilitation program
    MEDICATION

 and awaits the approval of the

    genetic treatment
    MEDICATION

 in

    Korea
    ETHNICITY

. This is the first report of an

    infantile
    AGE

    presymptomatic Duchenne muscular dystrophy
    DIAGNOSIS

 diagnosis using

    next-generation sequencing and chromosomal microarray analysis
    PARACLINICAL

.

genetic therapy
rehabilitation
enrolled in a rehabilitation program
genetic treatment

Creatine kinase
highly elevated creatine kinase level
profound hyperCKemia


Clinical outcome of SARS-CoV-2 infection in 7 adults with Duchenne muscular dystrophy attending a specialist neuromuscular centre.

Due to their frailty and cardiorespiratory compromise adults with DMD are considered extremely vulnerable and at high risk of severe infection should they contract COVID-19. We report 7 adults with DMD aged 17-26 years who tested positive on a nasopharyngeal PCR swab for SARS-CoV-2. Despite long term corticosteroid treatment, severe respiratory compromise requiring night-time ventilation and receiving treatment for moderate to severe cardiomyopathy, none of the patients developed moderate to severe symptoms; in fact two remained asymptomatic and two developed only anosmia and reduced sensation. The remaining three developed transient fever with or without sore throat, cough and runny nose. All recovered fully without complication and no patient required hospitalization.

Due to their frailty and

    cardiorespiratory compromise
    SYMPTOMS

    adults
    AGE

 with

    DMD
    DIAGNOSIS

 are considered extremely vulnerable and at high risk of

    severe infection
    SYMPTOMS

 should they contract

    COVID-19
    DIAGNOSIS

. We report 7

    adults
    AGE

 with

    DMD
    DIAGNOSIS

    aged 17-26 years
    AGE

 who tested

    positive on a nasopharyngeal PCR swab
    PARACLINICAL

 for

    SARS-CoV-2
    DIAGNOSIS

. Despite

    long term corticosteroid treatment
    MEDICATION

,

    severe respiratory compromise
    SYMPTOMS

 requiring

    night-time ventilation
    MEDICATION

 and

    receiving treatment for moderate to severe cardiomyopathy
    MEDICATION

,

    none
    NEG_FINDINGS

 of the patients developed

    moderate to severe symptoms
    NEG_FINDINGS

; in fact two remained

    asymptomatic
    NEG_FINDINGS

 and two developed only

    anosmia
    SYMPTOMS

 and

    reduced sensation
    SYMPTOMS

. The remaining three developed

    transient fever with or without sore throat
    SYMPTOMS

,

    cough
    SYMPTOMS

 and

    runny nose
    SYMPTOMS

. All recovered fully

    without complication
    NEG_FINDINGS

 and

    no patient required hospitalization
    NEG_FINDINGS

.

moderate to severe symptoms
asymptomatic
without complication
no patient required hospitalization


An approach to rapid characterization of DMD copy number variants for prenatal risk assessment.

Prenatal detection of structural variants of uncertain significance, including copy number variants (CNV), challenges genetic counseling, and creates ambiguity for expectant parents. In Duchenne muscular dystrophy, variant classification and phenotypic severity of CNVs are currently assessed by familial segregation, prediction of the effect on the reading frame, and precedent data. Delineation of pathogenicity by familial segregation is limited by time and suitable family members, whereas analytical tools can rapidly delineate potential consequences of variants. We identified a duplication of uncertain significance encompassing a portion of the dystrophin gene (DMD) in an unaffected mother and her male fetus. Using long-read whole genome sequencing and alignment of short reads, we rapidly defined the precise breakpoints of this variant in DMD and could provide timely counseling. The benign nature of the variant was substantiated, more slowly, by familial segregation to a healthy maternal uncle. We find long-read whole genome sequencing of clinical utility in a prenatal setting for accurate and rapid characterization of structural variants, specifically a duplication involving DMD.

    Prenatal
    AGE

 detection of structural variants of uncertain significance, including

    copy number variants (CNV)
    DIAGNOSIS

, challenges

    genetic counseling
    MEDICATION

, and creates ambiguity for expectant parents. In

    Duchenne muscular dystrophy
    DIAGNOSIS

, variant classification and phenotypic severity of CNVs are currently assessed by

    familial segregation
    PARACLINICAL

, prediction of the effect on the reading frame, and precedent data. Delineation of pathogenicity by

    familial segregation
    PARACLINICAL

 is limited by time and suitable family members, whereas analytical tools can rapidly delineate potential consequences of variants. We identified a

    duplication of uncertain significance encompassing a portion of the dystrophin gene (DMD)
    GENETICS

    in an unaffected mother and her male fetus
    FAMILY

. Using

    long-read whole genome sequencing and alignment of short reads
    PARACLINICAL

, we rapidly defined the precise breakpoints of this variant

    in DMD
    GENETICS

 and could provide timely

    counseling
    MEDICATION

. The benign nature of the variant was substantiated, more slowly, by

    familial segregation to a healthy maternal uncle
    FAMILY

. We find

    long-read whole genome sequencing
    PARACLINICAL

 of clinical utility in a

    prenatal
    AGE

 setting for accurate and rapid characterization of structural variants, specifically a

    duplication involving DMD
    GENETICS

.

copy number variants (CNV)
Duchenne muscular dystrophy


Prenatal diagnosis of de novo DMD duplication by multiplex ligation-dependent probe amplification (MLPA) after noninvasive prenatal screening (NIPS) at 11 gestational weeks.

Dystrophinopathy is an X-linked recessive muscular dystrophy caused by mutations in the DMD gene. Herein we describe the prenatal detection of DMD gene mutations in a patient with no family history, by multiplex ligation-dependent probe amplification (MLPA) after noninvasive prenatal screening (NIPS).

A 41-year-old woman underwent NIPS owing to an advanced maternal age. A copy number variation was detected in the maternal X chromosome, and uninformative results were obtained for the fetal sex chromosomes. Following amniocentesis, a duplication was identified in exons 1-29 of the dystrophin gene by MLPA. After interviewing her family members it was confirmed that the patient is a de novo carrier of DMD duplications, and her daughter is a carrier of the same mutation.

his is the first case report to describe the prenatal diagnosis of duplications in the DMD gene by MLPA following NIPS in a patient with no family history.

    Dystrophinopathy
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    muscular dystrophy
    DIAGNOSIS

 caused by

    mutations in the DMD gene
    GENETICS

. Herein we describe the

    prenatal detection
    PARACLINICAL

 of

    DMD gene mutations
    GENETICS

 in a patient with

    no family history
    NEG_FINDINGS

, by

    multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

 after

    noninvasive prenatal screening (NIPS)
    PARACLINICAL

.

A

    41-year-old
    AGE

    woman
    GENDER

 underwent

    NIPS
    PARACLINICAL

 owing to an

    advanced maternal age
    AGE

. A

    copy number variation was detected in the maternal X chromosome
    GENETICS

, and

    uninformative results were obtained for the fetal sex chromosomes
    NEG_FINDINGS

. Following

    amniocentesis
    PARACLINICAL

, a

    duplication
    GENETICS

 was identified

    in exons 1-29 of the dystrophin gene
    GENETICS

 by

    MLPA
    PARACLINICAL

. After

    interviewing her family members
    PARACLINICAL

 it was confirmed that the patient

    is a de novo carrier of DMD duplications
    FAMILY

, and

    her daughter is a carrier of the same mutation
    FAMILY

.

    his
    GENDER

 is the first case report to describe the

    prenatal diagnosis
    PARACLINICAL

 of

    duplications in the DMD gene
    GENETICS

 by

    MLPA
    PARACLINICAL

 following

    NIPS
    PARACLINICAL

 in a patient with

    no family history
    NEG_FINDINGS

.


[Basal cell nevus syndrome with Duchenne muscular dystrophy: a case report].

Basal cell nevus syndrome (BCNS), also known as Gorlin-Goltz syndrome, is a rare autosomal dominant genetic disease. It is thought to be caused by a mutation in the PTCH1 gene, and its incidence is 1/57 000 to 1/256 000. The case of a 7-year-old patient with BCNS and Duchenne muscular dystrophy was reported in this paper.

    Basal cell nevus syndrome (BCNS)
    DIAGNOSIS

, also known as

    Gorlin-Goltz syndrome
    DIAGNOSIS

, is a

    rare autosomal dominant genetic disease
    GENETICS

. It is thought to be caused by a

    mutation in the PTCH1 gene
    GENETICS

, and its incidence is 1/57 000 to 1/256 000. The case of a

    7-year-old
    AGE

 patient with

    BCNS
    DIAGNOSIS

 and

    Duchenne muscular dystrophy
    DIAGNOSIS

 was reported in this paper.

Basal cell nevus syndrome (BCNS)
Gorlin-Goltz syndrome
BCNS
Duchenne muscular dystrophy

rare autosomal dominant genetic disease
mutation in the PTCH1 gene


Alleviation of masticatory disturbance with an occlusal splint in a Duchenne muscular dystrophy patient.

To present an occlusal splint effective for alleviating masticatory disturbance in Duchenne muscular dystrophy (DMD).

