Severe, neonatal-onset OTC deficiency in twin sisters with a de novo balanced reciprocal translocation t(X;5)(p21.1;q11).

OTC deficiency, the most common urea cycle defect, is transmitted as a partially dominant X-linked trait. The most severe form of the disease, however, is usually restricted to males. We report on monozygotic female twins with severe neonatal-onset OTC deficiency and a de novo balanced reciprocal translocation t(X;5)(p21.1;q11). Disruption of the OTC gene on the derivative X-chromosome was confirmed by FISH analysis. Consistent inactivation of the normal X could be demonstrated by RGB staining. Manifestation of X-linked recessive disorders in females due to a balanced reciprocal X-autosome translocation has previously been described in Duchenne muscular dystrophy and several other disorders but not in OTC deficiency. This report emphasizes the importance of chromosome analysis in any female manifesting severe OTC deficiency.

    OTC deficiency
    BIOCHEMICAL

, the most common

    urea cycle defect
    BIOCHEMICAL

, is

    transmitted as a partially dominant X-linked trait
    GENETICS

. The most severe form of the disease, however, is usually restricted to

    males
    GENDER

. We report on

    monozygotic female
    FAMILY

 twins with

    severe neonatal-onset OTC deficiency
    BIOCHEMICAL

 and a

    de novo balanced reciprocal translocation t(X;5)(p21.1;q11)
    GENETICS

.

    Disruption of the OTC gene on the derivative X-chromosome
    GENETICS

 was confirmed by

    FISH analysis
    PARACLINICAL

.

    Consistent inactivation of the normal X
    GENETICS

 could be demonstrated by

    RGB staining
    PARACLINICAL

. Manifestation of

    X-linked recessive disorders
    GENETICS

 in

    females
    GENDER

 due to a

    balanced reciprocal X-autosome translocation
    GENETICS

 has previously been described in

    Duchenne muscular dystrophy
    DIAGNOSIS

 and several other disorders but not in

    OTC deficiency
    BIOCHEMICAL

. This report emphasizes the importance of

    chromosome analysis
    PARACLINICAL

 in any

    female
    GENDER

 manifesting

    severe OTC deficiency
    BIOCHEMICAL

.

OTC deficiency
urea cycle defect
severe neonatal-onset OTC deficiency
OTC deficiency
severe OTC deficiency


Duchenne muscular dystrophy with associated growth hormone deficiency.

A patient with Duchenne muscular dystrophy (DMD) and growth hormone (GH) deficiency is described who had no clinical evidence of muscular weakness before initiation of GH replacement therapy. Treatment with human GH resulted in appearance of symptoms of easy fatigability and proximal muscle weakness. Thorough investigations including serum creatinine phosphokinase (CK) levels is recommended in every patient with GH deficiency before starting GH replacement therapy.

A patient with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    growth hormone (GH) deficiency
    BIOCHEMICAL

 is described who had

    no clinical evidence of muscular weakness
    NEG_FINDINGS

 before

    initiation of GH replacement therapy
    NEG_FINDINGS

.

    Treatment with human GH
    MEDICATION

 resulted in appearance of

    symptoms of easy fatigability
    SYMPTOMS

 and

    proximal muscle weakness
    SYMPTOMS

.

    Thorough investigations
    PARACLINICAL

 including

    serum creatinine phosphokinase (CK) levels
    PARACLINICAL

 is recommended in every patient with

    GH deficiency
    BIOCHEMICAL

 before starting

    GH replacement therapy
    MEDICATION

.

growth hormone (GH) deficiency
GH deficiency

Treatment with human GH
GH replacement therapy

symptoms of easy fatigability
proximal muscle weakness


Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome.

We report on a prenatal diagnosis of DMD complicated by a 45,X karyotype that was revealed only in the chorionic villus long-term culture.

Cytogenetic investigations were performed on both short-term (STC) and long-term cultures (LTC) of the chorionic villus sample. Familial segregation was performed using a panel of intragenic polymorphic markers, and multiplex PCR was used to characterize exonic deletion.

Investigations performed for sex determination after STC of the chorionic villus sample showed a normal karyotype 46,XX, while the karyotype performed after LTC revealed a homogeneous monosomy X. Cytogenetic analysis performed on amniotic fluid cells showed 45,X/46,XX mosaicism. Familial segregation analysis for DMD showed loss of heterozygosity for the STR49 marker in the DNA of the proband, her mother and the foetus. Dystrophin gene analysis on the 45,X cells led to the identification of a deletion of exon 50.

The report described a rare situation of monosomy X associated with a DMD genotype. The data confirmed the DMD carrier status of the proband and her mother and indicated that the foetus had a high risk to combine a Turner phenotype and DMD. This study illustrated the potential risk of using short-term culture of villi as the only source of biological material for prenatal diagnosis.

We report on a

    prenatal diagnosis
    DIAGNOSIS

 of

    DMD
    DIAGNOSIS

 complicated by a

    45,X karyotype
    GENETICS

 that was revealed only in the

    chorionic villus long-term culture
    PARACLINICAL

.

    Cytogenetic investigations
    PARACLINICAL

 were performed

    on both short-term (STC) and long-term cultures (LTC) of the chorionic villus sample
    PARACLINICAL

.

    Familial segregation was performed using a panel of intragenic polymorphic markers
    PARACLINICAL

, and

    multiplex PCR
    PARACLINICAL

 was used to characterize

    exonic deletion
    GENETICS

.

Investigations performed for

    sex determination
    PARACLINICAL

 after

    STC of the chorionic villus sample
    PARACLINICAL

 showed a

    normal karyotype 46,XX
    NEG_FINDINGS

, while the

    karyotype performed after LTC
    PARACLINICAL

 revealed a homogeneous monosomy X.

    Cytogenetic analysis performed on amniotic fluid cells
    PARACLINICAL

 showed

    45,X/46,XX mosaicism
    GENETICS

.

    Familial segregation analysis for DMD
    PARACLINICAL

 showed

    loss of heterozygosity for the STR49 marker in the DNA of the proband, her mother and the foetus
    GENETICS

.

    Dystrophin gene analysis on the 45,X cells
    PARACLINICAL

 led to the identification of a

    deletion of exon 50.
    GENETICS

The report described a rare situation of

    monosomy X associated with a DMD genotype
    GENETICS

. The data confirmed

    the DMD carrier status of the proband and her mother
    FAMILY

 and indicated that the

    foetus had a high risk to combine a Turner phenotype and DMD
    FAMILY

. This study illustrated the potential risk of using

    short-term culture of villi
    PARACLINICAL

 as the only source of biological material for

    prenatal diagnosis
    PARACLINICAL

.


Detection of germline mosaicism in two Duchenne muscular dystrophy families using polymorphic dinucleotide (CA)n repeat loci within the dystrophin gene.

Approximately one-third of new cases of Duchenne muscular dystrophy (DMD) can be attributed to sporadically arising new mutations, however in the majority of cases the DMD mutation has been inherited from the mother. These female carriers can have either a constitutive or mosaic mutation.

The aim of this study was to determine the segregation of the at-risk haplotype and to find a deletion in the dystrophin gene of patients.

We analyzed individuals from two families with a history of DMD in order to predict the carrier status of related females. In one of these cases the mother had two affected sons, while in the other one son and two grandchildren were affected; therefore we predict that the mother would be an obligatory carrier.

Haplotype analysis of the DMD loci revealed that in the two families both the healthy and affected brothers had inherited the same X maternal chromosome. However, the affected brother carried a deletion, which was absent in the unaffected sibling.

These findings suggested that the mothers in the two families were germline mosaics for the DMD gene. The results of this study demonstrate the usefulness of the methodology that combine the haplotype analysis with the identification of the mutation in order to detect hidden germline mosaicisms and, thus, improve genetic counseling.

Approximately one-third of new cases of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 can be attributed to

    sporadically arising new mutations
    GENETICS

, however in the majority of cases the

    DMD mutation has been inherited from the mother
    FAMILY

. These

    female
    GENDER

 carriers can have either a

    constitutive or mosaic mutation
    GENETICS

.

The aim of this study was to determine the

    segregation of the at-risk haplotype
    GENETICS

 and to find a

    deletion in the dystrophin gene
    GENETICS

 of patients.

We analyzed individuals from two

    families with a history of DMD
    FAMILY

 in order to predict the carrier status of related

    females
    GENDER

. In one of these cases

    the mother had two affected sons
    FAMILY

, while in the other

    one son and two grandchildren were affected
    FAMILY

; therefore we predict that the

    mother would be an obligatory carrier
    FAMILY

.

    Haplotype analysis of the DMD loci
    PARACLINICAL

 revealed

    that in the two families both the healthy and affected brothers had inherited the same X maternal chromosome
    FAMILY

. However,

    the affected brother carried a deletion, which was absent in the unaffected sibling
    FAMILY

.

These findings suggested that

    the mothers in the two families were germline mosaics for the DMD gene
    FAMILY

. The results of this study demonstrate the usefulness of the methodology that combine the

    haplotype analysis
    PARACLINICAL

 with the

    identification of the mutation
    PARACLINICAL

 in order to detect

    hidden germline mosaicisms
    GENETICS

 and, thus, improve

    genetic counseling
    MEDICATION

.

sporadically arising new mutations
constitutive or mosaic mutation
segregation of the at-risk haplotype
deletion in the dystrophin gene
hidden germline mosaicisms


C-terminal truncated dystrophin identified in skeletal muscle of an asymptomatic boy with a novel nonsense mutation of the dystrophin gene.

Mutations that cause premature stop codons in the dystrophin gene lead to a complete loss of dystrophin from skeletal muscle, resulting in severe Duchenne muscular dystrophy. Here, a C-terminally truncated dystrophin resulting from a novel nonsense mutation is shown for the first time to be localized to the muscle plasma membrane. An asymptomatic 8-y-old boy was examined for dystrophin in skeletal muscle because of high serum creatine kinase activity. Remarkably, no dystrophin labeling was seen with an MAb against the C-terminal domain, suggesting the presence of an early stop codon in the dystrophin gene. Labeling with an antibody specific to the N-terminal domain, however, revealed weak, patchy, and discontinuous staining, suggesting limited production of a truncated form of the protein. Molecular analysis revealed a novel nonsense mutation (Q3625X) as a result of a single nucleotide change in the patient's genomic DNA (C10873T), leaving 1.6% of dystrophin gene product unsynthesized at the C terminus. Dystrophin mRNA analysis did not show rescue of the nonsense mutation as a result of exon-skipping by an alternative splicing mechanism. This is the first report of an asymptomatic dystrophinopathy with a nonsense mutation in the dystrophin gene.

Mutations that cause

    premature stop codons in the dystrophin gene
    GENETICS

 lead to a

    complete loss of dystrophin from skeletal muscle
    BIOCHEMICAL

, resulting in

    severe Duchenne muscular dystrophy
    DIAGNOSIS

. Here, a

    C-terminally truncated dystrophin
    BIOCHEMICAL

 resulting from a

    novel nonsense mutation
    GENETICS

 is shown for the first time to be

    localized to the muscle plasma membrane
    MICROSCOPIC

. An

    asymptomatic
    NEG_FINDINGS

    8-y-old
    AGE

    boy
    GENDER

 was examined for

    dystrophin in skeletal muscle
    MICROSCOPIC

 because of

    high serum creatine kinase activity
    BIOCHEMICAL

. Remarkably,

    no dystrophin labeling was seen with an MAb against the C-terminal domain, suggesting the presence of an early stop codon in the dystrophin gene
    NEG_FINDINGS

. Labeling with an antibody specific to the N-terminal domain, however, revealed

    weak, patchy, and discontinuous staining
    SYMPTOMS

, suggesting

    limited production of a truncated form of the protein
    BIOCHEMICAL

.

