Homozygous female Becker muscular dystrophy.

We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.

We report, for the first time, on a

    female
    GENDER

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 patient with

    homozygous dystrophin deletion
    GENETICS

. The

    14-year-old
    AGE

 patient,

    product of consanguineous parents
    FAMILY

, presented with a

    7-year history
    SYMPTOMS

 of

    exercise intolerance
    SYMPTOMS

 and

    recurrent myoglobinuria
    BIOCHEMICAL

. Although

    CK was elevated to 1,800 U/L
    BIOCHEMICAL

,

    no muscle weakness, atrophy, or hypertrophy
    NEG_FINDINGS

 was seen on examination.

    Muscle pathology
    PARACLINICAL

 demonstrated a

    minimal dystrophic change
    SYMPTOMS

 and

    faint dystrophin staining pattern
    SYMPTOMS

.

    Semi-quantitative PCR of dystrophin
    PARACLINICAL

 revealed a

    homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting
    GENETICS

.

    Western blot analysis of skeletal muscle for dystrophin
    PARACLINICAL

 showed a

    306 kDa band
    BIOCHEMICAL

; thus, we made a diagnosis of

    female
    GENDER

    BMD
    DIAGNOSIS

. We confirmed

    identical deletion in both father and mother, in hemizygous and heterozygous modes
    FAMILY

, respectively. Neither

    female
    GENDER

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 nor

    BMD
    DIAGNOSIS

 due to

    homozygous dystrophin mutation
    GENETICS

 has ever been identified although

    female
    GENDER

    DMD
    DIAGNOSIS

 has been found in patients with

    Turner syndrome
    DIAGNOSIS

 or

    unilateral parental disomy for X chromosome
    FAMILY

. Our results indicate that

    dystrophinopathy
    DIAGNOSIS

 can also be caused in

    females
    GENDER

 by

    homozygosity
    GENETICS

, albeit rare.

Becker muscular dystrophy (BMD)
BMD
Duchenne muscular dystrophy (DMD)
BMD
DMD
Turner syndrome
dystrophinopathy

7-year history
exercise intolerance
minimal dystrophic change
faint dystrophin staining pattern

recurrent myoglobinuria
CK was elevated to 1,800 U/L
306 kDa band


[Prenatal molecular diagnosis of a DMD carrier female fetus by chorionic villus sampling and linkage analysis].

Duchenne muscular dystrophy (DMD) is the most frequent inherited and lethal neuromuscular disorder in humans. Molecular prenatal diagnosis of DMD through amniocentesis is a real preventive reproductive option in our country, although experience with chorionic villus sampling is still limited (CVS).

Perform the first prenatal diagnosis in an obligate DMD carrier woman in Mexico by CVS.

CVS was performed in an obligate DMD carrier woman in which no partial intragenic deletions were present but a haplotype at-risk was identified. Cytogenetic analysis with GTG banding was performed and genomic DNA extraction from CVS sample was done without culture. Fetal gender assignment was achieved by ultrasonography at 12 weeks of gestation and confirmed by PCR amplification of two Y chromosome-linked loci (SRY and DYS389I/II). Identification of the DMD haplotype at-risk in the fetus was done through analysis of the intragenic markers pERT87.8/TaqI and pERT87.15/Xmnl.

Absence of PCR products corresponding to Y chromosome-linked loci in DNA CVS sample was compatible with a female fetus; it was confirmed later by cytogenetic study and prenatal ultrasound follow-up. Linkage analysis reveals that the female fetus inherited the DMD haplotype at-risk. We did not identify any maternal DNA contamination in CVS molecular analysis and these results were postnatally confirmed in DNA obtained from buccal cells.

Molecular prenatal diagnosis through chorionic villus sampling could be an early reproductive prevention strategy applicable to Duchenne/Becker muscular dystrophy carrier women in our country.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is the most frequent

    inherited
    GENETICS

 and

    lethal neuromuscular disorder
    DIAGNOSIS

 in humans.

    Molecular prenatal diagnosis
    PARACLINICAL

 of

    DMD
    DIAGNOSIS

 through

    amniocentesis
    PARACLINICAL

 is a real

    preventive reproductive option
    MEDICATION

 in our country, although experience with

    chorionic villus sampling
    PARACLINICAL

 is still limited (

    CVS
    PARACLINICAL

).

    Perform the first prenatal diagnosis in an obligate DMD carrier woman
    MEDICATION

 in

    Mexico
    ETHNICITY

 by

    CVS
    MEDICATION

.

    CVS
    MEDICATION

 was performed in an

    obligate DMD
    GENETICS

 carrier

    woman
    GENDER

 in which

    no partial intragenic deletions were present
    NEG_FINDINGS

 but a

    haplotype at-risk was identified
    GENETICS

.

    Cytogenetic analysis with GTG banding
    PARACLINICAL

 was performed and

    genomic DNA extraction from CVS sample
    PARACLINICAL

 was done

    without culture
    PARACLINICAL

.

    Fetal gender assignment
    PARACLINICAL

 was achieved by

    ultrasonography at 12 weeks of gestation
    PARACLINICAL

 and confirmed by

    PCR amplification of two Y chromosome-linked loci (SRY and DYS389I/II)
    PARACLINICAL

.

    Identification of the DMD haplotype at-risk in the fetus
    GENETICS

 was done through analysis of the intragenic markers pERT87.8/TaqI and pERT87.15/Xmnl.

    Absence of PCR products corresponding to Y chromosome-linked loci in DNA CVS sample
    GENETICS

 was compatible with a

    female
    GENDER

    fetus
    GENETICS

; it was confirmed later by

    cytogenetic study
    PARACLINICAL

 and

    prenatal ultrasound follow-up
    PARACLINICAL

.