A 13-year-old male DMD patient with masticatory disturbance presented with an open bite, with occlusal contact only between the first and second molars bilaterally and reduced masticatory performance. We applied an occlusal splint that achieved occlusal contact for all teeth and monitored its effects on masticatory function over 6 years. The occlusal splint increased occlusal contact points from 11 to 60. Although occlusal force remained at 13.9-16 kg, masticatory performance increased, and the number of mastication strokes increased from 124 to 169. Masseter muscle activity decreased from 76.8% to 33.4% maximum voluntary contraction (MVC) and digastric muscle activity increased from 8.7% to 18.0% MVC. Time from start of peanut mastication to swallowing decreased, and the vertical mastication cycle diameter and its width on the habitual side increased.

Masticatory disturbance in a DMD patient was alleviated using an occlusal splint. The number of mastication strokes and the digastric to masseter muscle activity ratio were increased. Furthermore, the mastication cycle was enlarged, which increased masticatory movement. As masseter muscle activity during mastication decreased, the occlusal splint likely reduced muscle fatigue during masticatory movement.

To present an

    occlusal splint
    MEDICATION

 effective for

    alleviating masticatory disturbance
    SYMPTOMS

 in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

.

A

    13-year-old
    AGE

    male
    GENDER

    DMD
    DIAGNOSIS

 patient with

    masticatory disturbance
    SYMPTOMS

 presented with an

    open bite, with occlusal contact only between the first and second molars bilaterally
    SYMPTOMS

 and

    reduced masticatory performance
    SYMPTOMS

. We

    applied an occlusal splint that achieved occlusal contact for all teeth
    MEDICATION

 and monitored its effects on

    masticatory function
    SYMPTOMS

 over 6 years. The

    occlusal splint increased occlusal contact points from 11 to 60
    MEDICATION

.

    Although occlusal force remained at 13.9-16 kg
    SYMPTOMS

,

    masticatory performance increased
    SYMPTOMS

, and the number

    of mastication strokes increased from 124 to 169
    SYMPTOMS

.

    Masseter muscle activity decreased from 76.8% to 33.4% maximum voluntary contraction (MVC)
    SYMPTOMS

 and

    digastric muscle activity increased from 8.7% to 18.0% MVC
    BIOCHEMICAL

. Time from

    start of peanut mastication to swallowing decreased
    SYMPTOMS

, and the

    vertical mastication cycle diameter and its width on the habitual side increased
    SYMPTOMS

.

    Masticatory disturbance
    SYMPTOMS

 in a

    DMD
    DIAGNOSIS

 patient was alleviated using an

    occlusal splint
    MEDICATION

. The

    number of mastication strokes
    SYMPTOMS

 and the

    digastric to masseter muscle activity ratio were increased
    SYMPTOMS

. Furthermore, the

    mastication cycle was enlarged
    SYMPTOMS

, which increased

    masticatory movement
    SYMPTOMS

. As

    masseter muscle activity during mastication
    SYMPTOMS

    decreased
    PARACLINICAL

, the

    occlusal splint
    MEDICATION

 likely reduced

    muscle fatigue during masticatory movement
    SYMPTOMS

.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Early extubation after left ventricular assist device implantation in a patient with Duchenne muscular dystrophy: a case report.

Management of Duchenne muscular dystrophy (DMD) cardiomyopathy is increasingly important for the survival of these patients. Left ventricular assist device (LVAD) is an alternative treatment for refractory heart failure in DMD. A 20-year-old man with DMD and dilated cardiomyopathy underwent surgery for LVAD implantation. Respiratory failure may occur due to muscle weakness after surgery under general anesthesia in patients with DMD, and weaning from mechanical ventilation may be delayed or difficult. Considering the application of fast-track anesthesia (FTA), preoperative pulmonary rehabilitation which includes thoracic expansion exercise, air stacking exercise with manual resuscitation bag and manually assisted cough technique, hight-frequency chest wall oscillation, and mechanical insufflation-exsufflation was performed. We report on a patient with DMD in whom FTA and early extubation within 6 h after LVAD implantation was successfully performed without complications.

Management of

    Duchenne muscular dystrophy (DMD) cardiomyopathy
    DIAGNOSIS

 is increasingly important for the survival of these patients.

    Left ventricular assist device (LVAD)
    MEDICATION

 is an alternative treatment for

    refractory heart failure
    SYMPTOMS

 in

    DMD
    DIAGNOSIS

. A

    20-year-old
    AGE

    man
    GENDER

 with

    DMD
    DIAGNOSIS

 and

    dilated cardiomyopathy
    DIAGNOSIS

 underwent

    surgery for LVAD implantation
    MEDICATION

.

    Respiratory failure
    SYMPTOMS

 may occur due to

    muscle weakness
    SYMPTOMS

 after

    surgery
    MEDICATION

 under

    general anesthesia
    MEDICATION

 in patients with

    DMD
    DIAGNOSIS

, and

    weaning from mechanical ventilation
    MEDICATION

 may be delayed or difficult. Considering the application of

    fast-track anesthesia (FTA)
    MEDICATION

,

    preoperative pulmonary rehabilitation which includes thoracic expansion exercise
    MEDICATION

,

    air stacking exercise with manual resuscitation bag and manually assisted cough technique
    MEDICATION

,

    hight-frequency chest wall oscillation
    MEDICATION

, and

    mechanical insufflation-exsufflation
    MEDICATION

 was performed. We report on a patient with

    DMD
    DIAGNOSIS

 in whom

    FTA and early extubation within 6 h after LVAD implantation
    MEDICATION

 was successfully performed

    without complications
    NEG_FINDINGS

.

refractory heart failure
Respiratory failure
muscle weakness


Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy.

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the DMD gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a Chinese family who present with clinical manifestations of both two diseases, including poor motor development and progressive muscle weakness. We identified a homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene by whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA). This case expands our understanding of diagnosis for synchronous SMA and DMD and highlights the importance of various genetic testing methods, including WES, in differential diagnosis of neuromuscular diseases.

    Spinal muscular atrophy (SMA)
    DIAGNOSIS

 and

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 are two common kinds of

    neuromuscular disorders
    DIAGNOSIS

 sharing various similarities in clinical manifestations.

    SMA
    DIAGNOSIS

 is an

    autosomal recessive genetic disorder
    GENETICS

 that results from

    biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome
    GENETICS

.

    DMD
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

 caused by

    defects in the DMD gene (OMIM 300377) on the X chromosome
    GENETICS

. Here, for the first time, we report a case from a

    Chinese
    ETHNICITY

 family who present with

    clinical manifestations of both two diseases
    SYMPTOMS

, including

    poor motor development
    SYMPTOMS

 and

    progressive muscle weakness
    SYMPTOMS

. We identified a

    homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene
    GENETICS

 by

    whole-exome sequencing (WES)
    PARACLINICAL

 and

    multiplex ligation-dependent probe amplification (MLPA)
    PARACLINICAL

. This case expands our understanding of diagnosis for

    synchronous SMA and DMD
    DIAGNOSIS

 and highlights the importance of various genetic testing methods, including WES, in

    differential diagnosis
    PARACLINICAL

 of

    neuromuscular diseases
    DIAGNOSIS

.

Spinal muscular atrophy (SMA)
Duchenne muscular dystrophy (DMD)
neuromuscular disorders
SMA
DMD
synchronous SMA and DMD
neuromuscular diseases


A rare case of monozygotic triplets with Duchenne muscular dystrophy.

Twins with Duchenne muscular dystrophy (DMD) have been widely studied. We report the first rare case of monozygotic triplets with DMD who shared consistent phenotypes, including delayed motor and language milestones, muscle wasting and weakness, joint contracture, and lumbar lordosis. Muscle magnetic resonance imaging and biopsy revealed the similar muscle injury characteristics and dystrophin absence. Short tandem repeat analysis confirmed monozygosity. A de novo mutation (exon 49-52 deletion) was found in the triplets but not in their mother. Treatment included prednisone, idebenone, and rehabilitation management. At the 2-year follow-up, motor function had deteriorated, and muscle fatty infiltration was more extensive and severe. Our case offers a unique opportunity for genetic and therapeutic research. Furthermore, it highlights the critical role of genetic factors in DMD phenotypes and provides a potential choice for treatment observations.

    Twins
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 have been widely studied. We report the first rare case of

    monozygotic triplets with DMD
    FAMILY

 who shared consistent phenotypes, including

    delayed motor and language milestones
    SYMPTOMS

,

    muscle wasting and weakness
    SYMPTOMS

,

    joint contracture
    SYMPTOMS

, and

    lumbar lordosis
    SYMPTOMS

.

    Muscle magnetic resonance imaging and biopsy
    PARACLINICAL

 revealed the

    similar muscle injury characteristics
    SYMPTOMS

 and

    dystrophin absence
    BIOCHEMICAL

.

    Short tandem repeat analysis
    PARACLINICAL

 confirmed

    monozygosity
    FAMILY

.

    A de novo mutation (exon 49-52 deletion) was found in the triplets but not in their mother
    GENETICS

. Treatment included

    prednisone, idebenone
    MEDICATION

, and

    rehabilitation management
    MEDICATION

. At the

    2-year follow-up
    PARACLINICAL

,

    motor function had deteriorated
    SYMPTOMS

, and

    muscle fatty infiltration was more extensive and severe
    SYMPTOMS

. Our case offers a unique opportunity for genetic and therapeutic research. Furthermore, it highlights the critical role of genetic factors in

    DMD
    DIAGNOSIS

 phenotypes and provides a potential choice for treatment observations.

prednisone, idebenone
rehabilitation management


Third case of Duchenne muscular dystrophy and West syndrome: Expanding the spectrum of the DMD neuropsychiatric phenotype.