    Molecular analysis
    PARACLINICAL

 revealed a

    novel nonsense mutation (Q3625X) as a result of a single nucleotide change in the patient's genomic DNA (C10873T)
    GENETICS

,

    leaving 1.6% of dystrophin gene product unsynthesized at the C terminus
    GENETICS

.

    Dystrophin mRNA analysis
    PARACLINICAL

    did not show rescue of the nonsense mutation as a result of exon-skipping by an alternative splicing mechanism
    NEG_FINDINGS

. This is the first report of an

    asymptomatic dystrophinopathy
    DIAGNOSIS

 with a

    nonsense mutation in the dystrophin gene
    GENETICS

.

severe Duchenne muscular dystrophy
asymptomatic dystrophinopathy


Chimeric RNA/ethylene-bridged nucleic acids promote dystrophin expression in myocytes of duchenne muscular dystrophy by inducing skipping of the nonsense mutation-encoding exon.

Editing of dystrophin mRNA by induction of exon skipping, using antisense oligonucleotides, has been proposed as one way to generate dystrophin expression in Duchenne muscular dystrophy (DMD) patients. Here, antisense chimeric oligonucleotides consisting of RNA and a new modified nucleic acid are tested for activity to induce skipping of an exon containing a nonsense mutation. In a Japanese DMD case, a nonsense mutation (R1967X) due to a single nucleotide change in exon 41 of the dystrophin gene (C5899T) was identified. Oligonucleotides consisting of 2'-O-methyl RNA and a new 2'-O,4'-C-ethylene-bridged nucleic acid (ENA) were designed to bind the mutation site of exon 41, and their ability to induce exon 41 skipping in dystrophin mRNA was evaluated. Finally, among the specific oligonucleotides tested, an 18-mer RNA/ENA chimera was found to have the strongest activity, inducing exon 41 skipping in nearly 90% of dystrophin mRNA. Accordingly, nearly 90% of cultured myocytes were shown to be dystrophin positive by immunohistochemical analysis. Western blot analysis disclosed the presence of nearly normal-sized dystrophin up to 1 week after the transfection. Our results suggest that an RNA/ENA chimera can be used to express dystrophin in DMD.

    Editing of dystrophin mRNA
    GENETICS

 by

    induction of exon skipping
    MEDICATION

, using

    antisense oligonucleotides
    MEDICATION

, has been proposed as one way to generate

    dystrophin expression
    MEDICATION

 in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patients. Here,

    antisense chimeric oligonucleotides consisting of RNA and a new modified nucleic acid
    MEDICATION

 are tested for activity to induce

    skipping of an exon containing a nonsense mutation
    GENETICS

. In a

    Japanese
    ETHNICITY

    DMD
    DIAGNOSIS

 case, a

    nonsense mutation (R1967X) due to a single nucleotide change in exon 41 of the dystrophin gene (C5899T)
    GENETICS

 was identified.

    Oligonucleotides consisting of 2'-O-methyl RNA and a new 2'-O,4'-C-ethylene-bridged nucleic acid (ENA)
    MEDICATION

 were designed to bind the

    mutation site of exon 41
    GENETICS

, and their ability to induce

    exon 41 skipping in dystrophin mRNA
    GENETICS

 was evaluated. Finally, among the specific oligonucleotides tested, an

    18-mer RNA/ENA chimera
    MEDICATION

 was found to have the strongest activity,

    inducing exon 41 skipping in nearly 90% of dystrophin mRNA
    GENETICS

. Accordingly,

    nearly 90% of cultured myocytes were shown to be dystrophin positive
    MICROSCOPIC

 by

    immunohistochemical analysis
    PARACLINICAL

.

    Western blot analysis
    PARACLINICAL

 disclosed the

    presence of nearly normal-sized dystrophin
    MICROSCOPIC

 up to 1 week after the transfection. Our results suggest that an

    RNA/ENA chimera
    MEDICATION

 can be used to express dystrophin in

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Late gadolinium enhanced cardiovascular magnetic resonance in Becker muscular dystrophy.

Becker muscular dystrophy is a rare cause of dilated cardiomyopathy. A case of Becker muscular dystrophy is reviewed in which cardiovascular magnetic resonance showed previously unreported findings of extensive mid-myocardial late gadolinium enhancement. Similar detection of late gadolinium enhancement in conjunction with other uses of cardiovascular magnetic resonance may contribute significantly to the diagnosis and management of patients with this unusual and important diagnosis.

    Becker muscular dystrophy
    DIAGNOSIS

 is a rare cause of

    dilated cardiomyopathy
    DIAGNOSIS

. A case of

    Becker muscular dystrophy
    DIAGNOSIS

 is reviewed in which

    cardiovascular magnetic resonance
    PARACLINICAL

 showed previously unreported findings of

    extensive mid-myocardial late gadolinium enhancement
    SYMPTOMS

. Similar detection of

    late gadolinium enhancement
    SYMPTOMS

 in conjunction with other uses of

    cardiovascular magnetic resonance
    PARACLINICAL

 may contribute significantly to the diagnosis and management of patients with this unusual and important diagnosis.

Becker muscular dystrophy
dilated cardiomyopathy
Becker muscular dystrophy


[Detection of micro mutation in dystrophin gene of DMD female carrier].

We attempted to identify a mutation in dystrophin gene in a female patient who was suspected a Duchenne muscular dystrophy (DMD) carrier with muscle weakness of upper limbs and congestive heart failure. We examined the mutation hot spots in DMD gene, exon 3, 6, 8, 13, 17, 19, 43, 44, 45, 47, 48, 49, 50, 52, 60 by multiplex PCR which had been a diagnostic screening strategy, and detected an extra band in exon 43 product. We also detected an extra band in exon 43 products by SSCP analysis for detection of small mutations which could not be detected by multiplex PCR. As a result of sequencing a PCR product of an exon 43, we confirmed an allele having the insertion of a 2 base of AT in Intron42, which is described for the first time. Although we can not conclude that this insertion is responsible for DMD, but it may cause abnormal splicing. In carrier detection of DMD without genetic information of proband, it is difficult to detect mutations by multiplex PCR solely. Therefore, SSCP of PCR products are recommended to detect mutation in DMD carrier.

We attempted to identify a

    mutation in dystrophin gene
    GENETICS

 in a

    female
    GENDER

 patient who was suspected a

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 carrier with

    muscle weakness of upper limbs
    SYMPTOMS

 and

    congestive heart failure
    SYMPTOMS

. We examined the

    mutation hot spots in DMD gene, exon 3, 6, 8, 13, 17, 19, 43, 44, 45, 47, 48, 49, 50, 52, 60
    GENETICS

 by

    multiplex PCR
    PARACLINICAL

 which had been a diagnostic screening strategy, and detected an

    extra band in exon 43 product
    GENETICS

. We also detected an

    extra band in exon 43 products
    GENETICS

 by

    SSCP analysis
    PARACLINICAL

 for detection of

    small mutations
    GENETICS

 which

    could not be detected by multiplex PCR
    NEG_FINDINGS

. As a result of

    sequencing a PCR product of an exon 43
    PARACLINICAL

, we confirmed an

    allele having the insertion of a 2 base of AT in Intron42
    GENETICS

, which is described for the first time. Although we can not conclude that this insertion is responsible for

    DMD
    DIAGNOSIS

, but it may cause

    abnormal splicing
    GENETICS

. In carrier detection of

    DMD
    DIAGNOSIS

    without genetic information of proband
    NEG_FINDINGS

, it is difficult to detect mutations by

    multiplex PCR
    PARACLINICAL

 solely. Therefore,

    SSCP of PCR products
    PARACLINICAL

 are recommended to detect mutation in

    DMD
    DIAGNOSIS

 carrier.

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD

muscle weakness of upper limbs
congestive heart failure

could not be detected by multiplex PCR
without genetic information of proband


A mitochondrial DNA mutation in a patient with an extensive family history of Duchenne muscular dystrophy.

One challenge in the molecular diagnosis of mitochondrial DNA (mtDNA) disorders is detection of a low percentage of mutant heteroplasmy. We report a patient who had a delayed molecular diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the complication of an extensive family history of another neuromuscular disease, Duchenne muscular dystrophy, and the failure to detect a low proportion of mutant A3243G mtDNA with a polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP)/ethidium bromide detection method. Using an improved, more sensitive allele-specific oligonucleotide (ASO) radioactive dot-blot hybridization method, a low degree of A3243G heteroplasmy was detected in several tissues from this patient. This case underscores the importance of a sensitive mutation detection method and the need for a search for mtDNA mutations if the patient's clinical symptoms suggest a mitochondrial disorder despite the family background of another neuromuscular disease.

One challenge in the

    molecular diagnosis
    PARACLINICAL

 of

    mitochondrial DNA (mtDNA) disorders
    DIAGNOSIS

 is detection of a

    low percentage of mutant heteroplasmy
    BIOCHEMICAL

. We report a patient who had a delayed molecular diagnosis of

    mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
    DIAGNOSIS

 (

    MELAS) syndrome
    DIAGNOSIS

 due to the complication of an

    extensive family history of another neuromuscular disease
    FAMILY

,

    Duchenne muscular dystrophy
    DIAGNOSIS

, and the

    failure to detect a low proportion of mutant A3243G mtDNA
    NEG_FINDINGS

 with a

    polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP)/ethidium bromide detection method
    PARACLINICAL

. Using an improved, more sensitive

    allele-specific oligonucleotide (ASO) radioactive dot-blot hybridization method
    PARACLINICAL

, a

    low degree of A3243G heteroplasmy was detected in several tissues
    BIOCHEMICAL

 from this patient. This case underscores the importance of a sensitive mutation detection method and the need for a search for

    mtDNA mutations
    PARACLINICAL

 if the patient's clinical symptoms suggest a

    mitochondrial disorder
    DIAGNOSIS

    despite the family background of another neuromuscular disease
    NEG_FINDINGS

.


Ventilator weaning by lung expansion and decannulation.

This case series of ventilator-dependent patients with neuromuscular disease who had no ventilator-free breathing ability demonstrates that decannulation and switching to continuous noninvasive intermittent positive-pressure ventilation combined with regular lung expansion therapy can result in improvements in pulmonary function and at least partial ventilator weaning. These six patients were also managed using mechanical insufflation-exsufflation for regular lung expansion and cough assistance. Thus, some ventilator users with neuromuscular disease can benefit from tracheostomy tube decannulation and transition to noninvasive intermittent positive-pressure ventilation and assisted coughing for ventilator weaning to predominantly nocturnal-only use.