    Linkage analysis
    PARACLINICAL

 reveals that the

    female
    GENDER

    fetus inherited the DMD haplotype at-risk
    FAMILY

. We

    did not identify any maternal DNA contamination
    NEG_FINDINGS

 in

    CVS molecular analysis
    NEG_FINDINGS

 and these results were postnatally confirmed in

    DNA obtained from buccal cells
    PARACLINICAL

.

    Molecular prenatal diagnosis through chorionic villus sampling
    PARACLINICAL

 could be an

    early reproductive prevention strategy
    MEDICATION

 applicable to

    Duchenne/Becker muscular dystrophy
    DIAGNOSIS

 carrier

    women
    GENDER

 in our country.

Duchenne muscular dystrophy (DMD)
lethal neuromuscular disorder
DMD
Duchenne/Becker muscular dystrophy


A case of X-linked adrenal hypoplasia congenita, central precocious puberty and absence of the DAX-1 gene: implications for pubertal regulation.

X-linked adrenal hypoplasia congenita (AHC) is typically associated with DAX-1 mutations and hypogonadotropic hypogonadism. However, atypical cases of X-linked AHC in association with central precocious puberty and even normal puberty have rarely been reported, although the mechanism of action remains unknown.

This is a case report of a boy with X-linked AHC associated with Duchenne muscular dystrophy, whose clinical presentation led to analysis of the DAX-1, glycerol kinase (GK1) and dystrophin genes, which were amplified by polymerase chain reaction, with Southern blot analysis of the AHC locus.

There was a non-contiguous deletion of the DAX-1 and GK1 genes, with deletion of the dystrophingene from exons 3 to 79.

This is the first report of X-linked AHC, central precocious puberty in the absence of the DAX-1 gene. The fact that a 'loss of function' DAX-1 mutation can be associated with hypogonadotropic hypogonadism, precocious and normal puberty, suggests that DAX-1 is but one of several transcription factors which regulate puberty, and provides further evidence that other transcription factors may interact with DAX-1 and influence gonadal regulation in a complex, but hierarchical fashion.

    X-linked
    GENETICS

    adrenal hypoplasia congenita (AHC)
    DIAGNOSIS

 is typically associated with

    DAX-1 mutations
    GENETICS

 and

    hypogonadotropic hypogonadism
    SYMPTOMS

. However, atypical cases of

    X-linked
    GENETICS

    AHC
    DIAGNOSIS

 in association with

    central precocious puberty
    SYMPTOMS

 and even

    normal puberty
    NEG_FINDINGS

 have rarely been reported, although the mechanism of action remains unknown.

This is a case report of a

    boy
    GENDER

 with

    X-linked AHC
    GENETICS

    associated with Duchenne muscular dystrophy
    DIAGNOSIS

, whose clinical presentation led to

    analysis of the DAX-1, glycerol kinase (GK1) and dystrophin genes
    PARACLINICAL

, which were

    amplified by polymerase chain reaction
    PARACLINICAL

, with

    Southern blot analysis of the AHC locus
    PARACLINICAL

.

This is the first report of

    X-linked
    GENETICS

    AHC
    DIAGNOSIS

,

    central precocious puberty
    SYMPTOMS

 in the

    absence of the DAX-1 gene
    GENETICS

. The fact that a '

    loss of function' DAX-1 mutation
    GENETICS

 can be associated with

    hypogonadotropic hypogonadism
    SYMPTOMS

,

    precocious
    SYMPTOMS

 and

    normal puberty
    SYMPTOMS

, suggests that

    DAX-1
    GENETICS

 is but one of several transcription factors which regulate

    puberty
    SYMPTOMS

, and provides further evidence that other transcription factors may interact with

    DAX-1
    GENETICS

 and influence

    gonadal regulation
    SYMPTOMS

 in a complex, but hierarchical fashion.

X-linked
DAX-1 mutations
X-linked
X-linked AHC
X-linked
absence of the DAX-1 gene
loss of function' DAX-1 mutation
DAX-1
DAX-1

hypogonadotropic hypogonadism
central precocious puberty
central precocious puberty
hypogonadotropic hypogonadism
precocious
normal puberty
puberty
gonadal regulation


Partial epilepsy in an adolescent male with limb-girdle muscular dystrophy 1B.

Muscular dystrophies are inherited muscle disorders associated with different gene mutations. Fukuyama congenital muscular dystrophy is associated with cobblestone lissencephaly and epilepsy frequently. Rarely, other types of muscular dystrophies are also associated with epilepsy including Duchenne and Becker muscular dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 chain, and limb-girdle muscular dystrophy 2A with calpain deficiency. We now report another rare case of partial epilepsy and limb-girdle muscular dystrophy type 1B with lamin A/C gene mutation.

    Muscular dystrophies
    DIAGNOSIS

 are

    inherited muscle disorders
    DIAGNOSIS

 associated with different

    gene mutations
    GENETICS

.

    Fukuyama congenital muscular dystrophy
    DIAGNOSIS

 is associated with

    cobblestone lissencephaly
    SYMPTOMS

 and

    epilepsy
    SYMPTOMS

 frequently. Rarely, other types of

    muscular dystrophies
    DIAGNOSIS

 are also associated with

    epilepsy
    SYMPTOMS

 including

    Duchenne and Becker muscular dystrophy
    DIAGNOSIS

,

    facioscapulohumeral dystrophy
    DIAGNOSIS

,

    congenital muscular dystrophy
    DIAGNOSIS

 with

    partial and complete deficiency of laminin alpha2 chain
    BIOCHEMICAL

, and

    limb-girdle muscular dystrophy 2A
    DIAGNOSIS

 with

    calpain deficiency
    BIOCHEMICAL

. We now report another rare case of

    partial epilepsy
    SYMPTOMS

 and

    limb-girdle muscular dystrophy type 1B
    DIAGNOSIS

 with

    lamin A/C gene mutation
    GENETICS

.