Duchenne muscular dystrophy is an X-Linked neuromuscular disorder, and the most common muscular dystrophy. Neuropsychiatric phenotype associated to DMD gene mutations include now low IQ scores, epilepsy, autism, and attention deficit disorder. These have been observed with higher frequency in mutations that disrupt the short isoforms Dp71 and Dp140. West syndrome has been previously reported in two unrelated patients with Duchenne muscular dystrophy. Here, we report the third patient with West syndrome who had a novel hemizygous nonsense pathogenic variant in the exon 8 of the DMD gene c.811C>T, p.(Gln271*), suggesting West syndrome as part of the neuropsychiatric spectrum in Duchenne muscular dystrophy.

    Duchenne muscular dystrophy
    DIAGNOSIS

 is an

    X-Linked
    GENETICS

    neuromuscular disorder
    DIAGNOSIS

, and the most common

    muscular dystrophy
    DIAGNOSIS

.

    Neuropsychiatric phenotype
    SYMPTOMS

 associated to

    DMD gene mutations
    GENETICS

 include

    now low IQ scores
    SYMPTOMS

,

    epilepsy
    SYMPTOMS

,

    autism
    SYMPTOMS

, and

    attention deficit disorder
    DIAGNOSIS

. These have been observed with higher frequency in

    mutations that disrupt the short isoforms Dp71 and Dp140
    GENETICS

.

    West syndrome
    DIAGNOSIS

 has been previously reported in two unrelated patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

. Here, we report the third patient with

    West syndrome
    DIAGNOSIS

 who had a

    novel hemizygous nonsense pathogenic variant in the exon 8 of the DMD gene c.811C>T, p.(Gln271*)
    GENETICS

, suggesting

    West syndrome
    DIAGNOSIS

 as part of the

    neuropsychiatric spectrum
    DIAGNOSIS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy
neuromuscular disorder
muscular dystrophy
attention deficit disorder
West syndrome
Duchenne muscular dystrophy
West syndrome
West syndrome
neuropsychiatric spectrum
Duchenne muscular dystrophy

Neuropsychiatric phenotype
now low IQ scores
epilepsy
autism


Case Report: Co-occurrence of Duchenne Muscular Dystrophy and Frontometaphyseal Dysplasia 1.

Herein, we present a rare case of co-occurring Duchenne muscular dystrophy (DMD) and frontometaphyseal dysplasia 1 (FMD1), two different X-linked diseases, in a 7-year-old boy. He presented with proximal muscle weakness and elevated creatine phosphokinase levels. A multiplex ligation-dependent probe amplification study of DMD revealed the de novo duplications of exons 2-37, thereby confirming the diagnosis of DMD. Initial evaluation revealed atypical features, such as facial dysmorphism, multiple joint contractures, and severe scoliosis, at an early age. However, these were overlooked and were assumed to be atypical manifestations of DMD. Then, the patient's maternal cousin was diagnosed with FMD1 with pathogenic missense variant in FLNA (NM_001110556.2: c.3557C>T/p.Ser1186Leu). A family genetic test revealed that the patient and his mother had the same pathogenic variant in FLNA. The patient's atypical manifestations were considered symptoms of FMD1. Therefore, if one disease does not fully explain the patient's clinical features, an expanded genetic study is needed to detect coincidental disease.

Herein, we present a rare case of

    co-occurring Duchenne muscular dystrophy (DMD) and frontometaphyseal dysplasia 1 (FMD1)
    DIAGNOSIS

, two different

    X-linked diseases
    GENETICS

, in a

    7-year-old
    AGE

    boy
    GENDER

.

    He
    GENDER

 presented with

    proximal muscle weakness
    SYMPTOMS

 and

    elevated creatine phosphokinase levels
    BIOCHEMICAL

. A

    multiplex ligation-dependent probe amplification study of DMD
    PARACLINICAL

 revealed the

    de novo duplications of exons 2-37
    GENETICS

, thereby confirming the diagnosis of

    DMD
    DIAGNOSIS

. Initial evaluation revealed

    atypical features
    SYMPTOMS

, such as

    facial dysmorphism
    SYMPTOMS

,

    multiple joint contractures
    SYMPTOMS

, and

    severe scoliosis
    SYMPTOMS

,

    at an early age
    AGE

. However, these were overlooked and were assumed to be

    atypical manifestations of DMD
    NEG_FINDINGS

. Then, the patient's maternal cousin was diagnosed with FMD1 with

    pathogenic missense variant in FLNA (NM_001110556.2: c.3557C>T/p.Ser1186Leu)
    GENETICS

. A

    family genetic test
    PARACLINICAL

 revealed

    that the patient and his mother had the same pathogenic variant in FLNA
    FAMILY

. The patient's

    atypical manifestations
    SYMPTOMS

 were considered symptoms of

    FMD1
    DIAGNOSIS

. Therefore, if one disease does not fully explain the patient's clinical features, an

    expanded genetic study
    PARACLINICAL

 is needed to detect coincidental disease.

proximal muscle weakness
atypical features
facial dysmorphism
multiple joint contractures
severe scoliosis
atypical manifestations


A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in DMD gene effecting the expression of dystrophin. Generally female carriers are asymptomatic; however, it has been suggested that carriers may exhibit symptoms. We investigated a 6-year-old Chinese girl exhibiting a suspected BMD phenotype, including persistently elevated creatine kinase and creatine kinase isoenzyme levels. The proband harbored a novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene inherited from her mother who had a completely normal phenotype and presented with mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]. In addition, X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%. Amplification of regions of the cDNA revealed different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%. Real-time PCR showed that mRNA expression was significantly decreased in both. We proposed that a frameshift or nonsense mutation may contribute to the development of symptoms in carriers. These phenotypes correlate with nonrandom XCI patterns and are compounded by the locus of the mutation. For incompletely skewed XCI patterns, although the mutant allele could suppress the expression of a normal allele, carriers would remain asymptomatic as long as there was adequate compensation from the normal allele. We also proposed a mechanism where mRNA from the mutant allele may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 are both caused by

    mutations in DMD gene
    GENETICS

 effecting the

    expression of dystrophin
    GENETICS

. Generally

    female
    GENDER

 carriers are

    asymptomatic
    NEG_FINDINGS

; however, it has been suggested that carriers may exhibit symptoms. We investigated a

    6-year-old
    AGE

    Chinese
    ETHNICITY

    girl
    GENDER

 exhibiting a suspected

    BMD
    DIAGNOSIS

 phenotype, including

    persistently elevated creatine kinase and creatine kinase isoenzyme levels
    BIOCHEMICAL

. The

    proband
    GENDER

 harbored a

    novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene
    GENETICS

    inherited from her mother who had a completely normal phenotype
    FAMILY

 and presented with

    mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]
    GENETICS

. In addition,

    X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%
    GENETICS

.

    Amplification of regions of the cDNA
    PARACLINICAL

 revealed

    different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%
    GENETICS

.

    Real-time PCR
    PARACLINICAL

 showed that

    mRNA expression was significantly decreased in both
    GENETICS

. We proposed that a

    frameshift or nonsense mutation
    GENETICS

 may contribute to the development of symptoms in carriers. These phenotypes correlate with

    nonrandom XCI patterns
    GENETICS

 and are compounded by the locus of the mutation. For

    incompletely skewed XCI patterns
    GENETICS

, although the

    mutant allele could suppress the expression of a normal allele
    GENETICS

, carriers would remain

    asymptomatic
    NEG_FINDINGS

 as long as there was adequate compensation from the normal allele. We also proposed a mechanism where

    mRNA from the mutant allele
    GENETICS

 may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.

Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
BMD


Widespread severe myodegeneration in a compound heterozygote female dog with dystrophin deficiency.

The University of Missouri (MU) has established a colony of dystrophin-deficient dogs with a mixed breed background to mirror the variable pathologic effects of dystrophinopathies between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a normal-appearing 10-month-old colony female that died suddenly. At necropsy examination, there were reduced skeletal and laryngeal muscle volume and mild dilatation of the oesophagus. Microscopic findings consisted of extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles that were characterized by considerable central nucleation, individual fibre mineralization and interstitial fibrosis. The myocardial findings were limited to infiltration of adipose cells in the interstitium. The female dog was a compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene. Although the direct cause of death was uncertain, it might likely be due to sudden cardiac death as has been seen in Duchenne muscular dystrophy patients. This case demonstrated dystrophinopathy in female dogs that have no ameliorating normal X chromosome.