This case series of

    ventilator-dependent
    MEDICATION

 patients with

    neuromuscular disease
    DIAGNOSIS

 who had

    no ventilator-free breathing ability
    NEG_FINDINGS

 demonstrates that

    decannulation
    MEDICATION

 and

    switching to continuous noninvasive intermittent positive-pressure ventilation combined with regular lung expansion therapy
    MEDICATION

 can result in

    improvements in pulmonary function
    SYMPTOMS

 and at least

    partial ventilator weaning
    SYMPTOMS

. These six patients were also managed using

    mechanical insufflation-exsufflation for regular lung expansion and cough assistance
    MEDICATION

. Thus, some

    ventilator users
    MEDICATION

 with

    neuromuscular disease
    DIAGNOSIS

 can benefit from

    tracheostomy tube decannulation
    MEDICATION

 and

    transition to noninvasive intermittent positive-pressure ventilation and assisted coughing for ventilator weaning to predominantly nocturnal-only use
    MEDICATION

.

neuromuscular disease
neuromuscular disease

improvements in pulmonary function
partial ventilator weaning


An automatic hinge system for leg orthoses.

This paper describes a new automatic hinge system for leg orthoses, which provides knee stability in stance, and allows knee-flexion during swing. Indications for the hinge system are a paresis or paralysis of the quadriceps muscles. Instrumented gait analysis was performed in three patients, fitted with this new hinge system in a knee orthosis. The orthosis proves to satisfy the patients allowing them to walk without a knee-lock system.

This paper describes a new

    automatic hinge system for leg orthoses
    MEDICATION

, which provides

    knee stability in stance
    MEDICATION

, and allows

    knee-flexion during swing
    MEDICATION

. Indications for the

    hinge system
    MEDICATION

 are a

    paresis or paralysis of the quadriceps muscles
    SYMPTOMS

.

    Instrumented gait analysis
    PARACLINICAL

 was performed in three patients,

    fitted with this new hinge system in a knee orthosis
    MEDICATION

. The

    orthosis
    MEDICATION

 proves to satisfy the patients allowing them to walk

    without a knee-lock system
    NEG_FINDINGS

.


[Report of four women with Duchenne or Becker muscular dystrophy].

Duchenne and Becker muscular dystrophy are X-linked and affect mainly males. The authors report four female cases.

Four patients presented muscular deficiency predominant to lower limbs and chronic disease. Female distrophinopathy is understandable by three mechanisms: Turner's syndrome, translocation X-chromosome with an autosome and skewed X-chromosome inactivation.

Diagnosis of female Duchenne and Becker muscular dystrophy is really difficult if there is not male case in family.

    Duchenne
    DIAGNOSIS

    and Becker muscular dystrophy
    DIAGNOSIS

 are

    X-linked
    GENETICS

 and affect mainly

    males
    GENDER

. The authors report four

    female
    GENDER

 cases.

Four patients presented

    muscular deficiency predominant to lower limbs
    SYMPTOMS

 and

    chronic disease
    DIAGNOSIS

.

    Female
    GENDER

    distrophinopathy
    SYMPTOMS

 is understandable by three mechanisms:

    Turner's syndrome
    DIAGNOSIS

,

    translocation X-chromosome with an autosome
    GENETICS

 and

    skewed X-chromosome inactivation
    GENETICS

.

Diagnosis of

    female
    GENDER

    Duchenne
    DIAGNOSIS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 is really difficult if

    there is not male case in family
    FAMILY

.

Duchenne
and Becker muscular dystrophy
chronic disease
Turner's syndrome
Duchenne
Becker muscular dystrophy


Pneumothorax associated with long-term non-invasive positive pressure ventilation in Duchenne muscular dystrophy.

Long-term non-invasive positive pressure ventilation (NPPV) is effective for improving the quality of life and survival of neuromuscular patients. This treatment is usually easy to administer and severe complications have rarely been reported. We describe two cases in which the development of pneumothorax was associated with long-term NPPV administered to Duchenne muscular dystrophy patients. Given the wide scale utilization of chronic NPPV, we suggest that care-givers and patients be made aware of this serious complication.

    Long-term non-invasive positive pressure ventilation (NPPV)
    MEDICATION

 is effective for improving the quality of life and survival of

    neuromuscular
    DIAGNOSIS

 patients. This treatment is usually easy to administer and

    severe complications
    SYMPTOMS

 have rarely been reported. We describe two cases in which the development of

    pneumothorax
    DIAGNOSIS

 was associated with

    long-term NPPV
    MEDICATION

 administered to

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients. Given the wide scale utilization of

    chronic NPPV
    MEDICATION

, we suggest that care-givers and patients be made aware of this serious complication.

neuromuscular
pneumothorax
Duchenne muscular dystrophy


An intragenic deletion/inversion event in the DMD gene determines a novel exon creation and results in a BMD phenotype.

Duchenne and Becker Muscular Dystrophy (DMD and BMD) are caused, in the majority of cases, by deletions in the dystrophin gene (DMD). Here we describe the unprecedented case of a BMD patient carrying a large out-of-frame intragenic deletion, together with an inversion in the DMD gene, resulting in the inclusion of a novel exon in the transcript. Multiplex PCR amplification revealed the presence of a 48-52 exon deletion, but transcript analysis identified two unexpected products, neither of them including exon 53. The shorter mRNA derived from the juxtaposition of exons 47-54 (in-frame), while the longer one resulted from the inclusion of a novel 73-bp exon between exons 47 and 54. Sequence analysis revealed that the inserted sequence derived from an inverted portion of intron 53; its inclusion is predicted to determine protein truncation. The presence of a genomic inversion involving exon 53 and flanking regions was confirmed, and inversion/deletion breakpoints were sequenced. The inverted 73-bp sequence displays splicing signals at both ends and thus it is probably recognized as a novel exon when the partially inverted hnRNA is processed. These findings highlight the importance of mRNA analysis on patients that, based on routine DNA screenings, do not follow the reading-frame rule. This is the first reported patient carrying both an intragenic deletion and inversion in the DMD locus. This case might provide further insight into both the mechanisms that determine genomic rearrangements in the DMD locus and the molecular signals that drive exon inclusion.

    Duchenne and Becker Muscular Dystrophy (DMD and BMD)
    DIAGNOSIS

 are caused, in the majority of cases, by

    deletions in the dystrophin gene (DMD)
    GENETICS

. Here we describe the unprecedented case of a

    BMD
    DIAGNOSIS

 patient carrying a

    large out-of-frame intragenic deletion, together with an inversion in the DMD gene
    GENETICS

, resulting in the

    inclusion of a novel exon in the transcript
    GENETICS

.

    Multiplex PCR amplification
    PARACLINICAL

 revealed the

    presence of a 48-52 exon deletion
    GENETICS

, but

    transcript analysis
    PARACLINICAL

 identified two unexpected products, neither of them including exon 53. The shorter

    mRNA derived from the juxtaposition of exons 47-54 (in-frame)
    GENETICS

, while the longer one resulted from the

    inclusion of a novel 73-bp exon between exons 47 and 54
    GENETICS

.

    Sequence analysis
    PARACLINICAL

 revealed that

    the inserted sequence derived from an inverted portion of intron 53; its inclusion is predicted to determine protein truncation
    GENETICS

. The

    presence of a genomic inversion involving exon 53 and flanking regions
    GENETICS

 was confirmed, and

    inversion/deletion breakpoints were sequenced
    GENETICS

.

    The inverted 73-bp sequence displays splicing signals at both ends and thus it is probably recognized as a novel exon when the partially inverted hnRNA is processed
    GENETICS

. These findings highlight the importance of

    mRNA analysis
    PARACLINICAL

 on patients that, based on

    routine DNA screenings
    NEG_FINDINGS

,

    do not follow the reading-frame rule
    NEG_FINDINGS

. This is the first reported patient carrying

    both an intragenic deletion and inversion in the DMD locus
    GENETICS

. This case might provide further insight into both the mechanisms that determine

    genomic rearrangements in the DMD locus
    GENETICS

 and the molecular signals that drive exon inclusion.

routine DNA screenings
do not follow the reading-frame rule


Subclinical Becker's muscular dystrophy presenting with severe heart failure.

We describe a rare case of Becker's muscular dystrophy (BMD) in a 28-year-old man complicated by rapidly progressing heart failure without apparent clinical signs of neuromuscular disease. He showed rhabdomyolysis, which repeatedly occurred causing acute renal failure as heart failure worsened. His serum creatine kinase (CK) level was generally below 300 IU/l. However, it exceeded more than 10,000 IU/l at the time of myoglobinuria. This suggests that the worsening of heart failure could induce rhabdomyolysis in a BMD patient. Gene analysis for BMD should be considered when the elevation of serum CK is noted in heart failure.

We describe a rare case of

    Becker's muscular dystrophy (BMD)
    DIAGNOSIS

 in a

    28-year-old
    AGE

    man
    GENDER

 complicated by

    rapidly progressing heart failure
    SYMPTOMS

    without apparent clinical signs of neuromuscular disease
    NEG_FINDINGS

.

    He
    GENDER

 showed

    rhabdomyolysis
    DIAGNOSIS

, which repeatedly occurred causing

    acute renal failure
    SYMPTOMS

 as

    heart failure
    SYMPTOMS

 worsened. His serum creatine kinase (CK) level was generally below 300 IU/l. However,

    it exceeded more than 10,000 IU/l at
    BIOCHEMICAL

 the time of

    myoglobinuria
    BIOCHEMICAL

. This suggests that the

    worsening of heart failure
    SYMPTOMS

 could induce

    rhabdomyolysis
    DIAGNOSIS

 in a

    BMD
    DIAGNOSIS

 patient.

    Gene analysis
    PARACLINICAL

 for

    BMD
    DIAGNOSIS

 should be considered when the

    elevation of serum CK
    BIOCHEMICAL

 is noted in

    heart failure
    SYMPTOMS

.

Becker's muscular dystrophy (BMD)
rhabdomyolysis
rhabdomyolysis
BMD
BMD

rapidly progressing heart failure
acute renal failure
heart failure
worsening of heart failure
heart failure

it exceeded more than 10,000 IU/l at
myoglobinuria
elevation of serum CK


[Cerebral embolism associated with Becker muscular dystrophy-related dilated cardiomyopathy].

A 65-year-old man with previous history of congestive heart failure and genetically proven Becker muscular dystrophy (BMD) was suddenly suffered from aphasia and right hemiplegia. Physical examination showed severe motor aphasia, right hemiplegia, and signs of left heart failure. An echocardiogram before the onset of aphasia showed markedly dilated left ventricle and decreased ventricular contraction. Intracardiac thrombus was not detected. Although his electrocardiogram on admission showed sinus rhythm, atrial fibrillation was noted at the time of neurological deterioration. MRI of the brain revealed acute infarction in the territory of the left middle cerebral artery and the left anterior inferior cerebellar artery. MR angiography showed vascular occlusion at the left M2 segment. Cerebral embolism due to atrial fibrillation associated with BMD-related DCM was diagnosed. While an administration of anti-coagulant, diuretics, and dopamine relieved his respiratory distress and right hemiplegia, severe motor aphasia persisted. Cerebral embolism may be a notable complication in patients with BMD presenting with late-life expression of skeletal muscular weakness and antecedent cardiac involvement.

A

    65-year-old
    AGE

    man
    GENDER

 with previous history of

    congestive heart failure
    SYMPTOMS

 and genetically proven

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 was suddenly suffered from

    aphasia
    SYMPTOMS

 and

    right hemiplegia
    SYMPTOMS

.

    Physical examination
    PARACLINICAL

 showed

    severe motor aphasia
    SYMPTOMS

,

    right hemiplegia
    SYMPTOMS

, and

    signs of left heart failure
    SYMPTOMS

. An

    echocardiogram
    PARACLINICAL

 before the onset of

    aphasia
    SYMPTOMS

 showed

    markedly dilated left ventricle
    SYMPTOMS

 and

    decreased ventricular contraction
    SYMPTOMS

.