Muscular dystrophies
inherited muscle disorders
Fukuyama congenital muscular dystrophy
muscular dystrophies
Duchenne and Becker muscular dystrophy
facioscapulohumeral dystrophy
congenital muscular dystrophy
limb-girdle muscular dystrophy 2A
limb-girdle muscular dystrophy type 1B

cobblestone lissencephaly
epilepsy
epilepsy
partial epilepsy


A case of manifesting carrier with DMD phenotype.

A case of a 35-year old female with a history of proximal weakness in lower limbs and bulkiness of both calves manifesting before ten years of age was reported. Clinical findings were suggestive of muscular dystrophy. Genetic analysis using polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) and direct sequencing revealed several point mutations, which account for dystrophin dysfunction and DMD type pathogenesis.

A case of a

    35-year old
    AGE

    female
    GENDER

 with a history of

    proximal weakness in lower limbs
    SYMPTOMS

 and

    bulkiness of both calves
    SYMPTOMS

 manifesting

    before ten years of age
    AGE

 was reported. Clinical findings were suggestive of

    muscular dystrophy
    DIAGNOSIS

.

    Genetic analysis using polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP)
    PARACLINICAL

 and

    direct sequencing
    PARACLINICAL

 revealed

    several point mutations
    GENETICS

, which account for

    dystrophin dysfunction
    GENETICS

 and

    DMD type pathogenesis
    DIAGNOSIS

.

proximal weakness in lower limbs
bulkiness of both calves

muscular dystrophy
DMD type pathogenesis

several point mutations
dystrophin dysfunction


An instructive case of an 8-year-old boy with intellectual disability.

A child with global developmental delay sparing motor skills evolving into later intellectual disability with a consistently normal neuromuscular examination was discovered to have a dystrophin specific mutation in the 3' end of the gene. The deletion in the DMD gene was unsuspected and discovered through array comparative genomic hybridization and confirmed on polymerase chain reaction analysis. This case shows a central nervous system-specific and restrictive phenotype for a disorder that is conceptualized as being progressively neuromuscular in clinical expression. Given the familial and therapeutic implications for accurate diagnosis of DMD mutations, this case raises the possible need for screening boys with global developmental delay/intellectual disability even in the absence of any overt muscle weakness and further shows the utility of comparative genomic hybridization (CGH) analysis in the evaluation of patients with nonsyndromic mental retardation.

A

    child
    AGE

 with

    global developmental delay sparing motor skills
    SYMPTOMS

 evolving into

    later intellectual disability
    SYMPTOMS

 with a

    consistently normal neuromuscular examination
    NEG_FINDINGS

 was discovered to have a

    dystrophin specific mutation in the 3' end of the gene
    GENETICS

. The

    deletion in the DMD gene
    GENETICS

 was

    unsuspected
    NEG_FINDINGS

 and discovered through

    array comparative genomic hybridization
    PARACLINICAL

 and confirmed on

    polymerase chain reaction analysis
    PARACLINICAL

. This case shows a

    central nervous system-specific and restrictive phenotype
    SYMPTOMS

 for a disorder that is conceptualized as being progressively neuromuscular in clinical expression. Given the familial and therapeutic implications for accurate diagnosis of

    DMD mutations
    GENETICS

, this case raises the possible need for screening

    boys
    AGE

 with

    global developmental delay
    SYMPTOMS

/

    intellectual disability
    SYMPTOMS

 even in the

    absence of any overt muscle weakness
    NEG_FINDINGS

 and further shows the utility of

    comparative genomic hybridization (CGH) analysis
    PARACLINICAL

 in the evaluation of patients with

    nonsyndromic mental retardation
    DIAGNOSIS

.


Body composition and resting energy expenditure of individuals with Duchenne and Becker muscular dystrophy.

The relationship between body composition and resting energy expenditure (REE) was investigated in two boys and two men with Duchenne muscular dystrophy (DMD) (ages 11 to 22.4 years) and two boys with Becker muscular dystrophy (BMD) (ages 7.75 and 13.75 years).

The REE was assessed by indirect calorimetry; body composition indices (weight, height, skinfolds, and mid-arm circumference) were measured using standardized techniques and compared with healthy reference data.

Those with DMD had reduced corrected mid-upper-arm muscle area (C-MUMA) in comparison with healthy peers, and approximately twice the subcutaneous fat levels of subjects with BMD and healthy peers. Boys with BMD had remarkably lower muscle status than did boys with DMD and healthy peers. In both groups, REE was lower than in healthy peers; REE was associated with body weight (r=0.85), height (r=0.92), mid-upper arm fat area (MUFA) (r=0.97), and C-MUMA (r=0.65).

Individuals with muscular dystrophy (MD) exhibit considerable disease-specific alterations in body composition. The REE had a stronger relationship with growth (weight and height) and subcutaneous body fat composition and a weaker association with C-MUMA. Understanding the effect of MD on body composition and REE will allow dietitians to individualize energy recommendations.

The relationship between body composition and

    resting energy expenditure (REE)
    PARACLINICAL

 was investigated in two

    boys
    GENDER

 and two

    men
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 (

    ages 11 to 22.4 years)
    AGE

 and two

    boys
    GENDER

 with

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 (

    ages 7.75 and 13.75 years)
    AGE

.