The University of Missouri (MU) has established a colony of

    dystrophin-deficient
    DIAGNOSIS

 dogs with a mixed breed background to mirror the variable pathologic effects of

    dystrophinopathies
    DIAGNOSIS

 between persons of a given kindred to further the understanding of the genetic and molecular basis of the variable phenotype; thus to facilitate discovery of an effective therapeutic strategy. Herein we report the phenotype and genotype of a

    normal-appearing
    SYMPTOMS

    10-month-old
    AGE

 colony

    female
    GENDER

 that

    died
    SYMPTOMS

 suddenly. At

    necropsy examination
    PARACLINICAL

, there were

    reduced skeletal and laryngeal muscle volume
    SYMPTOMS

 and

    mild dilatation of the oesophagus
    SYMPTOMS

. Microscopic findings consisted of

    extensive degeneration and regeneration of the axial skeletal, tongue, oesophageal, and laryngeal muscles
    SYMPTOMS

 that were characterized by

    considerable central nucleation
    MICROSCOPIC

,

    individual fibre mineralization
    MICROSCOPIC

 and

    interstitial fibrosis
    MICROSCOPIC

. The

    myocardial findings
    SYMPTOMS

 were limited to

    infiltration of adipose cells in the interstitium
    MICROSCOPIC

. The

    female
    GENDER

    dog
    GENDER

 was a

    compound heterozygote with one X chromosome carrying a point mutation in intron 6 of the dystrophin gene and the other X chromosome carrying a repetitive element insertion in intron 13 of the dystrophin gene
    GENETICS

. Although the direct cause of

    death
    SYMPTOMS

 was uncertain, it might likely be due to

    sudden cardiac death
    SYMPTOMS

 as has been seen in

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients. This case demonstrated

    dystrophinopathy
    DIAGNOSIS

 in

    female
    GENDER

 dogs that have

    no ameliorating normal X chromosome
    GENETICS

.

dystrophin-deficient
dystrophinopathies
Duchenne muscular dystrophy
dystrophinopathy


Transaminitis in a Three-year-old Boy with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disease of the neuromuscular system and is the most serious type of muscular dystrophy in humans. The disease is characterized by progressive muscular atrophy and a poor prognosis. The incidence rate is 1/3500, and symptoms appear at age of 5 years-old. Some patients present with abnormal aminotransferases as the first symptom. In addition to the clinical characteristics and genetic history, electromyography examination, muscle biopsy, serum enzyme examination, and measures of creatine kinase (CK), CK isoenzyme, and serum lactate dehydrogenase are important features of auxiliary examination. Clinicians who encounter unknown causes of transaminitis should consider the possibility of DMD. We describe here a 3 year-old pediatric patient with increased aminotransferases who had elevated CK and a family genetic history but without liver damage on computed tomography. He was suspected as having inherited the disorder and was finally diagnosed as having DMD by next-generation sequencing.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    fatal X-linked genetic disease of the neuromuscular system
    GENETICS

 and is the most serious type of

    muscular dystrophy
    DIAGNOSIS

 in humans. The disease is characterized by

    progressive muscular atrophy
    SYMPTOMS

 and a poor prognosis. The incidence rate is 1/3500, and symptoms appear at

    age of 5 years-old
    AGE

. Some patients present with

    abnormal aminotransferases
    BIOCHEMICAL

 as the first symptom. In addition to the clinical characteristics and

    genetic history
    PARACLINICAL

,

    electromyography examination
    PARACLINICAL

,

    muscle biopsy
    PARACLINICAL

,

    serum enzyme examination
    PARACLINICAL

, and

    measures of creatine kinase (CK), CK isoenzyme, and serum lactate dehydrogenase
    BIOCHEMICAL

 are important features of

    auxiliary examination
    PARACLINICAL

. Clinicians who encounter unknown causes of

    transaminitis
    BIOCHEMICAL

 should consider the possibility of

    DMD
    DIAGNOSIS

. We describe here a

    3 year-old
    AGE

    pediatric
    AGE

 patient with

    increased aminotransferases
    BIOCHEMICAL

 who had

    elevated CK
    BIOCHEMICAL

 and a

    family genetic history
    FAMILY

 but

    without liver damage on computed tomography
    NEG_FINDINGS

.

    He
    GENDER

 was suspected as having

    inherited the disorder
    DIAGNOSIS

 and was finally diagnosed as having

    DMD
    DIAGNOSIS

 by

    next-generation sequencing
    GENETICS

.

Duchenne muscular dystrophy (DMD)
muscular dystrophy
DMD
inherited the disorder
DMD


A 17-Year-Old With Becker Muscular Dystrophy and Unusual Polysomnography Findings.

A 17-year-old male patient who was diagnosed with Becker muscular dystrophy (nonsense mutation [c.3822C>A] within exon 28 of the DMD gene) at 6 years of age was evaluated in the multidisciplinary neuromuscular clinic for loss of ambulation for 1 year. From a pulmonary perspective, there were no acute or chronic respiratory symptoms, and no history of pneumonia or aspiration. Clinical examination revealed a nonambulant teenager, with normal oxygen saturation and end-tidal CO2 when awake, no respiratory distress, and symmetrically diminished aeration due to obesity (BMI 40 kg/m2). Results of pulmonary function testing revealed FVC of 83% predicted with actual volume of 3.5 L and peak cough flow of 445 L/min (all within normal limits).

A

    17-year-old
    AGE

    male
    GENDER

 patient who was diagnosed with

    Becker muscular dystrophy
    DIAGNOSIS

 (

    nonsense mutation [c.3822C>A] within exon 28 of the DMD gene)
    GENETICS

 at

    6 years of age
    AGE

 was evaluated in the multidisciplinary neuromuscular clinic for

    loss of ambulation for 1 year
    SYMPTOMS

. From a pulmonary perspective, there were

    no acute or chronic respiratory symptoms
    NEG_FINDINGS

, and

    no history of pneumonia or aspiration
    NEG_FINDINGS

. Clinical examination revealed a

    nonambulant
    NEG_FINDINGS

    teenager
    AGE

, with

    normal oxygen saturation and end-tidal CO2 when awake
    NEG_FINDINGS

,

    no respiratory distress
    NEG_FINDINGS

, and

    symmetrically diminished aeration
    SYMPTOMS

 due to

    obesity
    SYMPTOMS

 (

    BMI 40 kg/m2)
    SYMPTOMS

. Results of

    pulmonary function testing
    PARACLINICAL

 revealed

    FVC of 83% predicted with actual volume of 3.5 L
    SYMPTOMS

 and

    peak cough flow of 445 L/min (all within normal limits)
    SYMPTOMS

.


Expanded Carrier Screening and the Complexity of Implementation.

Advances in genetic technology have allowed for the development of multiplex panels that can test for hundreds of genetic disorders at the same time; these large panels are referred to as expanded carrier screening. This process can screen couples for far more conditions than the gene-by-gene approach used with traditional carrier screening; however, although expanded carrier screening has been promoted as an efficient means of detecting many more disorders, the complexities of genetic sequencing raise substantial challenges and concerns. In our practice, we have seen a number of complex cases in which only attention to detail on the part of thorough genetic counselors allowed identification of misclassified variants that could have resulted in significant patient harm. We raise issues that require urgent attention by professional societies, including: whether to endorse testing that uses sequencing compared with genotyping; required components of pretest and posttest counseling; reclassification of variants; whether obstetric health care professionals have a responsibility to assure that patients understand the iterative process of variant interpretation and how it relates to carrier screening results; and the question of rescreening in subsequent pregnancies. Implementation of expanded carrier screening needs to be considered thoughtfully in light of the complexity of genetic sequencing and limited knowledge of genetics of most front-line obstetric health care professionals.

Advances in genetic technology have allowed for the development of multiplex panels that can test for hundreds of

    genetic disorders
    GENETICS

 at the same time; these large panels are referred to as

    expanded carrier screening
    PARACLINICAL

. This process can screen

    couples
    GENDER

 for far more conditions than the gene-by-gene approach used with traditional

    carrier screening
    PARACLINICAL

; however, although

    expanded carrier screening
    PARACLINICAL

 has been promoted as an efficient means of detecting many more disorders, the complexities of genetic sequencing raise substantial challenges and concerns. In our practice, we have seen a number of complex cases in which only attention to detail on the part of thorough genetic counselors allowed identification of misclassified variants that could have resulted in significant patient harm. We raise issues that require urgent attention by professional societies, including: whether to endorse testing that uses sequencing compared with

    genotyping
    PARACLINICAL

; required components of

    pretest and posttest counseling
    MEDICATION

; reclassification of variants; whether obstetric health care professionals have a responsibility to assure that patients understand the iterative process of variant interpretation and how it relates to carrier screening results; and the question of rescreening in subsequent pregnancies. Implementation of

    expanded carrier screening
    MEDICATION

 needs to be considered thoughtfully in light of the complexity of

    genetic sequencing
    PARACLINICAL

 and limited knowledge of genetics of most front-line obstetric health care professionals.

pretest and posttest counseling
expanded carrier screening


A child with duchenne muscular dystrophy: A case report of a rare diagnosis among Africans.

In Africa, lack of awareness and low index of suspicion of rare diseases like dystrophinopathies, directly or indirectly, contributes to the increased morbidity and mortality. Therefore, even though the data on prevalence is limited, we need to have a high degree of suspicion in patients presenting with suggestive clinical features.

In

    Africa
    ETHNICITY

, lack of awareness and low index of suspicion of

    rare diseases
    DIAGNOSIS

 like

    dystrophinopathies
    DIAGNOSIS

, directly or indirectly, contributes to the increased morbidity and mortality. Therefore, even though the data on prevalence is limited, we need to have a high degree of suspicion in patients presenting with suggestive clinical features.


Confined placental mosaicism of Duchenne muscular dystrophy: a case report.

Small copy number variations confined to the placenta are extremely rare findings in chorionic villus sampling, nonetheless of great clinical importance. To the best of our knowledge, this is the first reported case of confined placental mosaicism for an intragenic Duchenne muscular dystrophy (DMD) gene deletion.

We describe a pregnant woman where confined placental mosaicism for an intragenic DMD deletion was detected. She was referred for a chorionic villus sampling due to an increased risk of trisomy 21 derived from combined first trimester screening. Rapid aneuploidy detection showed a male fetus with normal results for chromosomes 13, 18 and 21. A chromosomal microarray demonstrated a deletion of exons 61-62 in the DMD gene in approximately 50% of the cells. A follow-up analysis on amniotic cells showed a normal result for the DMD gene. Hence, confined placental mosaicism was confirmed.