    Intracardiac thrombus was not detected
    NEG_FINDINGS

. Although

    his
    GENDER

    electrocardiogram on admission showed sinus rhythm
    NEG_FINDINGS

,

    atrial fibrillation
    SYMPTOMS

 was noted at the time of

    neurological deterioration
    SYMPTOMS

.

    MRI of the brain
    PARACLINICAL

 revealed

    acute infarction in the territory of the left middle cerebral artery and the left anterior inferior cerebellar artery
    SYMPTOMS

.

    MR angiography
    PARACLINICAL

 showed

    vascular occlusion at the left M2 segment
    SYMPTOMS

.

    Cerebral embolism due to atrial fibrillation
    SYMPTOMS

    associated with BMD-related DCM
    DIAGNOSIS

 was diagnosed. While an

    administration of anti-coagulant, diuretics, and dopamine
    MEDICATION

 relieved his

    respiratory distress
    SYMPTOMS

 and

    right hemiplegia
    SYMPTOMS

,

    severe motor aphasia
    SYMPTOMS

 persisted.

    Cerebral embolism
    SYMPTOMS

 may be a notable complication in patients with

    BMD
    DIAGNOSIS

 presenting with

    late-life expression of skeletal muscular weakness
    SYMPTOMS

 and

    antecedent cardiac involvement
    SYMPTOMS

.

Becker muscular dystrophy (BMD)
associated with BMD-related DCM
BMD


[Repeated cerebral infarction in a patient with Duchenne's muscular dystrophy].

We describe a case of Duchenne muscular dystrophy (DMD) with multiple strokes related to dilated cardiomyopathy.

A 13 year old boy, with advanced stage DMD was admitted to the hospital because of acute motor and sensory impairment in his right bodyside. Imaging study revealed lesions in basal ganglia and prerolandic cortex in the left hemisphere that were compatible with infarcts in the territory of the medial cerebral artery. Cardiologic evaluation revealed dilation of the left ventriculi and systolic dysfunction with ejection fraction of 35 40%. The symptoms evolved to a residual right hemiparesia. Five months later, the patient developed a transient episode of aphasia and the study performed in this case revealed lesions compatible with infarcts in basal ganglia and insular cortex of the right cerebral hemisphere.

Cerebral infarction related to cardiomyopathy can worsen the clinical condition of patients with DMD. Early treatment of dilated cardiomyopathy with systolic dysfunction, including use of antithrombotic agents to prevent cerebrovascular complications, could help to improve the course of the disease.

We describe a case of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 with

    multiple strokes related to dilated cardiomyopathy
    SYMPTOMS

.

A

    13 year old
    AGE

    boy
    GENDER

, with

    advanced stage DMD
    DIAGNOSIS

 was admitted to the hospital because of

    acute motor and sensory impairment in his right bodyside
    SYMPTOMS

.

    Imaging study
    PARACLINICAL

 revealed

    lesions in basal ganglia and prerolandic cortex in the left hemisphere
    SYMPTOMS

 that were compatible with

    infarcts in the territory of the medial cerebral artery
    SYMPTOMS

.

    Cardiologic evaluation
    PARACLINICAL

 revealed

    dilation of the left ventriculi
    SYMPTOMS

 and

    systolic dysfunction with ejection fraction of 35 40%
    SYMPTOMS

. The symptoms evolved to a

    residual right hemiparesia
    SYMPTOMS

. Five months later, the patient developed a

    transient episode of aphasia
    SYMPTOMS

 and the study performed in this case revealed

    lesions compatible with infarcts in basal ganglia and insular cortex of the right cerebral hemisphere
    SYMPTOMS

.

    Cerebral infarction
    SYMPTOMS

 related to

    cardiomyopathy
    DIAGNOSIS

 can worsen the clinical condition of patients with

    DMD
    DIAGNOSIS

.

    Early treatment
    MEDICATION

 of

    dilated cardiomyopathy
    DIAGNOSIS

 with

    systolic dysfunction
    SYMPTOMS

, including use of

    antithrombotic agents
    MEDICATION

 to prevent

    cerebrovascular complications
    SYMPTOMS

, could help to improve the course of the disease.

Duchenne muscular dystrophy (DMD)
advanced stage DMD
cardiomyopathy
DMD
dilated cardiomyopathy


Urinary incontinence in a patient with Duchenne muscular dystrophy and cord in the normal position with fatty filum terminale.

To our knowledge, muscular dystrophy and specifically, Duchenne muscular dystrophy, has not previously been associated with gross intrathecal abnormalities.

We report a pediatric patient with Duchenne muscular dystrophy that was diagnosed a long time ago and recent onset urinary incontinence. MRI revealed a conus medullaris in a normal position with a fatty-infiltrated filum terminale. Operative intervention was performed entailing sectioning of the filum terminale. This resulted in resolution of the child's urinary incontinence.

Although seemingly rare and perhaps associated by serendipity, new, unusual neurological deficits in a patient with muscular dystrophy, especially of an upper motor neuron nature, should warrant MRI to rule out pathology of the spinal cord such as tethering.

To our knowledge,

    muscular dystrophy
    DIAGNOSIS

 and specifically,

    Duchenne muscular dystrophy
    DIAGNOSIS

, has not previously been associated with

    gross intrathecal abnormalities
    SYMPTOMS

.

We report a

    pediatric
    AGE

 patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 that was diagnosed a long time ago and

    recent onset urinary incontinence
    SYMPTOMS

.

    MRI
    PARACLINICAL

 revealed a

    conus medullaris in a normal position
    NEG_FINDINGS

 with a

    fatty-infiltrated filum terminale
    SYMPTOMS

.

    Operative intervention
    MEDICATION

 was performed

    entailing sectioning of the filum terminale
    MEDICATION

. This resulted in

    resolution of the child's urinary incontinence
    SYMPTOMS

.

Although seemingly rare and perhaps associated by serendipity,

    new, unusual neurological deficits
    SYMPTOMS

 in a patient with

    muscular dystrophy
    DIAGNOSIS

,

    especially of an upper motor neuron nature
    SYMPTOMS

, should warrant

    MRI
    PARACLINICAL

 to

    rule out pathology of the spinal cord such as tethering
    NEG_FINDINGS

.

muscular dystrophy
Duchenne muscular dystrophy
Duchenne muscular dystrophy
muscular dystrophy


Complex glycerol kinase deficiency leads to psychomotor and body-growth failure.

Complex glycerol kinase deficiency usually presents with Duchenne muscular dystrophy, glycerol kinase deficiency and adrenal hypoplasia congenital. We describe a follow-up patient with complex glycerol kinase deficiency who had appropriate intrauterine development, but who at 1 month of age manifested severe growth delay and psychomotor retardation. Targeted therapy did not bring about the regression of symptoms: both bodyweight and height were below the 3rd centile until 8 years of age, and his Griffith's Mental Development scale score was 71 at age 5 years.

    Complex glycerol kinase deficiency
    DIAGNOSIS

 usually presents with

    Duchenne muscular dystrophy
    DIAGNOSIS

,

    glycerol kinase deficiency
    BIOCHEMICAL

 and

    adrenal hypoplasia congenital
    SYMPTOMS

. We describe a follow-up patient with

    complex glycerol kinase deficiency
    DIAGNOSIS

 who had

    appropriate intrauterine development
    SYMPTOMS

, but who

    at 1 month of age
    AGE

 manifested

    severe growth delay
    SYMPTOMS

 and

    psychomotor retardation
    SYMPTOMS

.

    Targeted therapy did not bring about the regression of symptoms
    NEG_FINDINGS

: both

    bodyweight and height were below the 3rd centile until 8 years of age
    SYMPTOMS

, and

    his
    GENDER

    Griffith's Mental Development scale score was 71 at age 5 years
    PARACLINICAL

.

Complex glycerol kinase deficiency
Duchenne muscular dystrophy
complex glycerol kinase deficiency


Orthodontic treatment of a case of Becker muscular dystrophy.

Becker muscular dystrophy, similar to Duchenne muscular dystrophy, is a X-chromosomal linked anomaly characterized by progressive muscle wasting and weakness. Duchenne-type is known to have severe openbite with a steep mandibular plane, but there are no studies that describe the occlusal and skeletal patterns of the Becker-type. Here, we report the orthodontic treatment of a Becker muscular dystrophy patient. In the correction of his severe skeletal open bite general anesthesia or orthognathic surgery was not an option. Multiloop edgewise archwires were employed for orthodontic treatment. After 3 years and 8 months the open bite was corrected. During the retention period contact between the anterior teeth was maintained 8 months after active treatment despite a marked relapse tendency.

    Becker muscular dystrophy
    DIAGNOSIS

, similar to

    Duchenne muscular dystrophy
    DIAGNOSIS

, is a

    X-chromosomal linked anomaly
    GENETICS

 characterized by

    progressive muscle wasting
    SYMPTOMS

 and

    weakness
    SYMPTOMS

.

    Duchenne-type
    DIAGNOSIS

 is known to have

    severe openbite with a steep mandibular plane
    SYMPTOMS

, but there are no studies that describe the occlusal and skeletal patterns of the

    Becker-type
    DIAGNOSIS

. Here, we report the

    orthodontic treatment
    MEDICATION

 of a

    Becker muscular dystrophy
    DIAGNOSIS

 patient. In the correction of his

    severe skeletal open bite
    SYMPTOMS

    general anesthesia or orthognathic surgery
    NEG_FINDINGS

    was not an option
    NEG_FINDINGS

.

    Multiloop edgewise archwires were employed for orthodontic treatment
    MEDICATION

. After

    3 years and 8 months
    MEDICATION

 the

    open bite was corrected
    SYMPTOMS

. During the

    retention period
    MEDICATION

    contact between the anterior teeth was maintained 8 months after active treatment
    SYMPTOMS

    despite a marked relapse tendency
    NEG_FINDINGS

.

Becker muscular dystrophy
Duchenne muscular dystrophy
Duchenne-type
Becker-type
Becker muscular dystrophy


Loss of a single amino acid from dystrophin resulting in Duchenne muscular dystrophy with retention of dystrophin protein.

Almost all of the thousands of pathogenic mutations which have been described in the dystrophin gene either reduce protein production or remove large regions of the protein. This has severely limited the use of mutational information for the functional dissection of the dystrophin protein and increases the value of rare subtle mutations. We report a 3-bp deletion which removes a single highly conserved residue (glutamic acid 3367) adjacent to the dystrophin ZZ domain. This results in a phenotype of Duchenne muscular dystrophy with substantial retention of a presumably functionally compromised dystrophin protein. Two missense mutations (both affecting nearby residues) have been previously reported to result in this unusual combination of severe phenotype and high protein level. We discuss the functional implications of this and other mutations in the light of the predicted structure of the region. The pathogenicity of E3367del serves to emphasise the functional importance of this region of the dystrophin protein.