The

    REE was assessed by indirect calorimetry
    PARACLINICAL

;

    body composition indices (weight, height, skinfolds, and mid-arm circumference) were measured using standardized techniques
    SYMPTOMS

 and compared with healthy reference data.

Those with

    DMD
    DIAGNOSIS

 had

    reduced corrected mid-upper-arm muscle area (C-MUMA)
    SYMPTOMS

 in comparison with healthy peers, and

    approximately twice the subcutaneous fat levels
    SYMPTOMS

 of subjects with

    BMD
    DIAGNOSIS

 and healthy peers.

    Boys
    GENDER

 with

    BMD
    DIAGNOSIS

 had

    remarkably lower muscle status
    SYMPTOMS

 than did

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

 and healthy peers. In both groups,

    REE was lower
    BIOCHEMICAL

 than in healthy peers; REE was associated with body weight (r=0.85), height (r=0.92),

    mid-upper arm fat area (MUFA)
    SYMPTOMS

 (r=0.97), and

    C-MUMA
    SYMPTOMS

 (r=0.65).

Individuals with

    muscular dystrophy (MD)
    DIAGNOSIS

 exhibit

    considerable disease-specific alterations in body composition
    SYMPTOMS

. The REE had a stronger relationship with growth (weight and height) and

    subcutaneous body fat composition
    SYMPTOMS

 and a weaker association with

    C-MUMA
    BIOCHEMICAL

. Understanding the effect of

    MD
    DIAGNOSIS

 on body composition and REE will allow dietitians to individualize energy recommendations.

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


Asymptomatic Becker muscular dystrophy in a family with a multiexon deletion.

We report a Becker muscular dystrophy (BMD) family with one 5-year-old affected patient and a 69-year-old asymptomatic grandfather. Dystrophin gene multiplex polymerase chain reaction and multiplex ligation-dependant probe amplification analysis showed that both males carried an in-frame deletion of exons 45-55. Segregation analysis revealed two additional asymptomatic boys in this family. Our finding supports previous predictions that exons 45-55 are the optimal multiexon skipping target in antisense gene therapy to transform the severe Duchenne muscular dystrophy into the milder BMD, or even asymptomatic, phenotype.

We report a

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 family with one

    5-year-old
    AGE

    affected patient and a 69-year-old
    FAMILY

    asymptomatic grandfather
    FAMILY

.

    Dystrophin gene multiplex polymerase chain reaction
    PARACLINICAL

 and

    multiplex ligation-dependant probe amplification analysis
    PARACLINICAL

 showed that both

    males
    GENDER

 carried an

    in-frame deletion of exons 45-55
    GENETICS

.

    Segregation analysis
    PARACLINICAL

 revealed

    two additional asymptomatic boys in this family
    FAMILY

. Our finding supports previous predictions that

    exons 45-55
    GENETICS

 are the optimal

    multiexon skipping
    MEDICATION

 target in

    antisense gene therapy
    MEDICATION

 to transform the

    severe Duchenne muscular dystrophy
    DIAGNOSIS

 into the

    milder BMD
    DIAGNOSIS

, or even

    asymptomatic
    SYMPTOMS

, phenotype.

Becker muscular dystrophy (BMD)
severe Duchenne muscular dystrophy
milder BMD

in-frame deletion of exons 45-55
exons 45-55

multiexon skipping
antisense gene therapy


Convexity of scoliosis related to handedness in identical twin boys with Duchenne's muscular dystrophy: a case report.

The interplay between hand dominance and directionality of scoliosis in boys with Duchenne's muscular dystrophy (DMD) is not clearly defined. We describe an extremely rare presentation of monozygotic twin boys with DMD and opposing hand dominance who developed major spine curvature with opposite convexities. The unique clinical presentation of progressive neuromuscular disease and scoliosis in monozygotic twins should allow for a unique evaluation of some of the contributory factors associated with the development of neuromuscular scoliosis in DMD. In this case report, we explore the pathophysiology involved in neuromuscular scoliosis, examine the role of conservative, surgical, and medical treatments, and discuss potential future avenues of research.

The interplay between hand dominance and directionality

    of scoliosis
    SYMPTOMS

 in

    boys
    GENDER

 with

    Duchenne's muscular dystrophy (DMD)
    DIAGNOSIS

 is not clearly defined. We describe an extremely rare presentation of

    monozygotic twin boys
    FAMILY

 with

    DMD
    FAMILY

 and

    opposing hand dominance
    SYMPTOMS

 who developed

    major spine curvature with opposite convexities
    SYMPTOMS

. The unique clinical presentation of

    progressive neuromuscular disease
    DIAGNOSIS

 and

    scoliosis
    DIAGNOSIS

 in

    monozygotic twins
    FAMILY

 should allow for a unique evaluation of some of the contributory factors associated with the development of

    neuromuscular scoliosis
    DIAGNOSIS

 in

    DMD
    DIAGNOSIS

. In this case report, we explore the pathophysiology involved in

    neuromuscular scoliosis
    DIAGNOSIS

, examine the role of

    conservative, surgical
    MEDICATION

, and medical treatments, and discuss potential future avenues of research.

Duchenne's muscular dystrophy (DMD)
progressive neuromuscular disease
scoliosis
neuromuscular scoliosis
DMD
neuromuscular scoliosis


Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family.