We propose tissue specific fragile sites as a possible theoretical mechanism for the formation of submicroscopic copy number variations and highlight that the finding of DMD deletion mosaicism in a chorionic villus sample might be isolated to the placenta. Therefore, confirmation by amniocentesis is of crucial clinical importance to avoid misdiagnosis of the fetus.

    Small copy number variations confined to the placenta
    SYMPTOMS

 are extremely rare findings in

    chorionic villus sampling
    PARACLINICAL

, nonetheless of great clinical importance. To the best of our knowledge, this is the first reported case of

    confined placental mosaicism for an intragenic Duchenne muscular dystrophy (DMD) gene deletion
    GENETICS

.

We describe a

    pregnant
    AGE

    woman
    GENDER

 where

    confined placental mosaicism for an intragenic DMD deletion
    GENETICS

 was detected.

    She
    GENDER

 was referred for a

    chorionic villus sampling
    PARACLINICAL

 due to an increased risk of

    trisomy 21
    DIAGNOSIS

 derived from

    combined first trimester screening
    PARACLINICAL

.

    Rapid aneuploidy detection
    PARACLINICAL

 showed a

    male fetus
    SYMPTOMS

 with

    normal results for chromosomes 13, 18 and 21
    NEG_FINDINGS

. A

    chromosomal microarray
    PARACLINICAL

 demonstrated a

    deletion of exons 61-62 in the DMD gene in approximately 50% of the cells
    GENETICS

. A

    follow-up analysis on amniotic cells
    PARACLINICAL

 showed a

    normal result for the DMD gene
    NEG_FINDINGS

. Hence,

    confined placental mosaicism
    DIAGNOSIS

 was confirmed.

We propose

    tissue specific fragile sites
    GENETICS

 as a possible theoretical mechanism for the formation of

    submicroscopic copy number variations
    GENETICS

 and highlight that the finding of

    DMD deletion mosaicism
    GENETICS

 in a

    chorionic villus sample
    SYMPTOMS

 might be isolated to the placenta. Therefore,

    confirmation by amniocentesis
    PARACLINICAL

 is of crucial clinical importance to avoid

    misdiagnosis of the fetus
    NEG_FINDINGS

.


Recurrent Exercise-Induced Rhabdomyolysis in a Healthy Adolescent Girl.

Female symptomatic carriers of Duchenne muscular dystrophy (DMD) are uncommon findings. Much of this disease has been studied from a male perspective, but female disease presentation and progression are rarely described. This report describes a female adolescent patient with a rare and unconventional presentation of DMD.

    Female
    GENDER

 symptomatic carriers of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 are uncommon findings. Much of this disease has been studied from a

    male
    GENDER

 perspective, but

    female
    GENDER

 disease presentation and progression are rarely described. This report describes a

    female
    GENDER

    adolescent
    AGE

 patient with a rare and unconventional presentation of

    DMD
    DIAGNOSIS

.


Thyroid storm after mitral valve repair in a patient with Becker muscular dystrophy.

A 40-year-old male with Becker muscular dystrophy presented with severe mitral regurgitation and underwent mitral valve repair. Following the surgery, the patient became tachycardic and developed a continuous high-grade fever and hyperbilirubinemia. The patient's condition worsened and we eventually tested his thyroid levels and discovered abnormally high thyroid levels. After diagnosing a severe thyroid storm, the patient was treated with oral administration of Lugol's iodine and thiamazole, as well as an intravenous steroid, which led to an immediate improvement of symptoms. The incidence of thyroid storm after open-heart surgery is extremely rare but highly life-threatening if unrecognized.

A

    40-year-old
    AGE

    male
    GENDER

 with

    Becker muscular dystrophy
    DIAGNOSIS

 presented with

    severe mitral regurgitation
    SYMPTOMS

 and underwent

    mitral valve repair
    MEDICATION

. Following the

    surgery
    MEDICATION

, the patient became

    tachycardic
    SYMPTOMS

 and developed a

    continuous high-grade fever
    SYMPTOMS

 and

    hyperbilirubinemia
    BIOCHEMICAL

. The patient's condition worsened and we eventually tested his

    thyroid levels
    PARACLINICAL

 and discovered

    abnormally high thyroid levels
    BIOCHEMICAL

. After diagnosing a

    severe thyroid storm
    DIAGNOSIS

, the patient was treated with

    oral administration of Lugol's iodine and thiamazole, as well as an intravenous steroid
    MEDICATION

, which led to an

    immediate improvement of symptoms
    SYMPTOMS

. The incidence of

    thyroid storm
    DIAGNOSIS

 after

    open-heart surgery
    MEDICATION

 is extremely rare but highly life-threatening if unrecognized.

Becker muscular dystrophy
severe thyroid storm
thyroid storm

severe mitral regurgitation
tachycardic
continuous high-grade fever
immediate improvement of symptoms

hyperbilirubinemia
abnormally high thyroid levels


Beneficial effects of one-month sacubitril/valsartan treatment in a patient affected by end-stage dystrophinopathic cardiomyopathy.

Dystrophinopathic cardiomyopathy (DCM) is an almost constant manifestation in Becker muscular dystrophy (BMD) patients signiﬁcantly contributing to morbidity and mortality. The nearly complete replacement of the myocardium by fibrous and fatty connective tissue results in an irreversible cardiac failure, characterized by progressive reduction of the ejection fraction. According to PARADIGM-HF trial results, the European Society of Cardiology (ESC) guidelines recommend the use of sacubitril/valsartan in ambulatory patients with heart failure and reduced ejection fraction, who remain symptomatic despite an optimal medical therapy. To date, little is still known about the use of sacubitril/valsartan in DCM. We report the case of a patient with dystrophinopathic end stage dilated cardiomyopathy with reduced ejection fraction who successfully responded to sacubitril/valsartan treatment.

    Dystrophinopathic cardiomyopathy (DCM)
    DIAGNOSIS

 is an almost constant manifestation in

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 patients signiﬁcantly contributing to morbidity and mortality. The

    nearly complete replacement of the myocardium by fibrous and fatty connective tissue
    MICROSCOPIC

 results in an

    irreversible cardiac failure
    SYMPTOMS

, characterized by

    progressive reduction of the ejection fraction
    SYMPTOMS

. According to PARADIGM-HF trial results, the European Society of Cardiology (ESC) guidelines recommend the use of

    sacubitril/valsartan
    MEDICATION

 in ambulatory patients with

    heart failure
    SYMPTOMS

 and

    reduced ejection fraction
    SYMPTOMS

, who

    remain symptomatic despite an optimal medical therapy
    NEG_FINDINGS

. To date, little is still known about the use of

    sacubitril/valsartan
    MEDICATION

 in

    DCM
    DIAGNOSIS

. We report the case of a patient with

    dystrophinopathic end stage dilated cardiomyopathy
    DIAGNOSIS

 with

    reduced ejection fraction
    SYMPTOMS

 who successfully responded to

    sacubitril/valsartan treatment
    MEDICATION

.

sacubitril/valsartan
sacubitril/valsartan
sacubitril/valsartan treatment


Psychological Case Conference Following the Death of a Patient With Neuromuscular Disease: A Source of Emotional Support for Participating Medical Staff.

Healthcare professionals involved in the treatment and care of patients with intractable diseases, such as muscular dystrophy, increasingly encounter situations that can elicit emotional distress for them as well as the patients. Therefore, medical professionals also need support. This article describes a psychological case conference of multidisciplinary professionals involved in the treatment of a deceased patient with Duchenne muscular dystrophy. The conference aimed to support medical professionals in reflecting on and sharing their thoughts, feelings, and conflicts. Such a practice could support medical professionals in reflecting patients' thoughts and sharing their personal experiences with other staff members, which may alleviate emotional and personal conflicts. Reflecting on their interactions and dealings with patients serves this supportive function. Psychological case conferences for medical staff may serve as an opportunity for participants to feel emotionally supported and may perhaps help prevent burnout.

Healthcare professionals involved in the treatment and care of patients with

    intractable diseases
    DIAGNOSIS

, such as

    muscular dystrophy
    DIAGNOSIS

, increasingly encounter situations that can elicit

    emotional distress
    SYMPTOMS

 for them as well as the patients. Therefore, medical professionals also need support. This article describes a

    psychological case conference
    MEDICATION

 of multidisciplinary professionals involved in the treatment of a deceased patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

. The conference aimed to support medical professionals in reflecting on and sharing their thoughts, feelings, and conflicts. Such a practice could support medical professionals in reflecting patients' thoughts and sharing their personal experiences with other staff members, which may

    alleviate emotional and personal conflicts
    SYMPTOMS

. Reflecting on their interactions and dealings with patients serves this supportive function. Psychological case conferences for medical staff may serve as an opportunity for participants to feel emotionally supported and may perhaps help prevent

    burnout
    SYMPTOMS

.

intractable diseases
muscular dystrophy
Duchenne muscular dystrophy


Infection-associated decrease of serum creatine kinase levels in Fukuyama congenital muscular dystrophy.

Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases.

The influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy.

A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions.

Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.

    Marked decreases in serum creatine kinase levels
    BIOCHEMICAL

 have been noted in

    Duchenne
    DIAGNOSIS

 and

    Becker muscular dystrophies
    DIAGNOSIS

 as rare complications of

    autoimmune or autoinflammatory diseases
    DIAGNOSIS

.