Almost all of the thousands of pathogenic mutations which have been described in the

    dystrophin gene
    GENETICS

 either

    reduce protein production
    BIOCHEMICAL

 or

    remove large regions of the protein
    GENETICS

. This has severely limited the use of mutational information for the functional dissection of the dystrophin protein and increases the value of rare subtle mutations. We report a

    3-bp deletion which removes a single highly conserved residue (glutamic acid 3367) adjacent to the dystrophin ZZ domain
    GENETICS

. This results in a phenotype of

    Duchenne muscular dystrophy
    DIAGNOSIS

 with

    substantial retention of a presumably functionally compromised dystrophin protein
    MICROSCOPIC

. Two

    missense mutations (both affecting nearby residues)
    GENETICS

 have been previously reported to result in this unusual combination of

    severe phenotype
    SYMPTOMS

 and

    high protein level
    BIOCHEMICAL

. We discuss the functional implications of this and other mutations in the light of the predicted structure of the region. The pathogenicity of

    E3367del
    GENETICS

 serves to emphasise the functional importance of this region of the dystrophin protein.

reduce protein production
high protein level


Non-operative treatment for perforated gastro-duodenal peptic ulcer in Duchenne muscular dystrophy: a case report.

Clinical characteristics and complications of Duchenne muscular dystrophy caused by skeletal and cardiac muscle degeneration are well known. Gastro-intestinal involvement has also been recognised in these patients. However an acute perforated gastro-duodenal peptic ulcer has not been documented up to now.

A 26-year-old male with Duchenne muscular dystrophy with a clinical and radiographic diagnosis of acute perforated gastro-duodenal peptic ulcer is treated non-operatively with naso-gastric suction and intravenous medication. Gastrointestinal involvement in Duchenne muscular dystrophy and therapeutic considerations in a high risk patient are discussed.

Non-surgical treatment for perforated gastro-duodenal peptic ulcer should be considered in high risk patients, as is the case in patients with Duchenne muscular dystrophy. Patients must be carefully observed and operated on if non-operative treatment is unsuccessful.

Clinical characteristics and complications of

    Duchenne muscular dystrophy
    DIAGNOSIS

 caused by

    skeletal and cardiac muscle degeneration
    SYMPTOMS

 are well known.

    Gastro-intestinal involvement
    SYMPTOMS

 has also been recognised in these patients. However an

    acute perforated gastro-duodenal peptic ulcer
    DIAGNOSIS

 has not been documented up to now.

A

    26-year-old
    AGE

    male
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 with a clinical and radiographic diagnosis of

    acute perforated gastro-duodenal peptic ulcer
    SYMPTOMS

 is treated

    non-operatively with naso-gastric suction and intravenous medication
    MEDICATION

.

    Gastrointestinal involvement
    SYMPTOMS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

 and therapeutic considerations in a high risk patient are discussed.

    Non-surgical treatment
    MEDICATION

 for

    perforated gastro-duodenal peptic ulcer
    DIAGNOSIS

 should be considered in high risk patients, as is the case in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

. Patients must be carefully observed and operated on if

    non-operative treatment is unsuccessful
    NEG_FINDINGS

.


Becker muscular dystrophy in a patient with Hodgkin's disease.

Genetic disease often predisposes to neoplastic processes because of either alterations in both oncogenes and tumor suppressor genes or imbalances in the cell cycle. The authors present the case of a 15-year-old boy with Hodgkin's disease associated with Becker muscular dystrophy. Becker muscular dystrophy is an X-linked neuromuscular disease due to in-frame mutations in the dystrophin gene, and it is considered a milder variant of Duchenne muscular dystrophy. In most patients with Becker muscular dystrophy, the myopathic process affects the myocardium, leading to cardiomyopathy.

    Genetic disease
    GENETICS

 often predisposes to

    neoplastic processes
    SYMPTOMS

 because of either

    alterations in both oncogenes and tumor suppressor genes
    GENETICS

 or

    imbalances in the cell cycle
    GENETICS

. The authors present the case of a

    15-year-old
    AGE

    boy
    GENDER

 with

    Hodgkin's disease
    DIAGNOSIS

 associated with

    Becker muscular dystrophy
    DIAGNOSIS

.

    Becker muscular dystrophy
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    neuromuscular disease
    DIAGNOSIS

 due to

    in-frame mutations in the dystrophin gene
    GENETICS

, and it is considered a milder variant of

    Duchenne muscular dystrophy
    DIAGNOSIS

. In most patients with

    Becker muscular dystrophy
    DIAGNOSIS

, the

    myopathic process affects the myocardium
    SYMPTOMS

, leading to

    cardiomyopathy
    SYMPTOMS

.

Hodgkin's disease
Becker muscular dystrophy
Becker muscular dystrophy
neuromuscular disease
Duchenne muscular dystrophy
Becker muscular dystrophy


Tracheocoele in a Duchenne muscular dystrophy patient. Case report.

Tracheocoele, a congenital or acquired lesion, is rarely detected radiologically and even more rarely diagnosed clinically. This tracheal lesion is characterised by the presence of a single cystic lesion filled with air or a mixture of liquid and air, of extremely variable size, occurring in almost all cases, in a locus minoris resistentiae situated in the right posterolateral portion of the trachea. The rare case is described of a voluminous tracheocoele located in the left paratracheal region, extending from the cricoid to sternal notch, manifesting clinically, 3 months prior to evaluation in our hospital in a 27-year-old male suffering from Duchenne muscular dystrophy since the age of 5 years. For 10 years, the patient had been treated with intermittent positive pressure ventilation via nasal mask, due to progressive deterioration of respiratory function. Diagnosis of tracheocoele, initially made at computed axial tomography scan, was confirmed by flexible laryngotracheoscopy under local anaesthesia. Due to severe comorbidity associated with the clinical picture described, the absence of a significant set of symptoms, and the problems concerning anaesthesiological management of the patient, palliative treatment was the only choice. This consisted in cervical compression bandaging during assisted nasal ventilation. Close follow-up was performed in order to monitor any progression of the lesion or onset of related complications. This is the second case of tracheocoele originating in the left paratracheal region reported in the literature, and the first associated with Duchenne muscular dystrophy and prolonged use of a positive pressure respirator. The aetiopathogenic mechanisms that may have determined the formation of this rare lesion are then taken into consideration.

    Tracheocoele
    SYMPTOMS

, a congenital or acquired lesion, is rarely detected radiologically and even more rarely diagnosed clinically. This

    tracheal lesion
    SYMPTOMS

 is characterised by the presence of a

    single cystic lesion filled with air or a mixture of liquid and air, of extremely variable size
    SYMPTOMS

, occurring in almost all cases, in a

    locus minoris resistentiae situated in the right posterolateral portion of the trachea
    SYMPTOMS

. The rare case is described of a

    voluminous tracheocoele located in the left paratracheal region
    SYMPTOMS

,

    extending from the cricoid to sternal notch
    SYMPTOMS

, manifesting clinically, 3 months prior to evaluation in our hospital in a

    27-year-old
    AGE

    male
    GENDER

 suffering from

    Duchenne muscular dystrophy
    DIAGNOSIS

    since the age of 5 years
    AGE

. For 10 years, the patient had been treated with

    intermittent positive pressure ventilation via nasal mask
    MEDICATION

, due to

    progressive deterioration of respiratory function
    SYMPTOMS

. Diagnosis of

    tracheocoele
    DIAGNOSIS

, initially made at

    computed axial tomography scan
    PARACLINICAL

, was confirmed by

    flexible laryngotracheoscopy
    PARACLINICAL

 under

    local anaesthesia
    MEDICATION

. Due to

    severe comorbidity associated with the clinical picture
    SYMPTOMS

 described, the

    absence of a significant set of symptoms
    NEG_FINDINGS

, and the problems concerning anaesthesiological management of the patient,

    palliative treatment
    MEDICATION

 was the only choice. This consisted in

    cervical compression bandaging during assisted nasal ventilation
    MEDICATION

.

    Close follow-up
    PARACLINICAL

 was performed in order to monitor any progression of the lesion or onset

    of related complications
    SYMPTOMS

. This is the second case of

    tracheocoele originating in the left paratracheal region
    SYMPTOMS

 reported in the literature, and the first associated with

    Duchenne muscular dystrophy
    DIAGNOSIS

 and

    prolonged use of a positive pressure respirator
    MEDICATION

. The aetiopathogenic mechanisms that may have determined the formation of this rare lesion are then taken into consideration.

Duchenne muscular dystrophy
tracheocoele
Duchenne muscular dystrophy


Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene.

In the course of a mutation search performed by muscle dystrophin transcript analysis in 72 Duchenne and Becker Muscular Dystrophies (DMD/BMD) patients without gross gene defect, we encountered four unrelated cases with additional out-of-frame sequences precisely intercalated between two intact exons of the mature muscle dystrophin mRNA. An in silico search of the whole dystrophin genomic sequence revealed that these inserts correspond to cryptic exons flanked by one strong and one weak consensus splice site and located in the mid-part of large introns (introns 60, 9, 1M, and 62, respectively). In each case we identified an intronic point mutation activating the cryptic donor or acceptor splice site. The patients exhibited a BMD/intermediate phenotype consistent with the presence of reduced amounts of normally spliced transcript and normal dystrophin. The frequency of this new type of mutation is not negligible (6% of our series of 65 patients with 'small' mutations). It would be missed if the exploration of the DMD gene is exclusively performed on exons and flanking sequences of genomic DNA.

In the course of a

    mutation
    PARACLINICAL

 search performed by

    muscle dystrophin transcript analysis
    PARACLINICAL

 in 72

    Duchenne and Becker Muscular Dystrophies (DMD/BMD)
    DIAGNOSIS

 patients

    without gross gene defect
    NEG_FINDINGS

, we encountered four unrelated cases with

    additional out-of-frame sequences precisely intercalated between two intact exons of the mature muscle dystrophin mRNA
    GENETICS

. An

    in silico search of the whole dystrophin genomic sequence
    PARACLINICAL

 revealed that these

    inserts correspond to cryptic exons flanked by one strong and one weak consensus splice site and located in the mid-part of large introns (introns 60, 9, 1M, and 62, respectively)
    GENETICS

. In each case we identified an

    intronic point mutation activating the cryptic donor or acceptor splice site
    GENETICS

. The patients exhibited a

    BMD/intermediate phenotype
    SYMPTOMS

 consistent with the presence of

    reduced amounts of normally spliced transcript
    BIOCHEMICAL

 and

    normal dystrophin
    BIOCHEMICAL

. The frequency of this new type of mutation is not negligible (6% of our series of 65 patients with 'small' mutations). It would be missed if the

    exploration of the DMD gene
    PARACLINICAL

 is exclusively performed

    on exons and flanking sequences of genomic DNA
    PARACLINICAL

.


Myocardial cell damage in Duchenne muscular dystrophy.

We report two cases of Duchenne muscular dystrophy that presented with laboratory evidence of acute transient myocardial cell damage. The mechanism for development of cardiomyopathy associated with Duchenne muscular dystrophy is not well understood, and this report raises the possibility that the progressive deterioration of cardiac function is punctuated by acute episodes of cell damage.

We report two cases of

    Duchenne muscular dystrophy
    DIAGNOSIS

 that presented with

    laboratory evidence of acute transient myocardial cell damage
    SYMPTOMS

. The mechanism for development of

    cardiomyopathy
    DIAGNOSIS

 associated with

    Duchenne muscular dystrophy
    DIAGNOSIS

 is not well understood, and this report raises the possibility that the

    progressive deterioration of cardiac function
    SYMPTOMS

 is punctuated by

    acute episodes of cell damage
    SYMPTOMS

.