Familial hyperCKemia is a rare condition, and a combination with Duchenne muscular dystrophy (DMD) is extremely rare. A boy showed muscle weakness from the age of 10 months and presented typical signs of DMD at the age of 18 months. The diagnosis was supported by markedly elevated serum creatine kinase (CK) value as well as by neurophysiological and muscle biopsy findings at the age of 23 months. The diagnosis was confirmed by identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene. Interestingly, the father and his near relatives had increased serum CK values without any clinical symptoms or signs, nor a defect in caveolin-3 gene. We suggest that the occurrence of familial hyperCKemia may have triggered the early onset of symptoms in our patient.

    Familial hyperCKemia
    BIOCHEMICAL

 is a rare condition, and a

    combination with Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is extremely rare. A

    boy
    GENDER

 showed

    muscle weakness
    SYMPTOMS

    from the age of 10 months
    AGE

 and presented

    typical signs of DMD
    SYMPTOMS

 at the

    age of 18 months
    AGE

. The diagnosis was supported by

    markedly elevated serum creatine kinase (CK) value
    BIOCHEMICAL

 as well as by

    neurophysiological and muscle biopsy
    PARACLINICAL

 findings at the

    age of 23 months
    AGE

. The diagnosis was confirmed by

    identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene
    GENETICS

. Interestingly,

    the father and his near relatives had increased serum CK values
    FAMILY

    without any clinical symptoms or signs
    NEG_FINDINGS

,

    nor a defect in caveolin-3 gene
    NEG_FINDINGS

. We suggest that the occurrence of

    familial hyperCKemia
    BIOCHEMICAL

 may have triggered the

    early onset of symptoms
    SYMPTOMS

 in our patient.

muscle weakness
typical signs of DMD
early onset of symptoms

without any clinical symptoms or signs
nor a defect in caveolin-3 gene


Complete atrioventricular block in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. It is characterized by progressive muscle wasting and weakness of variable distribution and severity. Heart is involved leading to heart failure. Conduction abnormalities are unusual. We report a case of complete atrio-ventricular block in a DMD patient.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is an

    inherited myogenic disorder
    GENETICS

 due to

    mutations in the dystrophin gene on chromosome Xp21.1
    GENETICS

. It is characterized by

    progressive muscle wasting
    SYMPTOMS

 and

    weakness of variable distribution and severity
    SYMPTOMS

.

    Heart is involved
    SYMPTOMS

 leading to

    heart failure
    SYMPTOMS

.

    Conduction abnormalities
    SYMPTOMS

 are unusual. We report a case of

    complete atrio-ventricular block
    SYMPTOMS

 in a

    DMD
    DIAGNOSIS

 patient.


Use of remifentanil and propofol without muscle relaxant combined with intrathecal morphine in children with Duchenne's muscular dystrophy undergoing spinal surgery.

Duchenne's muscular dystrophy (DMD) is the most common and severe form of myopathy occurring in pediatric patients. Sensitivity of patients with DMD to sedative, anesthetic and neuromuscular blocking agents may result in intraoperative and early postoperative cardiovascular and respiratory complications, as well as prolonged recovery from anesthesia. Anesthetic management of these patients is challenging and may cause serious problems to the anesthesiologist. We report the use of a total intravenous anesthesia technique (TIVA) with remifentanil and propofol without muscle relaxants, associated with intrathecal morphine in three children with DMD undergoing posterior spinal surgery (PSS). Tracheal intubation was successfully done with good conditions. The intraoperative course of these patients was uneventful. Controlled hypotension, rapid recovery and uneventful postoperative period were achieved with this technique. In conclusion, good conditions for tracheal intubation, controlled hypotension, rapid recovery and uneventful postoperative period can be achieved with this anesthesia technique in patients with DMD.

    Duchenne's muscular dystrophy (DMD)
    DIAGNOSIS

 is the most common and severe form of

    myopathy
    DIAGNOSIS

 occurring in

    pediatric
    AGE

 patients. Sensitivity of patients with

    DMD
    DIAGNOSIS

 to

    sedative, anesthetic and neuromuscular blocking agents
    MEDICATION

 may result in

    intraoperative and early postoperative cardiovascular and respiratory complications
    SYMPTOMS

, as well as

    prolonged recovery from anesthesia
    SYMPTOMS

. Anesthetic management of these patients is challenging and may cause serious problems to the

    anesthesiologist
    PARACLINICAL

. We report the use of a

    total intravenous anesthesia technique (TIVA) with remifentanil and propofol without muscle relaxants
    MEDICATION

    , associated with intrathecal morphine
    MEDICATION

 in three

    children
    AGE

 with

    DMD
    DIAGNOSIS

 undergoing

    posterior spinal surgery (PSS)
    MEDICATION

.

    Tracheal intubation
    MEDICATION

 was successfully done with good conditions. The intraoperative course of these patients was

    uneventful
    SYMPTOMS

.

    Controlled hypotension
    SYMPTOMS

,

    rapid recovery
    SYMPTOMS

 and

    uneventful postoperative period
    SYMPTOMS

 were achieved with this technique. In conclusion, good conditions for

    tracheal intubation
    MEDICATION

,

    controlled hypotension
    SYMPTOMS

,

    rapid recovery
    SYMPTOMS

 and

    uneventful postoperative period
    SYMPTOMS

 can be achieved with this

    anesthesia technique
    MEDICATION

 in patients with

    DMD
    DIAGNOSIS

.

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


Cardiac involvement in a female carrier of Duchenne muscular dystrophy.