The influence of

    systemic inflammation
    SYMPTOMS

 on

    serum creatine kinase levels
    BIOCHEMICAL

 was reviewed from the charts of three subjects with

    Fukuyama congenital muscular dystrophy
    DIAGNOSIS

.

A total of 30

    infectious events
    SYMPTOMS

 were identified.

    Elevated serum C-reactive protein levels
    BIOCHEMICAL

 coincided with

    decreased creatine kinase levels
    BIOCHEMICAL

 on 19 occasions. In one subject,

    administration of 2 mg/kg/d prednisolone for bronchial asthma
    MEDICATION

 resulted in a

    decrease in creatine kinase level
    BIOCHEMICAL

 on six other occasions.

Apart from an

    increase in endogenous cortisol secretion
    BIOCHEMICAL

, certain

    inflammation-related molecules
    BIOCHEMICAL

 could play a role in

    mitigating muscle cell damage
    SYMPTOMS

 in

    Fukuyama congenital muscular dystrophy
    DIAGNOSIS

 during

    febrile infectious episodes
    SYMPTOMS

.

    Corticosteroids
    MEDICATION

 may be a promising agent for the treatment of

    muscular symptoms
    SYMPTOMS

 in this disorder.

Duchenne
Becker muscular dystrophies
autoimmune or autoinflammatory diseases
Fukuyama congenital muscular dystrophy
Fukuyama congenital muscular dystrophy

systemic inflammation
infectious events
mitigating muscle cell damage
febrile infectious episodes
muscular symptoms


Prenatal diagnosis of Duchenne muscular dystrophy revealed a novel mosaic mutation in Dystrophin gene: a case report.

Duchenne muscular dystrophies (DMDs) are X-linked recessive neuromuscular disorders with malfunction or absence of the Dystrophin protein. Precise genetic diagnosis is critical for proper planning of patient care and treatment. In this study, we described a Chinese family with mosaic DMD mutations and discussed the best method for prenatal diagnosis and genetic counseling of X-linked familial disorders.

We investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family and identified two variants of the DMD gene in a sick boy and two female carriers by targeted next generation sequencing (TNGS), Sanger sequencing, and haplotype analysis.

We identified the hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD in the sick boy, which was inherited from his mother. Unexpectedly, a novel heterozygous mutation c.6796delA (p.I2266Ffs*5) of the same gene, which was considered to be a de novo variant, was detected from his younger sister instead of his mother by Sanger sequencing. However, further NGS analysis of the mother and her amniotic fluid samples revealed that the mother carried a low-level mosaic c.6796delA mutation.

We reported two different mutations of the DMD gene in two siblings, including the novel mutation c.6796delA (p.I2266Ffs*5) inherited from the asymptomatic mosaic-carrier mother. This finding has enriched the knowledge of the pathogenesis of DMD. If no mutation is detected in obligate carriers, the administration of intricate STR/NGS/Sanger analysis will provide new ideas on the prenatal diagnosis of DMD.

    Duchenne muscular dystrophies (DMDs)
    DIAGNOSIS

 are

    X-linked recessive
    GENETICS

    neuromuscular disorders
    DIAGNOSIS

 with

    malfunction or absence of the Dystrophin protein
    SYMPTOMS

. Precise

    genetic diagnosis
    PARACLINICAL

 is critical for proper planning of patient care and treatment. In this study, we described a

    Chinese
    ETHNICITY

 family with

    mosaic DMD mutations
    GENETICS

 and discussed the best method for

    prenatal diagnosis
    PARACLINICAL

 and

    genetic counseling
    MEDICATION

 of

    X-linked familial disorders
    GENETICS

.

We

    investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family
    PARACLINICAL

 and identified

    two variants of the DMD gene
    GENETICS

 in a sick

    boy
    GENDER

 and two

    female
    GENDER

    carriers
    FAMILY

 by

    targeted next generation sequencing (TNGS), Sanger sequencing, and haplotype analysis
    PARACLINICAL

.

We identified the

    hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD
    GENETICS

 in the sick

    boy
    GENDER

,

    which was inherited from his mother
    FAMILY

. Unexpectedly, a

    novel heterozygous mutation c.6796delA (p.I2266Ffs*5) of the same gene, which was considered to be a de novo variant, was detected from his younger sister instead of his mother
    GENETICS

 by

    Sanger sequencing
    PARACLINICAL

. However,

    further NGS analysis of the mother and her amniotic fluid samples
    PARACLINICAL

 revealed that the

    mother carried a low-level mosaic c.6796delA mutation
    FAMILY

.

We reported

    two different mutations of the DMD gene
    GENETICS

    in two siblings
    FAMILY

, including the

    novel mutation c.6796delA (p.I2266Ffs*5)
    GENETICS

    inherited from the asymptomatic mosaic-carrier mother
    FAMILY

. This finding has enriched the knowledge of the pathogenesis of

    DMD
    DIAGNOSIS

. If

    no mutation is detected in obligate carriers
    NEG_FINDINGS

, the administration of

    intricate STR/NGS/Sanger analysis
    PARACLINICAL

 will provide new ideas on the

    prenatal diagnosis
    PARACLINICAL

 of

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophies (DMDs)
neuromuscular disorders
DMD
DMD


Flexible intramedullary nailing for supracondylar femoral fractures in children with Duchenne muscular dystrophy.

BACKGROUND Femoral fractures are common in patients with Duchenne muscular dystrophy (DMD) and represent a critical moment in the natural history of the disease. The immobilization required for fracture healing frequently leads to further weakening and worsening (or definitive loss) of functional abilities. Surgical treatment has been advocated in ambulatory and nonambulatory patients with rapid mobilization of patients as the main goal; however, it exposes patients to considerable anesthetic risk. CASE REPORT We present a previously unreported experience of flexible intramedullary nailing (FIN) in 2 DMD patients (aged 11.7 and 12.8 years) who were still able to walk or stand when the supracondylar femoral fractures occurred. The surgical procedures were performed with sufficient reduction and stabilization of fractures. Rapid mobilization of the patients was achieved, including muscle strengthening exercises. A prompt recovery of the upright standing position and successive ambulation was accomplished in the patient with the higher functional status before the fracture, whereas the standing ability was not recovered in the other patient. No increase of knee flexion contractures and no growth disturbances were recorded at the follow-up. CONCLUSIONS The operative treatment option should be considered by a multidisciplinary team; they should evaluate the advantages and risks for each patient considering their functional status. For ambulatory children (or patients still able to stand), FIN can represent a valid, minimally invasive, apparently growth-sparing and sufficiently stable osteosynthesis, allowing rapid rehabilitation of the patient that can limit, but not completely avoid the consequences of the femoral fracture.

BACKGROUND

    Femoral fractures
    SYMPTOMS

 are common in patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and represent a critical moment in the natural history of the disease. The

    immobilization
    MEDICATION

 required for

    fracture healing
    MEDICATION

 frequently leads to

    further weakening and worsening (or definitive loss) of functional abilities
    SYMPTOMS

.

    Surgical treatment
    MEDICATION

 has been advocated in

    ambulatory
    MEDICATION

 and

    nonambulatory
    MEDICATION

 patients with

    rapid mobilization of patients
    MEDICATION

 as the main goal; however, it exposes patients to considerable anesthetic risk. CASE REPORT We present a previously unreported experience of

    flexible intramedullary nailing (FIN)
    MEDICATION

 in 2

    DMD
    DIAGNOSIS

 patients (

    aged 11.7 and 12.8 years
    AGE

) who were

    still able to walk or stand
    NEG_FINDINGS

 when the

    supracondylar femoral fractures
    SYMPTOMS

 occurred. The

    surgical procedures
    MEDICATION

 were performed with

    sufficient reduction and stabilization of fractures
    MEDICATION

.

    Rapid mobilization of the patients
    MEDICATION

 was achieved, including

    muscle strengthening exercises
    MEDICATION

. A

    prompt recovery of the upright standing position and successive ambulation
    SYMPTOMS

 was accomplished in the patient with the

    higher functional status before the fracture
    SYMPTOMS

, whereas

    the standing ability was not recovered
    NEG_FINDINGS

 in the other patient.

    No increase of knee flexion contractures
    NEG_FINDINGS

 and

    no growth disturbances
    NEG_FINDINGS

 were recorded at the

    follow-up
    PARACLINICAL

. CONCLUSIONS The

    operative treatment
    MEDICATION

 option should be considered by a multidisciplinary team; they should evaluate the advantages and risks for each patient considering their functional status. For

    ambulatory children
    AGE

 (or patients still

    able to stand
    NEG_FINDINGS

),

    FIN
    MEDICATION

 can represent a valid,

    minimally invasive, apparently growth-sparing and sufficiently stable osteosynthesis
    MEDICATION

, allowing

    rapid rehabilitation
    MEDICATION

 of the patient that can limit, but not completely avoid the consequences of the

    femoral fracture
    SYMPTOMS

.


Tension Pneumocephalus in a Tracheostomized, Chronically Ventilated, Duchenne's Muscular Dystrophy Patient Without Prior Head Trauma.