Duchenne muscular dystrophy
cardiomyopathy
Duchenne muscular dystrophy


Different expressions of X-linked cardiomyopathy in monozygotic triplets with Becker's dystrophy.

Cardiac involvement is common in skeletal muscles disorders associated with dystrophin defect. It has been suggested however, that X-linked dilated cardiomyopathies with minimal or absent skeletal disease are distinct entities, resulting from mutations in cardiac-specific regions of dystrophin gene. This study presents a unique observation of phenotypic variability in monozygotic triplets with Becker's muscular dystrophy. The expressions of the disease range from severe peripheral myopathy to severe congestive heart failure. No deletion in dystrophin gene was observed and the mechanisms responsible for selective impairment of morphologically and functionally different muscles in three monozygotic siblings remain unclear.

    Cardiac involvement
    SYMPTOMS

 is common in

    skeletal muscles disorders
    DIAGNOSIS

 associated with

    dystrophin defect
    GENETICS

. It has been suggested however, that

    X-linked
    GENETICS

    dilated cardiomyopathies
    DIAGNOSIS

 with

    minimal or absent skeletal disease
    SYMPTOMS

 are distinct entities, resulting from

    mutations in cardiac-specific regions of dystrophin gene
    GENETICS

. This study presents a unique observation of

    phenotypic variability
    SYMPTOMS

 in

    monozygotic triplets
    FAMILY

 with

    Becker's muscular dystrophy
    DIAGNOSIS

. The expressions of the disease range from

    severe peripheral myopathy
    SYMPTOMS

 to

    severe congestive heart failure
    SYMPTOMS

.

    No deletion in dystrophin gene was observed
    NEG_FINDINGS

 and the mechanisms responsible for

    selective impairment of morphologically and functionally different muscles
    SYMPTOMS

    in three monozygotic siblings
    FAMILY

 remain unclear.

skeletal muscles disorders
dilated cardiomyopathies
Becker's muscular dystrophy


Identification of transcripts from a subtraction library which might be responsible for the mild phenotype in an intrafamilially variable course of Duchenne muscular dystrophy.

While frame-shift mutations are usually found in Duchenne muscular dystrophy (DMD), in-frame mutations are associated with the less severe phenotype of Becker's muscular dystrophy. Exceptions have been reported in both directions suggesting the existence of modifying genes, which might be helpful for innovation of new therapeutic strategies. We report on the very rare case of an intrafamilially different course of DMD, with the younger brother being far less affected than the older one when compared at the same age. In this context, we constructed a subtraction library enriched for transcripts over-expressed in the patient with the milder phenotype. Twelve random clones were sequenced, followed by database analysis. Six of them, casein kinase 1 alpha 1, RAP2B, dynactin 3 light chain, core binding factor beta, myosin light polypeptide 2 and one hypothetical gene, were further analysed by real-time RT-PCR. All these genes were over-expressed 3-20 times in the less affected patient compared with the more severely affected one. Casein kinase 1 and the hypothetical gene showed even a slightly higher expression than the control. Up-regulation of myosin light polypeptide 2, one of the most sensitive markers of muscle fibre regeneration, obviously reflects the milder phenotype. Casein kinase 1, dynactin and core binding factor are supposed to be involved in cell cycle pathways. RAP is a component of the signalling network which controls fundamental cellular processes such as proliferation and differentiation. All four might be interesting candidates for a therapeutic approach to diminish progression of dystrophy in DMD.

While

    frame-shift mutations
    GENETICS

 are usually found in

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

,

    in-frame mutations
    GENETICS

 are associated with the less severe phenotype of

    Becker's muscular dystrophy
    DIAGNOSIS

. Exceptions have been reported in both directions suggesting the existence of modifying genes, which might be helpful for innovation of new therapeutic strategies. We report on the very rare case of an

    intrafamilially different course of DMD
    FAMILY

,

    with the younger brother being far less affected than the older one when compared at the same age
    FAMILY

. In this context, we constructed a

    subtraction library
    PARACLINICAL

 enriched for

    transcripts over-expressed
    GENETICS

 in the patient with the milder phenotype. Twelve random clones were sequenced, followed by

    database analysis
    PARACLINICAL

. Six of them,

    casein kinase 1 alpha 1
    BIOCHEMICAL

,

    RAP2B
    GENETICS

,

    dynactin 3 light chain
    BIOCHEMICAL

,

    core binding factor beta
    BIOCHEMICAL

,

    myosin light polypeptide 2
    BIOCHEMICAL

 and one hypothetical gene, were further analysed by

    real-time RT-PCR
    PARACLINICAL

. All these genes were

    over-expressed 3-20 times in
    GENETICS

 the less affected patient compared with the more severely affected one.

    Casein kinase 1 and the hypothetical gene
    BIOCHEMICAL

 showed even a slightly higher expression than the control.

    Up-regulation of myosin light polypeptide 2
    BIOCHEMICAL

, one of the most sensitive markers of

    muscle fibre regeneration
    SYMPTOMS

, obviously reflects the milder phenotype.

    Casein kinase 1
    BIOCHEMICAL

,

    dynactin
    BIOCHEMICAL

 and

    core binding factor
    BIOCHEMICAL

 are supposed to be involved in

    cell cycle pathways
    SYMPTOMS

. RAP is a component of the signalling network which controls fundamental cellular processes such as proliferation and differentiation. All four might be interesting candidates for a therapeutic approach to diminish progression of

    dystrophy
    DIAGNOSIS

 in

    DMD
    DIAGNOSIS

.

frame-shift mutations
in-frame mutations
transcripts over-expressed
RAP2B
over-expressed 3-20 times in

Duchenne muscular dystrophy (DMD)
Becker's muscular dystrophy
dystrophy
DMD

muscle fibre regeneration
cell cycle pathways


[Symptomatic carriers of dystrophinopathy with chromosome X inactivation bias].

Several studies have recently highlighted the fact that the clinical involvement in females carrying a mutation in the dystrophin gene could be more frequent than usually thought, suggesting the need of a careful cardiac follow-up. Except for the classical chromosomal rearrangements, it was shown that a bias in the X chromosome inactivation process could be found in some affected females. We report two families illustrating different situations. The propositus of the first family, aged 32, presented with a proximal muscular weakness, increasing for three years, as well as elevated muscular enzymes in blood. Her brother suffered from classical Duchenne muscular dystrophy. Her mother was more severely affected, whereas her sister remained asymptomatic. A duplication of exons 3 to 7 of the dystrophin gene was found in all four patients. The affected carrier from the second family was a sporadic case. She has been suffering from proximal muscular weakness for six years. Muscle biopsy showed a mosaic pattern of the immunostaining using specific antidystrophin antibodies. A stop mutation was found in exon 52. Her ten year-old daughter, carrying the mutation, was asymptomatic. In both families, the inactivation profiles were in accordance with the clinical presentation. We discuss the different mechanisms that may lead to the inactivation bias in these patients, as well as the advantage and limits of using the X chromosome inactivation test as a tool for diagnosis and prognosis purpose in symptomatic carriers for dystrophinopathies.

Several studies have recently highlighted the fact that the clinical involvement in

    females
    GENDER

 carrying a

    mutation in the dystrophin gene
    GENETICS

 could be more frequent than usually thought, suggesting the need of a careful

    cardiac follow-up
    PARACLINICAL

. Except for the classical

    chromosomal rearrangements
    GENETICS

, it was shown that a

    bias in the X chromosome inactivation process
    GENETICS

 could be found in some affected

    females
    GENDER

. We report two families illustrating different situations. The propositus of the first family,

    aged 32
    AGE

, presented with a

    proximal muscular weakness, increasing for three years
    SYMPTOMS

, as well as

    elevated muscular enzymes in blood
    BIOCHEMICAL

.

    Her
    GENDER

    brother suffered from classical Duchenne muscular dystrophy
    FAMILY

.

    Her
    GENDER

    mother was more severely affected
    FAMILY

, whereas

    her
    GENDER

    sister remained asymptomatic
    FAMILY

. A

    duplication of exons 3 to 7 of the dystrophin gene
    GENETICS

 was found in all four patients. The affected carrier from the second family was a sporadic case.

    She
    GENDER

 has been suffering from

    proximal muscular weakness for six years
    SYMPTOMS

.

    Muscle biopsy
    PARACLINICAL

 showed a

    mosaic pattern of the immunostaining using specific antidystrophin antibodies
    MICROSCOPIC

. A

    stop mutation was found in exon 52
    GENETICS

.

    Her
    GENDER

    ten year-old daughter, carrying the mutation, was asymptomatic
    FAMILY

. In both families, the inactivation profiles were in accordance with the clinical presentation. We discuss the different mechanisms that may lead to the inactivation bias in these patients, as well as the advantage and limits of using the

    X chromosome inactivation test
    PARACLINICAL

 as a tool for diagnosis and prognosis purpose in symptomatic carriers for

    dystrophinopathies
    DIAGNOSIS

.


ST-segment displacement in Duchenne muscular dystrophy: myocardial necrosis or apoptosis?

An electrocardiographic pattern resembling myocardial infarction is a rare condition in Duchenne muscular dystrophy. We report the case of a Duchenne boy, aged 12 years and 7 month, who, during a programmed examination, showed electrocardiographic signs of ST segment elevation, without symptoms usually accompanying myocardial infarction (chest pain, dyspnoea, sweating). The biological markers of myocardial damage became positive on the 2nd day and recovered on the 5th day. Clinical features of this uncommon pattern are described, with the retrospective evaluation of similar cases from personal records. The differential diagnosis between myocardial necrosis and apoptosis is discussed.

An

    electrocardiographic pattern resembling myocardial infarction
    SYMPTOMS

 is a rare condition in

    Duchenne muscular dystrophy
    DIAGNOSIS

. We report the case of a

    Duchenne
    DIAGNOSIS

    boy
    GENDER

,

    aged 12 years and 7 month
    AGE

, who, during a

    programmed examination
    PARACLINICAL

, showed

    electrocardiographic signs of ST segment elevation
    SYMPTOMS

,

    without symptoms usually accompanying myocardial infarction (chest pain, dyspnoea, sweating)
    NEG_FINDINGS

.

    The biological markers of myocardial damage became positive
    BIOCHEMICAL

 on the 2nd day and

    recovered
    BIOCHEMICAL

 on the 5th day. Clinical features of this uncommon pattern are described, with the retrospective evaluation of similar cases from personal records. The

    differential diagnosis
    PARACLINICAL

 between

    myocardial necrosis
    DIAGNOSIS

 and

    apoptosis
    SYMPTOMS

 is discussed.

Duchenne muscular dystrophy
Duchenne
myocardial necrosis


[A case of Duchenne muscular dystrophy showing coagulation cascade activation induced by muscle destruction due to convulsion].

A male patient with advanced Duchenne muscular dystrophy (DMD) had tonic-clonic convulsion. He showed transient elevations of serum creatine kinase (CK) and plasma D-dimer. Serum CK, ordinarily 122-386 IU/l, was elevated to 9,262 IU/l, while plasma D-dimer, below 66 ng/ml in normal subjects, was at 543 ng/ml, and these levels were significantly correlated. Serum fibrin and fibrinogen degradation products levels were within a normal range. In the present case, acute muscle destruction due to tonic-clonic convulsion was considered to transiently activate a coagulation cascade. Plasma D-dimer elevation is the result of fibrin thrombus and can induce thrombosis, such as a pulmonary embolism. Thrombosis is a serious life-threatening complication of DMD, though the mechanism remains unclear. There were no thrombotic complications in the present patient, however, acute muscle destruction enhances the coagulation and fibrinolysis status in patients with advanced DMD and may be a candidate cause of thrombosis.