A 42 year-old female carrier of Duchenne muscular dystrophy (DMD) was referred with suspected subacute myocarditis and non-sustained ventricular tachycardia. Echochardiography and cardiac catheterization revealed severely reduced left ventricular function (LVF). Coronary artery disease was excluded. Cardiac magnetic resonance imaging showed transmural, intramural and subepicardial late gadolinium enhancement. Myocardial biopsy excluded viral infection and showed severe myopathic changes with abnormal expression of dystrophin and utrophin. Moleculargenetic analysis of the DMD gene revealed frameshift duplication of exon 2. The patient received conventional heart failure therapy, implantable cardioverter/defibrillator-implantation and prednisolone to attenuate cardiac degradation. 6 months later she had improved clinically though LVF was still severely reduced.

A

    42 year-old
    AGE

    female
    GENDER

 carrier of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 was referred with suspected

    subacute myocarditis
    DIAGNOSIS

 and

    non-sustained ventricular tachycardia
    SYMPTOMS

.

    Echochardiography
    PARACLINICAL

 and

    cardiac catheterization
    PARACLINICAL

 revealed

    severely reduced left ventricular function (LVF)
    SYMPTOMS

.

    Coronary artery disease was excluded
    NEG_FINDINGS

.

    Cardiac magnetic resonance imaging
    PARACLINICAL

 showed

    transmural, intramural and subepicardial late gadolinium enhancement
    SYMPTOMS

.

    Myocardial biopsy
    PARACLINICAL

    excluded viral infection
    NEG_FINDINGS

 and showed

    severe myopathic changes
    SYMPTOMS

 with

    abnormal expression of dystrophin and utrophin
    BIOCHEMICAL

.

    Moleculargenetic analysis of the DMD gene
    PARACLINICAL

 revealed

    frameshift duplication of exon 2
    GENETICS

. The patient received

    conventional heart failure therapy
    MEDICATION

,

    implantable cardioverter/defibrillator-implantation
    MEDICATION

 and

    prednisolone
    MEDICATION

 to

    attenuate cardiac degradation
    SYMPTOMS

. 6 months later

    she
    GENDER

 had

    improved clinically
    SYMPTOMS

 though

    LVF was still severely reduced
    SYMPTOMS

.

Duchenne muscular dystrophy (DMD)
subacute myocarditis

Coronary artery disease was excluded
excluded viral infection


Becker's muscular dystrophy aggravating facioscapulohumeral muscular dystrophy--double trouble as an explanation for an atypical phenotype.

We report a 12-year-old patient with mental impairment and proximal muscle weakness who had marked involvement of the shoulder girdle and facial muscles. CK levels were above 7000 U/l, multiplex PCR dystrophin gene deletion screening was negative. Further molecular studies revealed shortened D4Z4 fragments in the patient and his asymptomatic father, establishing the diagnosis of facioscapulohumeral muscular dystrophy (FSHD). Under the assumption of a second disease mechanism, a muscle biopsy was performed which revealed marked dystrophin deficiency. Eventually, a donor splice site mutation (c.4071+1 G>T) was found by direct sequencing of the dystrophin gene in the patient and his mother and confirmed the diagnosis of Becker's muscular dystrophy along with FSHD.

We report a

    12-year-old
    AGE

 patient with

    mental impairment
    SYMPTOMS

 and

    proximal muscle weakness
    SYMPTOMS

 who had

    marked involvement of the shoulder girdle and facial muscles
    SYMPTOMS

.

    CK levels were above 7000 U/l
    BIOCHEMICAL

,

    multiplex PCR dystrophin gene deletion screening was negative
    NEG_FINDINGS

. Further

    molecular studies
    PARACLINICAL

 revealed

    shortened D4Z4 fragments
    GENETICS

    in the patient and his asymptomatic father
    FAMILY

, establishing the diagnosis of

    facioscapulohumeral muscular dystrophy (FSHD)
    DIAGNOSIS

. Under the assumption of a second disease mechanism, a

    muscle biopsy
    PARACLINICAL

 was performed which revealed

    marked dystrophin deficiency
    BIOCHEMICAL

. Eventually, a

    donor splice site mutation (c.4071+1 G>T)
    GENETICS

 was found by

    direct sequencing of the dystrophin gene in the patient and his mother
    PARACLINICAL

 and confirmed the diagnosis of

    Becker's muscular dystrophy along with FSHD
    DIAGNOSIS

.

CK levels were above 7000 U/l
marked dystrophin deficiency


Becker muscular dystrophy with r(X) carrying an out-of-frame DMD deletion.

We describe a case of female Becker muscular dystrophy with 45,X/46,X,r(X), carrying an out-of-frame deletion in a nonhot-spot region of the DMD gene. Multiplex polymerase chain reaction did not detect the deletion, because the deleted exons 31-42 comprise a nonhot-spot region, and the product for exon 43 was detected because of the amplification of the DMD gene in the ring X chromosome, affecting 24% of cells. We identified the somatic mutation by assessing relative probe signal intensity for exons 31-43, using a multiple ligation probe amplification assay. This case did not conform to the reading-frame rule. The presence of the ring X chromosome that retains the DMD gene that escapes X inactivation may have contributed some degree of compensation for the dystrophin deficiency. This finding could indicate that the reading-frame rule for correlation of clinical severity with type of deletion may not be applicable in Turner mosaicism. Approximately half of patients with Turner syndrome manifest some degree of chromosomal mosaicism. Multiple ligation probe amplification analysis could be a first-choice method for detecting deletions or duplications in Turner mosaic patients such as female carriers.

We describe a case of

    female
    GENDER

    Becker muscular dystrophy
    DIAGNOSIS

 with

    45,X/46,X,r(X)
    GENETICS

, carrying an

    out-of-frame deletion in a nonhot-spot region of the DMD gene
    GENETICS

.