Tension pneumocephalus is a rare condition that can be a life-threatening neurosurgical emergency. It usually results from head trauma, but there have been case reports of iatrogenic causes including on non-invasive mechanical ventilation. We report a case of pneumocephalus resulting from high mechanical ventilation pressures in a patient without prior head trauma. A 37-year-old male with Duchenne's muscular dystrophy who had been ventilator-dependent through tracheostomy was admitted for shortness of breath and intermittent fevers. The patient was found to have pneumonia, with left-lower lobe consolidation, and was started on linezolid given known Methicillin-resistant Staphylococcus aureus from previous sputum culture; he was later switched to vancomycin and piperacillin-tazobactam given persistent fevers to cover for hospital-acquired pneumonia. The patient went into septic shock requiring multiple pressors as well as stress steroids for persistent shock, with eventual improvement in hemodynamics. He developed further respiratory acidosis on his usual ventilator settings, and peak inspiratory pressures (PIPs) progressively increased to as high as 45-70 cm H2O during his hospital course. PIPs did not improve with suctioning or after bronchoscopy. On the 17th day of the patient's stay, he had acutely altered mental status with non-reactive fixed and dilated pupils and disconjugate gaze of the right eye on neurologic examination. CT of the head at that time revealed extensive pneumocephalus along the bifrontal convexities, suprasellar cisterns, and posterior fossa, with a possible fracture of the frontal skull base near the ethmoid roof. Mount Fuji sign was present on CT scan, indicative of "tension pneumocephalus". Neurosurgical consultation was obtained but the family declined intervention given his overall debilitated stated. Comfort measures were instituted, and the patient expired the following day. Pneumocephalus is the accumulation of air entry into the cranial cavity, generally from head trauma, inflammation, or surgery. Patients may have underlying base skull defects or microfractures that permit air to enter the intracranial cavity. Increased sphenoid sinus pressure from mechanical ventilation may enter the subperiosteal space, allowing air to enter the intracranial cavity. It is important to consider pneumocephalus in a patient with new neurological findings after mechanical ventilation.

    Tension pneumocephalus
    SYMPTOMS

 is a rare condition that can be a life-threatening neurosurgical emergency. It usually results from

    head trauma
    SYMPTOMS

, but there have been case reports of iatrogenic causes including on

    non-invasive mechanical ventilation
    MEDICATION

. We report a case of

    pneumocephalus
    SYMPTOMS

 resulting from

    high mechanical ventilation pressures
    MEDICATION

 in a patient

    without prior head trauma
    NEG_FINDINGS

. A

    37-year-old
    AGE

    male
    GENDER

 with

    Duchenne's muscular dystrophy
    DIAGNOSIS

 who had been

    ventilator-dependent through tracheostomy
    MEDICATION

 was admitted for

    shortness of breath
    SYMPTOMS

 and

    intermittent fevers
    SYMPTOMS

. The patient was found to have

    pneumonia
    DIAGNOSIS

, with

    left-lower lobe consolidation
    SYMPTOMS

, and was started on

    linezolid
    MEDICATION

 given known

    Methicillin-resistant Staphylococcus aureus
    DIAGNOSIS

 from previous

    sputum culture
    PARACLINICAL

;

    he
    GENDER

 was later

    switched to vancomycin and piperacillin-tazobactam
    MEDICATION

 given

    persistent fevers
    SYMPTOMS

 to cover for

    hospital-acquired pneumonia
    DIAGNOSIS

. The patient went into

    septic shock
    SYMPTOMS

 requiring

    multiple pressors as well as stress steroids
    MEDICATION

 for

    persistent shock
    SYMPTOMS

, with eventual

    improvement in hemodynamics
    SYMPTOMS

.

    He
    GENDER

 developed

    further respiratory acidosis
    SYMPTOMS

    on his usual ventilator settings
    NEG_FINDINGS

, and

    peak inspiratory pressures (PIPs) progressively increased to as high as 45-70 cm H2O
    SYMPTOMS

 during his hospital course.

    PIPs did not improve with suctioning or after bronchoscopy
    NEG_FINDINGS

. On the 17th day of the patient's stay,

    he
    GENDER

 had

    acutely altered mental status
    SYMPTOMS

 with

    non-reactive fixed and dilated pupils
    NEG_FINDINGS

 and

    disconjugate gaze of the right eye
    SYMPTOMS

 on

    neurologic examination
    PARACLINICAL

.

    CT of the head
    PARACLINICAL

 at that time revealed

    extensive pneumocephalus along the bifrontal convexities, suprasellar cisterns, and posterior fossa
    SYMPTOMS

, with a

    possible fracture of the frontal skull base near the ethmoid roof
    SYMPTOMS

.

    Mount Fuji sign was present on CT scan
    SYMPTOMS

, indicative of "

    tension pneumocephalus"
    SYMPTOMS

.

    Neurosurgical consultation
    MEDICATION

 was obtained but the

    family declined intervention
    NEG_FINDINGS

 given

    his
    GENDER

    overall debilitated stated
    NEG_FINDINGS

.

    Comfort measures
    MEDICATION

 were instituted, and the patient

    expired
    SYMPTOMS

 the following day.

    Pneumocephalus
    SYMPTOMS

 is the

    accumulation of air entry into the cranial cavity
    SYMPTOMS

, generally from

    head trauma
    SYMPTOMS

,

    inflammation
    SYMPTOMS

, or

    surgery
    MEDICATION

. Patients may have

    underlying base skull defects
    SYMPTOMS

 or

    microfractures
    SYMPTOMS

 that

    permit air to enter the intracranial cavity
    SYMPTOMS

.

    Increased sphenoid sinus pressure from mechanical ventilation
    SYMPTOMS

 may enter the subperiosteal space, allowing

    air to enter the intracranial cavity
    SYMPTOMS

. It is important to consider

    pneumocephalus
    SYMPTOMS

 in a patient with

    new neurological findings
    SYMPTOMS

 after

    mechanical ventilation
    MEDICATION

.


Splicing Characteristics of Dystrophin Pseudoexons and Identification of a Novel Pathogenic Intronic Variant in the DMD Gene.

Pseudoexon (PE) inclusion has been implicated in various dystrophinopathies; however, its splicing characteristics have not been fully investigated. This study aims to analyze the splicing characteristics of dystrophin PEs and compare them with those of dystrophin canonical exons (CEs). Forty-two reported dystrophin PEs were divided into a splice site (ss) group and a splicing regulatory element (SRE) group. Five dystrophin PEs with characteristics of poison exons were identified and categorized as the possible poison exon group. The comparative analysis of each essential splicing signal among different groups of dystrophin PEs and dystrophin CEs revealed that the possible poison exon group had a stronger 3' ss compared to any other group. As for auxiliary SREs, different groups of dystrophin PEs were found to have a smaller density of diverse types of exonic splicing enhancers and a higher density of several types of exonic splicing silencers compared to dystrophin CEs. In addition, the possible poison exon group had a smaller density of 3' ss intronic splicing silencers compared to dystrophin CEs. To our knowledge, our findings indicate for the first time that poison exons might exist in DMD (the dystrophin gene) and present with different splicing characteristics than other dystrophin PEs and CEs.

    Pseudoexon (PE) inclusion
    GENETICS

 has been implicated in various

    dystrophinopathies
    DIAGNOSIS

; however, its splicing characteristics have not been fully investigated. This study aims to analyze the splicing characteristics of

    dystrophin PEs
    GENETICS

 and compare them with those of dystrophin canonical exons (CEs). Forty-two reported

    dystrophin PEs
    GENETICS

 were divided into a splice site (ss) group and a splicing regulatory element (SRE) group. Five

    dystrophin PEs
    GENETICS

 with

    characteristics of poison exons
    GENETICS

 were identified and categorized as the possible poison exon group. The comparative analysis of each essential splicing signal among different groups of dystrophin PEs and dystrophin CEs revealed that the possible poison exon group had a

    stronger 3' ss
    GENETICS

 compared to any other group. As for

    auxiliary SREs
    GENETICS

, different groups of

    dystrophin PEs
    GENETICS

 were found to have a

    smaller density of diverse types of exonic splicing enhancers and a higher density of several types of exonic splicing silencers
    GENETICS

 compared to

    dystrophin CEs
    GENETICS

. In addition, the possible poison exon group had a

    smaller density of 3' ss intronic splicing silencers
    GENETICS

 compared to

    dystrophin CEs
    GENETICS

. To our knowledge, our findings indicate for the first time that poison exons might exist in

    DMD (the dystrophin gene
    GENETICS

) and present with different splicing characteristics than other dystrophin PEs and CEs.


X-Linked Duchenne-Type Muscular Dystrophy in Jack Russell Terrier Associated with a Partial Deletion of the Canine DMD Gene.

A 9-month old male Jack Russell Terrier started showing paraparesis of the hindlimbs after a walk. Hospitalized, the dog went into cardiac arrest, and later died. Necroscopic examination revealed a severe thickness of the diaphragm, esophagus, and base of the tongue, leading to the diagnosis of muscular dystrophy. The histology confirmed the marked size variation, regeneration, and fibrosis replacement of the skeletal muscle fibers. Immunohistochemistry demonstrated the absence of dystrophin confirming the diagnosis. Transmission electron microscopy showed disarrangement of skeletal muscle fibers. Finally, whole-genome sequencing identified a ~368kb deletion spanning 19 exons of the canine dystrophin (DMD) gene. This pathogenic loss-of-function variant most likely explains the observed disease phenotype. The X-chromosomal variant was absent in seven controls of the same breed. Most likely, this partial deletion of the DMD gene was either transmitted on the maternal path within the family of the affected dog or arose de novo. This study revealed a spontaneous partial deletion in DMD gene in a Jack Russell Terrier showing a Duchenne-type muscular dystrophy due to non-functional dystrophin.