A

    male
    GENDER

 patient with

    advanced Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 had

    tonic-clonic convulsion
    SYMPTOMS

.

    He
    GENDER

 showed

    transient elevations of serum creatine kinase (CK) and plasma D-dimer
    BIOCHEMICAL

.

    Serum CK, ordinarily 122-386 IU/l, was elevated to 9,262 IU/l
    BIOCHEMICAL

, while

    plasma D-dimer, below 66 ng/ml in normal subjects, was at 543 ng/ml
    BIOCHEMICAL

, and these

    levels were significantly correlated
    BIOCHEMICAL

.

    Serum fibrin and fibrinogen degradation products levels were within a normal range
    NEG_FINDINGS

. In the present case,

    acute muscle destruction
    SYMPTOMS

 due to

    tonic-clonic convulsion
    SYMPTOMS

 was considered to

    transiently activate a coagulation cascade
    BIOCHEMICAL

.

    Plasma D-dimer elevation
    BIOCHEMICAL

 is the result of

    fibrin thrombus
    SYMPTOMS

 and can induce

    thrombosis, such as a pulmonary embolism
    SYMPTOMS

.

    Thrombosis
    SYMPTOMS

 is a serious life-threatening complication of

    DMD
    DIAGNOSIS

, though the mechanism remains unclear. There were

    no thrombotic complications
    NEG_FINDINGS

 in the present patient, however,

    acute muscle destruction
    SYMPTOMS

    enhances the coagulation and fibrinolysis status
    BIOCHEMICAL

 in patients with

    advanced DMD
    DIAGNOSIS

 and may be a candidate cause of

    thrombosis
    SYMPTOMS

.


Successful heart transplantation in patients with inherited myopathies associated with end-stage cardiomyopathy.

Inherited myopathies in patients with secondary end-stage cardiomyopathies have always been considered a relative contraindication for cardiac transplantation. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the poor prognosis.

The aim of this study was to evaluate the outcome in patients who underwent cardiac transplantation in our hospital due to end-stage cardiomyopathy secondary to inherited myopathies.

Among 311 patients who underwent heart transplantation in our hospital, five (2%) had end-stage cardiomyopathies related to inherited myopathies. Four patients had muscular dystrophy (three Becker's muscular dystrophy and one hips-dystrophy) and the fifth desminopathy. In one patient cardiomyopathy was the initial manifestation of the disease. Mean age at the time of transplantation was 38.6 years (range from 24 to 55). The mean follow-up after transplantation was 57.4 months (range from 13 to 128). The intraoperative and postoperative course of these individuals did not show higher complication rates than other patients. All recipients experienced successful rehabilitation; no evidence of graft dysfunction has been detected during follow-up. All of them are alive with a good performance status.

In our experience, patients who underwent heart transplantation due to end-stage cardiomyopathy secondary to inherited myopathy with only a mild degree of muscle impairment did not display higher postoperative nor long-term complications compared to other recipients.

    Inherited myopathies
    DIAGNOSIS

 in patients with

    secondary end-stage cardiomyopathies
    DIAGNOSIS

 have always been considered a relative contraindication for

    cardiac transplantation
    MEDICATION

. High operative risk related to

    muscle impairment
    SYMPTOMS

 and

    potential graft involvement secondary to the underlying myopathy
    SYMPTOMS

 have been the two main reasons implicated in the poor prognosis.

The aim of this study was to evaluate the outcome in patients who underwent

    cardiac transplantation
    MEDICATION

 in our hospital due to

    end-stage cardiomyopathy
    DIAGNOSIS

 secondary to

    inherited myopathies
    DIAGNOSIS

.

Among 311 patients who underwent

    heart transplantation
    MEDICATION

 in our hospital, five (2%) had

    end-stage cardiomyopathies
    DIAGNOSIS

 related to

    inherited myopathies
    DIAGNOSIS

. Four patients had

    muscular dystrophy
    DIAGNOSIS

 (three

    Becker's muscular dystrophy
    DIAGNOSIS

 and one

    hips-dystrophy
    DIAGNOSIS

) and the fifth

    desminopathy
    DIAGNOSIS

. In one patient

    cardiomyopathy
    SYMPTOMS

 was the initial manifestation of the disease.

    Mean age at the time of transplantation
    AGE

    was 38.6 years (range from 24 to 55)
    AGE

. The mean follow-up after

    transplantation
    MEDICATION

    was 57.4 months (range from 13 to 128)
    AGE

. The intraoperative and postoperative course of these individuals did not show higher complication rates than other patients. All recipients experienced

    successful rehabilitation
    MEDICATION

;

    no evidence of graft dysfunction
    NEG_FINDINGS

 has been detected during

    follow-up
    PARACLINICAL

. All of them are alive with a

    good performance status
    SYMPTOMS

.

In our experience, patients who underwent

    heart transplantation
    MEDICATION

 due to

    end-stage cardiomyopathy
    DIAGNOSIS

 secondary to

    inherited myopathy
    DIAGNOSIS

 with

    only a mild degree of muscle impairment
    SYMPTOMS

 did not display higher postoperative nor

    long-term complications
    SYMPTOMS

 compared to other recipients.

Inherited myopathies
secondary end-stage cardiomyopathies
end-stage cardiomyopathy
inherited myopathies
end-stage cardiomyopathies
inherited myopathies
muscular dystrophy
Becker's muscular dystrophy
hips-dystrophy
desminopathy
end-stage cardiomyopathy
inherited myopathy

cardiac transplantation
cardiac transplantation
heart transplantation
transplantation
successful rehabilitation
heart transplantation


[A case of Duchenne muscular dystrophy complicated by thrombotic thrombocytopenic purpura].

We experienced a patient with Duchenne muscular dystrophy (DMD) complicated by thrombotic thrombocytopenic purpura (TTP). This patient exhibited abrupt high fever, renal dysfunction and thrombocytopenia from February 2, 2002. Hemolysis was also indicated by indirect dominant hyperbilirubinemia, although hemoglobin was only slightly decreased. No central nervous system signs and symptoms were detected. TTP was suggested by these findings and confirmed by decreased activity (21%) of von Willebrand factor cleaving protease activity. Plasma exchange was performed for 4 days from February 5, and enabled recovery. Thrombosis, such as cerebral and lung infarction, has occasionally been seen in DMD. Recently, several findings associating muscle degeneration with hypercoagulation have been reported, for example, a strong correlation between serum CK level and FDP. In seven cases of DMD with pulmonary infarction, transient elevation of serum CK was detected prior to LDH elevation. However, there have been no reports of TTP in DMD patients. Since serum CK was not elevated during our patient's clinical course, it is unlikely that muscle degeneration played a role in TTP in this patient. It should be noted that endothelial abnormalities have been reported in DMD, since endothelial injury is considered a fundamental factor in TTP.

We experienced a patient with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 complicated by

    thrombotic thrombocytopenic purpura (TTP)
    DIAGNOSIS

. This patient exhibited

    abrupt high fever
    SYMPTOMS

,

    renal dysfunction
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

 from February 2, 2002.

    Hemolysis
    BIOCHEMICAL

 was also indicated by

    indirect dominant hyperbilirubinemia
    BIOCHEMICAL

, although

    hemoglobin was only slightly decreased
    BIOCHEMICAL

.

    No central nervous system signs and symptoms were detected
    NEG_FINDINGS

.

    TTP
    DIAGNOSIS

 was suggested by these findings and confirmed by

    decreased activity (21%) of von Willebrand factor cleaving protease activity
    BIOCHEMICAL

.

    Plasma exchange was performed for 4 days
    MEDICATION

 from February 5, and enabled recovery.

    Thrombosis
    SYMPTOMS

, such as

    cerebral and lung infarction
    SYMPTOMS

, has occasionally been seen in

    DMD
    DIAGNOSIS

. Recently, several findings associating

    muscle degeneration
    SYMPTOMS

 with

    hypercoagulation
    BIOCHEMICAL

 have been reported, for example, a

    strong correlation between serum CK level and FDP
    BIOCHEMICAL

. In seven cases of

    DMD
    DIAGNOSIS

 with

    pulmonary infarction
    SYMPTOMS

,

    transient elevation of serum CK was detected
    BIOCHEMICAL

 prior to

    LDH elevation
    BIOCHEMICAL

. However, there have been no reports of

    TTP
    DIAGNOSIS

 in

    DMD
    DIAGNOSIS

 patients. Since

    serum CK was not elevated
    NEG_FINDINGS

 during our patient's clinical course, it is unlikely that

    muscle degeneration
    NEG_FINDINGS

 played a role in

    TTP
    DIAGNOSIS

 in this patient. It should be noted that

    endothelial abnormalities
    SYMPTOMS

 have been reported in

    DMD
    DIAGNOSIS

, since

    endothelial injury
    SYMPTOMS

 is considered a fundamental factor in

    TTP
    DIAGNOSIS

.

abrupt high fever
renal dysfunction
Thrombosis
cerebral and lung infarction
muscle degeneration
pulmonary infarction
endothelial abnormalities
endothelial injury


Dilated cardiomyopathy and new 16 bp deletion in exon 44 of the Dystrophin gene: the possible role of repeated motifs in mutation generation.

Here we report a boy with dilated cardiomyopathy and severe Duchenne muscular dystrophy (DMD). The disease-causing mutation was a new 16 bp deletion in exon 44 of the dystrophin gene, which led to frameshifting and premature translation termination. This deletion in exon 44 was associated with dilated cardiomyopathy. The dystrophin region in exon 44 might be considered as one of the high-risk regions in which mutations could lead to myocardial damage, dilated cardiomyopathy, and early death. The abundance of repeated motifs was detected within the deleted segment and in the region. These sequence motifs might be involved in secondary structure formation and thus they could participate in the mutation generation.

Here we report a

    boy
    GENDER

 with

    dilated cardiomyopathy
    DIAGNOSIS

 and

    severe Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. The

    disease-causing mutation was a new 16 bp deletion in exon 44 of the dystrophin gene
    GENETICS

, which led to

    frameshifting and premature translation termination
    GENETICS

. This

    deletion in exon 44
    GENETICS

 was associated with

    dilated cardiomyopathy
    DIAGNOSIS

. The

    dystrophin region in exon 44
    GENETICS

 might be considered as one of the high-risk regions in which mutations could lead to

    myocardial damage
    SYMPTOMS

,

    dilated cardiomyopathy
    SYMPTOMS

, and

    early death
    SYMPTOMS

. The

    abundance of repeated motifs was detected within the deleted segment and in the
    GENETICS

 region. These sequence motifs might be involved in secondary structure formation and thus they could participate in the mutation generation.

myocardial damage
dilated cardiomyopathy
early death


Acute heart failure during spinal surgery in a boy with Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) are at high risk of perioperative complications. DMD may be accompanied by heart failure resulting from dystrophic involvement of the myocardium, which can be subclinical in the early stages of the disease. This case demonstrates that a normal preoperative ECG and echocardiograph cannot exclude the development of heart failure during anaesthesia in DMD patients undergoing major surgery.

Patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 are at high risk of

    perioperative complications
    SYMPTOMS

.