    Multiplex polymerase chain reaction
    PARACLINICAL

    did not detect the deletion
    NEG_FINDINGS

, because

    the deleted exons 31-42 comprise a nonhot-spot region
    GENETICS

, and the

    product for exon 43 was detected
    GENETICS

 because of the

    amplification of the DMD gene in the ring X chromosome, affecting 24% of cells
    GENETICS

. We identified the

    somatic mutation
    GENETICS

 by assessing relative probe signal intensity

    for exons 31-43
    GENETICS

, using a

    multiple ligation probe amplification assay
    PARACLINICAL

. This case

    did not conform to the reading-frame rule
    NEG_FINDINGS

. The

    presence of the ring X chromosome that retains the DMD gene that escapes X inactivation
    GENETICS

 may have contributed some degree of compensation for the

    dystrophin deficiency
    BIOCHEMICAL

. This finding could indicate that the reading-frame rule for correlation of clinical severity with type of deletion may not be applicable in

    Turner mosaicism
    DIAGNOSIS

. Approximately half of patients with

    Turner syndrome
    DIAGNOSIS

 manifest some degree of

    chromosomal mosaicism
    GENETICS

.

    Multiple ligation probe amplification analysis
    PARACLINICAL

 could be a first-choice method for detecting

    deletions or duplications
    GENETICS

 in

    Turner mosaic
    DIAGNOSIS

 patients such as

    female
    GENDER

 carriers.

Becker muscular dystrophy
Turner mosaicism
Turner syndrome
Turner mosaic


Pneumothorax associated with mechanical insufflation-exsufflation and related factors.

Impaired cough that results in ineffective airway secretion clearance is an important contributor to pulmonary complications in patients with neuromuscular weakness including spinal cord injury. Mechanical insufflation-exsufflation (MI-E) is a respiratory aid used by patients with weak respiratory muscles to increase cough peak flows and improve cough effectiveness. Relative contraindications to MI-E are said to include susceptibility to pneumothorax, but the association of pneumothorax with MI-E use has never before been described. We report two cases of pneumothorax in patients with respiratory muscle weakness associated with daily use of MI-E: one was a 58-yr-old male with C4 ASIA C tetraplegia, and the other was a 26-yr-old male with Duchenne muscular dystrophy. Both patients also used positive-pressure ventilatory assistance. Although seemingly rare in this patient population, ventilator users also using MI-E who have increasing dyspnea or who require increasing positive inspiratory pressures when using noninvasive ventilation should be evaluated for pneumothorax.

    Impaired cough
    SYMPTOMS

 that results in

    ineffective airway secretion clearance
    NEG_FINDINGS

 is an important contributor to

    pulmonary complications
    SYMPTOMS

 in patients with

    neuromuscular weakness
    DIAGNOSIS

 including

    spinal cord injury
    DIAGNOSIS

.

    Mechanical insufflation-exsufflation (MI-E)
    MEDICATION

 is a

    respiratory aid
    MEDICATION

 used by patients with

    weak respiratory muscles
    SYMPTOMS

 to

    increase cough peak flows
    SYMPTOMS

 and

    improve cough effectiveness
    SYMPTOMS

. Relative contraindications to

    MI-E
    MEDICATION

 are said to include susceptibility to

    pneumothorax
    SYMPTOMS

, but the association of

    pneumothorax
    DIAGNOSIS

 with

    MI-E use
    MEDICATION

 has never before been described. We report two cases of

    pneumothorax
    DIAGNOSIS

 in patients with

    respiratory muscle weakness
    SYMPTOMS

 associated with

    daily use of MI-E
    MEDICATION

: one was a

    58-yr-old
    AGE

    male
    GENDER

 with

    C4 ASIA C tetraplegia
    DIAGNOSIS

, and the other was a

    26-yr-old
    AGE

    male
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

. Both patients also

    used positive-pressure ventilatory assistance
    MEDICATION

. Although seemingly rare in this patient population,

    ventilator users
    MEDICATION

 also using

    MI-E
    MEDICATION

 who have

    increasing dyspnea
    SYMPTOMS

 or who require

    increasing positive inspiratory pressures
    MEDICATION

 when using

    noninvasive ventilation
    MEDICATION

 should be evaluated for

    pneumothorax
    DIAGNOSIS

.

Impaired cough
pulmonary complications
weak respiratory muscles
increase cough peak flows
improve cough effectiveness
pneumothorax
respiratory muscle weakness
increasing dyspnea

neuromuscular weakness
spinal cord injury
pneumothorax
pneumothorax
C4 ASIA C tetraplegia
Duchenne muscular dystrophy
pneumothorax


Percutaneous arterial closure for inadvertent cannulation of the subclavian artery--a call for caution.

An uncommon occurrence during central venous catheterization, inadvertent arterial sheath placement can cause potentially serious complications. When the subclavian artery is inadvertently cannulated, catheter removal may be complicated by significant hemorrhage due to its noncompressible location. We report a case of inadvertent insertion of a 7 Fr central venous catheter into the subclavian artery of a patient with severe kyphoscoliosis, Duchenne muscular dystrophy and cardiomyopathy. The catheter was successfully removed, however the initial attempt at closure device deployment resulted in abrupt closure of the subclavian artery. Prompt angiography and balloon inflation via an already present sheath in the brachiocephalic artery resulted in restoration of flow and successful closure at the puncture site with the collagen-based vascular closure device was confirmed. This averted an otherwise urgent surgical sheath removal and arteriotomy repair in an extremely high-risk patient who was deemed a poor candidate for open surgical repair.