A

    9-month old
    AGE

    male
    GENDER

    Jack Russell Terrier
    ETHNICITY

 started showing

    paraparesis of the hindlimbs
    SYMPTOMS

 after a walk. Hospitalized, the

    dog
    GENDER

 went into

    cardiac arrest
    SYMPTOMS

, and later

    died
    SYMPTOMS

.

    Necroscopic examination
    PARACLINICAL

 revealed a

    severe thickness of the diaphragm, esophagus, and base of the tongue
    SYMPTOMS

, leading to the diagnosis of

    muscular dystrophy
    DIAGNOSIS

. The

    histology
    PARACLINICAL

 confirmed the

    marked size variation, regeneration, and fibrosis replacement of the skeletal muscle fibers
    SYMPTOMS

.

    Immunohistochemistry
    PARACLINICAL

 demonstrated the

    absence of dystrophin
    BIOCHEMICAL

 confirming the diagnosis.

    Transmission electron microscopy
    PARACLINICAL

 showed

    disarrangement of skeletal muscle fibers
    MICROSCOPIC

. Finally,

    whole-genome sequencing
    PARACLINICAL

 identified a

    ~368kb deletion spanning 19 exons of the canine dystrophin (DMD) gene
    GENETICS

. This

    pathogenic loss-of-function variant
    GENETICS

 most likely explains the observed disease phenotype.

    The X-chromosomal variant
    GENETICS

 was absent in seven controls of the same breed. Most likely, this

    partial deletion of the DMD gene was either transmitted on the maternal path
    GENETICS

    within the family of the affected dog
    FAMILY

 or arose de novo. This study revealed a

    spontaneous partial deletion in DMD gene
    GENETICS

 in a

    Jack Russell Terrier
    ETHNICITY

 showing a

    Duchenne-type muscular dystrophy
    DIAGNOSIS

 due to

    non-functional dystrophin
    NEG_FINDINGS

.

Jack Russell Terrier
Jack Russell Terrier

muscular dystrophy
Duchenne-type muscular dystrophy


The Neurocognitive and Behavioral Profiles of 3 Brothers With Becker Muscular Dystrophy.

Becker muscular dystrophy patients generally carry in-frame mutations in the dystrophin gene, allowing the production of partially functional dystrophin protein. The presence of cognitive and behavioral comorbidities and the relation with the location of mutations has been scarcely investigated in Becker. This case report describes the neurocognitive and behavioral profiles of 3 brothers with Becker carrying an in-frame deletion of exons 45-48. The 3 cases underwent 2 consecutive neuropsychological assessments of which one assessment took place when they completed their primary education (age range of the cases: 11.2 -12.1 years). Intellectual abilities were normal to high and all cases had difficulties with processing speed and math. The brothers differed in intellectual abilities, executive functions, working memory, attention and reading abilities. Variability in cognitive development was noted as well. This report suggests that cognitive and behavioral functions in Becker vary regardless of gene mutation and exposer to similar environmental factors.

    Becker muscular dystrophy
    DIAGNOSIS

 patients generally carry

    in-frame mutations in the dystrophin gene
    GENETICS

, allowing the production of

    partially functional dystrophin protein
    BIOCHEMICAL

. The presence of

    cognitive and behavioral comorbidities
    SYMPTOMS

 and the relation with the location of mutations has been scarcely investigated in

    Becker
    DIAGNOSIS

. This case report describes the

    neurocognitive and behavioral profiles
    SYMPTOMS

 of 3

    brothers
    GENDER

 with

    Becker
    DIAGNOSIS

 carrying an

    in-frame deletion of exons 45-48
    GENETICS

. The 3 cases underwent 2 consecutive

    neuropsychological assessments
    PARACLINICAL

 of which one assessment took place when they

    completed their primary education
    AGE

 (

    age range of the cases: 11.2 -12.1 years)
    AGE

.

    Intellectual abilities were normal to high
    NEG_FINDINGS

 and all cases had

    difficulties with processing speed and math
    SYMPTOMS

. The

    brothers
    GENDER

 differed in

    intellectual abilities, executive functions, working memory, attention and reading abilities
    SYMPTOMS

.

    Variability in cognitive development
    SYMPTOMS

 was noted as well. This report suggests that

    cognitive and behavioral functions
    SYMPTOMS

 in

    Becker
    DIAGNOSIS

 vary regardless of gene mutation and exposer to similar environmental factors.

Becker muscular dystrophy
Becker
Becker
Becker


MPV promote adherence to nocturnal NIV in a Duchenne patient.

We described a case of a patient 20 years old, affected by Duchenne dystrophy with obstructive sleep apnoea syndrome and severe nocturnal desaturation. He was not compliant to non-invasive ventilation (NIV) for claustrophobia and panic attacks. Mouthpiece ventilation was successfully used in this patient, who later accepted the nighttime NIV.

We described a case of a patient

    20 years old
    AGE

, affected by

    Duchenne dystrophy
    DIAGNOSIS

 with

    obstructive sleep apnoea syndrome
    DIAGNOSIS

 and

    severe nocturnal desaturation
    SYMPTOMS

.

    He
    GENDER

    was not compliant to non-invasive ventilation (NIV) for claustrophobia and panic attacks
    NEG_FINDINGS

.

    Mouthpiece ventilation
    MEDICATION

 was successfully used in this patient, who later

    accepted the nighttime NIV
    MEDICATION

.

Duchenne dystrophy
obstructive sleep apnoea syndrome

Mouthpiece ventilation
accepted the nighttime NIV


Complex Glycerol Kinase Deficiency (Xp21 Deletion Syndrome): A Case Report of a Contiguous Gene Disorder Necessitating Creative Anesthetic Planning.

We report a case of Xp21 deletion syndrome, a contiguous gene syndrome associating glycerol kinase deficiency, Duchenne muscular dystrophy, and congenital adrenal hypoplasia. This results in a contraindication to the use of all halogenated agents and of propofol. We used regional anesthesia combined with dexmedetomidine and ketamine. Previously, the patient had received inadvertently a propofol-based total intravenous anesthesia (TIVA) with no clinical side effects. We were unfortunately unable to document the metabolic consequences of this glycerol load. We suggest that if propofol is deemed necessary in such cases, it should only be used as a bolus dose of a 2% solution.

We report a case of

    Xp21 deletion syndrome
    GENETICS

, a

    contiguous gene syndrome
    GENETICS

 associating

    glycerol kinase deficiency
    BIOCHEMICAL

,

    Duchenne muscular dystrophy
    DIAGNOSIS

, and

    congenital adrenal hypoplasia
    SYMPTOMS

. This results in a

    contraindication to the use of all halogenated agents and of propofol
    NEG_FINDINGS

. We used

    regional anesthesia combined with dexmedetomidine and ketamine
    MEDICATION

. Previously, the patient had

    received inadvertently a propofol-based total intravenous anesthesia (TIVA)
    MEDICATION

    with no clinical side effects
    NEG_FINDINGS

. We were

    unfortunately unable to document the metabolic consequences of this glycerol load
    NEG_FINDINGS

. We suggest that if

    propofol
    MEDICATION

 is deemed necessary in such cases, it should only be used

    as a bolus dose of a 2% solution
    MEDICATION

.

Xp21 deletion syndrome
contiguous gene syndrome


X-Linked Myotubular Myopathy and Duchenne Muscular Dystrophy in a Preterm Infant: A Rare Combination.

Disorders of central and peripheral nervous system should be considered in floppy infants with ventilator dependence. Workup for neuromuscular disorders should be undertaken in infants with hypotonia, weakness, contractures, feeding difficulties, or failed attempts at extubation. We present the case of a preterm infant with hypotonia and ventilator dependence where despite a positive result, further investigations were undertaken because of lack of clinical correlation. The infant had a rare combination of 2 neuromuscular conditions: X-linked myotubular myopathy and Duchenne muscular dystrophy. One was the reason for immediate clinical manifestation and the other influenced the prognosis and decision-making in determining reorientation of care. This case demonstrates the value of interpretation of a positive result that did not explain the clinical picture and warranted consideration of further diagnosis. This case also emphasizes the importance of discussions with family about the prognosis of 2 conditions that influenced decision making.

    Disorders of central and peripheral nervous system
    DIAGNOSIS

 should be considered in

    floppy infants
    AGE

 with

    ventilator dependence
    SYMPTOMS

. Workup for

    neuromuscular disorders
    DIAGNOSIS

 should be undertaken in

    infants
    AGE

 with

    hypotonia
    SYMPTOMS

,

    weakness
    SYMPTOMS

,

    contractures
    SYMPTOMS

,

    feeding difficulties
    SYMPTOMS

, or

    failed attempts at extubation
    NEG_FINDINGS

. We present the case of a

    preterm
    AGE

    infant
    AGE

 with

    hypotonia
    SYMPTOMS

 and

    ventilator dependence
    SYMPTOMS

 where

    despite a positive result, further investigations were undertaken because of lack of clinical correlation
    NEG_FINDINGS

. The

    infant
    AGE

 had a

    rare combination of 2 neuromuscular conditions: X-linked myotubular myopathy and Duchenne muscular dystrophy
    DIAGNOSIS

. One was the reason for immediate clinical manifestation and the other influenced the prognosis and decision-making in determining reorientation of care. This case demonstrates the value of interpretation of a positive result that did not explain the clinical picture and warranted consideration of further diagnosis. This case also emphasizes the importance of discussions with family about the prognosis of 2 conditions that influenced decision making.

ventilator dependence
hypotonia
weakness
contractures
feeding difficulties
hypotonia
ventilator dependence