    DMD
    DIAGNOSIS

 may be accompanied by

    heart failure
    SYMPTOMS

 resulting from

    dystrophic involvement of the myocardium
    SYMPTOMS

, which can be subclinical in the early stages of the disease. This case demonstrates that a

    normal preoperative ECG and echocardiograph
    NEG_FINDINGS

 cannot exclude the development of

    heart failure
    SYMPTOMS

 during

    anaesthesia
    MEDICATION

 in

    DMD
    DIAGNOSIS

 patients undergoing

    major surgery
    MEDICATION

.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Two children with muscular dystrophies ascertained due to referral for diagnosis of autism.

We report two children who were referred for diagnostic assessment for autism and were subsequently determined to have a muscular dystrophy (MD). Each child had a history of speech delay and social impairments, but also had motor delays that had not previously been investigated. Both children met diagnostic criteria for autism spectrum disorders on standardized assessment. Each child was hypotonic and had other mild motor impairments. Serum creatine kinase (CK) activity was markedly elevated in each child, and subsequent muscle biopsy led to diagnosis of Becker's MD and congenital (autosomal recessive) MD, respectively. These cases highlight the importance of a thorough neuromotor examination for all children with suspected autism spectrum disorders.

We report two

    children
    AGE

 who were referred for diagnostic assessment for

    autism
    DIAGNOSIS

 and were subsequently determined to have a

    muscular dystrophy (MD)
    DIAGNOSIS

. Each

    child
    AGE

 had a history of

    speech delay
    SYMPTOMS

 and

    social impairments
    SYMPTOMS

, but also had

    motor delays
    SYMPTOMS

 that had not previously been investigated. Both children met diagnostic criteria for

    autism spectrum disorders
    DIAGNOSIS

 on

    standardized assessment
    PARACLINICAL

. Each child was

    hypotonic
    SYMPTOMS

 and had

    other mild motor impairments
    SYMPTOMS

.

    Serum creatine kinase (CK) activity was markedly elevated
    BIOCHEMICAL

 in each child, and subsequent

    muscle biopsy
    PARACLINICAL

 led to diagnosis of

    Becker's MD
    DIAGNOSIS

 and

    congenital (autosomal recessive) MD
    DIAGNOSIS

, respectively. These cases highlight the importance of a

    thorough neuromotor examination
    PARACLINICAL

 for all

    children
    AGE

 with suspected

    autism spectrum disorders
    DIAGNOSIS

.

autism
muscular dystrophy (MD)
autism spectrum disorders
Becker's MD
congenital (autosomal recessive) MD
autism spectrum disorders

speech delay
social impairments
motor delays
hypotonic
other mild motor impairments


Large in-frame deletions of the rod-shaped domain of the dystrophin gene resulting in severe phenotype.

The prediction that Duchenne muscular dystrophy patients have out-of-frame deletions and Becker muscular dystrophy patients have in-frame deletions of the dystrophin gene holds well in the vast majority of cases. Large in-frame deletions involving the rod domain only have usually been associated with mild (BMD) phenotype.

Screening for dystrophin gene deletion was performed on genomic DNA by using multiplex polymerase chain reaction. Needle muscle biopsies from the quadriceps were obtained using a Bergström needle. The biopsies were stained with histologic and histochemical techniques as well as monoclonal antibodies to dystrophin 1, 2 and 3.

In three children with large in-frame deletions of the rod domain (exons 10-44, 13-40 and 3-41), early-onset weakness and a disease course suggested the DMD phenotype.

This observation emphasizes the uncertainty in predicting the Becker phenotype in a young patient based on laboratory evaluation, and that the clinical picture should always be considered.

The prediction that

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients have

    out-of-frame deletions
    GENETICS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 patients have

    in-frame deletions of the dystrophin gene
    GENETICS

 holds well in the vast majority of cases.

    Large in-frame deletions involving the rod domain only
    GENETICS

 have usually been associated with

    mild (BMD) phenotype
    SYMPTOMS

.

To describe unusual cases with

    large in-frame deletions of the rod-shaped domain of the dystrophin gene associated with severe (Duchenne) clinical phenotype
    GENETICS

    Screening for dystrophin gene deletion
    PARACLINICAL

 was performed

    on genomic DNA by using multiplex polymerase chain reaction
    PARACLINICAL

.

    Needle muscle biopsies from the quadriceps
    PARACLINICAL

 were obtained using a

    Bergström needle
    PARACLINICAL

.

    The biopsies
    PARACLINICAL

 were

    stained with histologic and histochemical techniques
    PARACLINICAL

 as well as monoclonal antibodies to dystrophin 1, 2 and 3.

In three

    children
    AGE

 with

    large in-frame deletions of the rod domain (exons 10-44, 13-40 and 3-41)
    GENETICS

,

    early-onset weakness
    SYMPTOMS

 and a disease course suggested the

    DMD
    DIAGNOSIS

 phenotype.

This observation emphasizes the uncertainty in predicting the

    Becker
    DIAGNOSIS

 phenotype in a

    young
    AGE

 patient based on

    laboratory evaluation
    PARACLINICAL

, and that the clinical picture should always be considered.

Duchenne muscular dystrophy
Becker muscular dystrophy
DMD
Becker

mild (BMD) phenotype
early-onset weakness


[First case of successful pregnancy after preimplantation genetic diagnosis].

Preimplantation genetic diagnosis is introduced for prevention of genetic disorders. The combination of in vitro fertilization technique and single cell molecular genetic diagnosis allows only unaffected embryos to be selected for embryotransfer, providing a healthy pregnancy and so also avoiding the need for its possible termination.

The authors report the first successful case of the clinical application of preimplantation genetic diagnosis in Hungary, resulting the birth of an unaffected baby. Preembryonal biopsy and subsequent fluorescent-PCR analysis of the blastomeres taken from the preembryos of a woman who is a carrier for Duchenne muscular dystrophy was performed. Sexing of the preembryos by X and Y chromosome specific primers were performed and three female preembryos were found.

All three preembryos were transferred into the uterus, which resulted a singleton pregnancy, resulting the birth of a healthy female baby. The authors are offering preimplantation genetic diagnosis with sexing for couples, who are at risk of having a child with X-linked diseases, or are carriers for the delta-F508 mutation of cystic fibrosis.

The application of this diagnostic tool is also planned for other monogenic disorders.

    Preimplantation genetic diagnosis
    PARACLINICAL

 is introduced for prevention of

    genetic disorders
    DIAGNOSIS

. The combination of

    in vitro fertilization technique
    MEDICATION

 and

    single cell molecular genetic diagnosis
    PARACLINICAL

 allows only unaffected embryos to be selected for

    embryotransfer
    MEDICATION

, providing a healthy pregnancy and so also avoiding the need for

    its possible termination
    NEG_FINDINGS

.

The authors report the first successful case of the clinical application of

    preimplantation genetic diagnosis
    MEDICATION

 in

    Hungary
    ETHNICITY

, resulting the birth of an unaffected baby.

    Preembryonal biopsy
    PARACLINICAL

 and subsequent

    fluorescent-PCR analysis of the blastomeres taken from the preembryos
    PARACLINICAL

 of a

    woman
    GENDER

 who is a carrier for

    Duchenne muscular dystrophy
    DIAGNOSIS

 was performed.

    Sexing of the preembryos by X and Y chromosome specific primers
    PARACLINICAL

 were performed and three

    female preembryos
    MICROSCOPIC

 were found.

    All three preembryos were transferred into the uterus, which resulted a singleton pregnancy
    MEDICATION

, resulting the

    birth of a healthy female baby
    MEDICATION

. The authors are offering

    preimplantation genetic diagnosis with sexing
    MEDICATION

 for

    couples
    GENDER

, who are at risk

    of having a child with X-linked diseases
    FAMILY

, or are

    carriers for the delta-F508 mutation of cystic fibrosis
    GENETICS

.

The application of this diagnostic tool is also planned for other

    monogenic disorders
    DIAGNOSIS

.

genetic disorders
Duchenne muscular dystrophy
monogenic disorders


Heterogous dystrophin mRNA produced by a novel splice acceptor site mutation in intermediate dystrophinopathy.

The molecular background of an intermediate type of dystrophinopathy [Duchenne and Becker muscular dystrophy (DMD/BMD)] remains to be clarified, and out-of -frame and in-frame mutations of the dystrophin gene are shown to be causes of DMD and BMD, respectively. In a boy with this disease, dystrophin mRNA extracted from lymphocytes and muscle were analyzed both qualitatively and quantitatively using reverse transcription PCR. Three different dystrophin mRNA were found to be produced via the use of three cryptic splice acceptor sites resulting from a novel point mutation of 2831-2A>G at the conserved splice acceptor site of intron 20. One of three mRNA showed an insertion of six nucleotides of intron 20 between exons 20 and 21 (dys+6) that encoded two novel amino acids in the rod domain of dystrophin. Two other mRNA species showed an insertion of seven nucleotides of intron 20 between exons 20 and 21 (dys+7) or a seven-nucleotide deletion in exon 21 (dys-7). Quantitative analysis of each dystrophin mRNA expressed in the boy's skeletal muscle disclosed that around 95% and 5% of dystrophin mRNAs were dys-7 and dys+6, respectively, whereas these two mRNA were almost equally expressed in lymphocytes. It is suggested that production of a small fraction of in-frame mRNA in muscle explains the molecular background of the intermediate type of dystrophinopathy in the index case. This finding underlines the potential of genetic therapeutic strategies aimed to modify mRNA in DMD to generate a much milder disease.

The molecular background of an

    intermediate type of dystrophinopathy [Duchenne and Becker muscular dystrophy (DMD/BMD)
    DIAGNOSIS

] remains to be clarified, and

    out-of -frame and in-frame mutations of the dystrophin gene
    GENETICS

 are shown to be causes of

    DMD
    DIAGNOSIS

 and

    BMD
    DIAGNOSIS

, respectively. In a

    boy
    GENDER

 with this disease,

    dystrophin mRNA extracted from lymphocytes and muscle were analyzed both qualitatively and quantitatively
    PARACLINICAL

 using

    reverse transcription PCR
    PARACLINICAL

. Three different dystrophin mRNA were found to be produced via the use of three cryptic splice acceptor sites resulting from a

    novel point mutation of 2831-2A>G at the conserved splice acceptor site of intron 20
    GENETICS

. One of three mRNA showed

    an insertion of six nucleotides of intron 20 between exons 20 and 21 (dys+6) that encoded two novel amino acids in the rod domain of dystrophin
    GENETICS

. Two other mRNA species showed

    an insertion of seven nucleotides of intron 20 between exons 20 and 21 (dys+7) or a seven-nucleotide deletion in exon 21 (dys-7)
    GENETICS

.

    Quantitative analysis of each dystrophin mRNA expressed in the boy's skeletal muscle
    PARACLINICAL

 disclosed that around 95% and 5% of

    dystrophin mRNAs were dys-7 and dys+6
    GENETICS

, respectively, whereas these two mRNA were almost equally expressed in lymphocytes. It is suggested that

    production of a small fraction of in-frame mRNA in muscle
    MICROSCOPIC

 explains the molecular background of the

    intermediate type of dystrophinopathy
    DIAGNOSIS

 in the index case. This finding underlines the potential of genetic therapeutic strategies aimed to modify mRNA in

    DMD
    DIAGNOSIS

 to generate a much milder disease.