An uncommon occurrence during

    central venous catheterization
    PARACLINICAL

,

    inadvertent arterial sheath placement
    SYMPTOMS

 can cause potentially serious complications. When the

    subclavian artery
    NEG_FINDINGS

 is

    inadvertently cannulated
    MEDICATION

,

    catheter removal
    MEDICATION

 may be complicated by

    significant hemorrhage
    SYMPTOMS

 due to its

    noncompressible location
    SYMPTOMS

. We report a case of

    inadvertent insertion of a 7 Fr central venous catheter into the subclavian artery
    MEDICATION

 of a patient with

    severe kyphoscoliosis
    DIAGNOSIS

,

    Duchenne muscular dystrophy
    DIAGNOSIS

 and

    cardiomyopathy
    DIAGNOSIS

.

    The catheter
    MEDICATION

 was successfully removed, however the

    initial attempt at closure device deployment resulted in abrupt closure of the subclavian artery
    NEG_FINDINGS

.

    Prompt angiography
    PARACLINICAL

 and

    balloon inflation via an already present sheath in the brachiocephalic artery
    MEDICATION

 resulted in

    restoration of flow
    SYMPTOMS

 and

    successful closure at the puncture site with the collagen-based vascular closure device
    MEDICATION

 was confirmed. This averted an

    otherwise urgent surgical sheath removal and arteriotomy repair
    MEDICATION

 in an extremely high-risk patient who was deemed a

    poor candidate for open surgical repair
    NEG_FINDINGS

.

inadvertent arterial sheath placement
significant hemorrhage
noncompressible location
restoration of flow

severe kyphoscoliosis
Duchenne muscular dystrophy
cardiomyopathy


Phenotype of combined Duchenne and facioscapulohumeral muscular dystrophy.

This case report describes a young boy with concomitant genetically-confirmed Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy with a novel dystrophin mutation in exon 6 and a D4Z4 fragment of 31 kb. This child presented with a more severe phenotype than expected for either individual disease process and underscores the role for thorough diagnostic investigation in identifying atypical clinical presentations.

This case report describes a

    young
    AGE

    boy
    GENDER

 with

    concomitant genetically-confirmed
    DIAGNOSIS

    Duchenne muscular dystrophy
    DIAGNOSIS

 and

    facioscapulohumeral muscular dystrophy
    DIAGNOSIS

 with a

    novel dystrophin mutation in exon 6 and a D4Z4 fragment of 31 kb
    GENETICS

. This

    child
    AGE

 presented with a more severe phenotype than expected for either individual disease process and underscores the role for

    thorough diagnostic investigation
    PARACLINICAL

 in identifying atypical clinical presentations.

concomitant genetically-confirmed
Duchenne muscular dystrophy
facioscapulohumeral muscular dystrophy


Wolff-Parkinson-White syndrome as initial manifestation of Becker muscular dystrophy.

Cardiac involvement may precede the onset of muscular manifestations in Becker muscular dystrophy (BMD), but Wolff-Parkinson-White (WPW) syndrome has not been reported as initial cardiac manifestation of BMD.

In a 43-year-old, HIV-negative male, WPW syndrome was diagnosed at age 26 years upon a routine surface ECG, carried out for recurrent palpitations since childhood. Since then, WPW syndrome was occasionally found on repeated cardiologic follow-up investigations. From age 27 years, he developed proximal muscle weakness predominantly of the lower limbs, a positive Gower sign, and a waddling gait. Needle electromyograms were repeatedly myogenic, and upon reinvestigation at age 42 years, a deletion of exons 45-47 in the dystrophin gene was detected. Radiofrequency catheter ablation, initially refused by the patient, was scheduled again but no accessory pathways were detected on electrophysiological investigations.

This case suggests that intermittent WPW syndrome may be a cardiac manifestation of BMD and that cardiac involvement may precede the development of evident skeletal muscle abnormalities.

    Cardiac involvement
    SYMPTOMS

 may precede the onset of

    muscular manifestations
    SYMPTOMS

 in

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

, but

    Wolff-Parkinson-White (WPW) syndrome
    DIAGNOSIS

 has not been reported as

    initial cardiac manifestation
    SYMPTOMS

 of

    BMD
    DIAGNOSIS

.

In a

    43-year-old
    AGE

,

    HIV-negative
    NEG_FINDINGS

    male
    GENDER

,

    WPW syndrome
    DIAGNOSIS

 was diagnosed at

    age 26 years
    AGE

 upon a routine

    surface ECG
    PARACLINICAL

, carried out for

    recurrent palpitations
    SYMPTOMS

 since

    childhood
    AGE

. Since then,

    WPW syndrome
    DIAGNOSIS

 was occasionally found on repeated

    cardiologic follow-up investigations
    PARACLINICAL

. From

    age 27 years
    AGE

,

    he
    GENDER

 developed

    proximal muscle weakness predominantly of the lower limbs
    SYMPTOMS

, a

    positive Gower sign
    SYMPTOMS

, and a

    waddling gait
    SYMPTOMS

.

    Needle electromyograms
    PARACLINICAL

 were repeatedly myogenic, and upon

    reinvestigation
    PARACLINICAL

 at

    age 42 years
    AGE

, a

    deletion of exons 45-47 in the dystrophin gene
    GENETICS

 was detected.

    Radiofrequency catheter ablation
    MEDICATION

,

    initially refused by the patient
    NEG_FINDINGS

, was scheduled again but

    no accessory pathways were detected on electrophysiological investigations
    NEG_FINDINGS

.

This case suggests that

    intermittent WPW syndrome
    DIAGNOSIS

 may be a cardiac manifestation of

    BMD
    DIAGNOSIS

 and that

    cardiac involvement
    SYMPTOMS

 may precede the development of

    evident skeletal muscle abnormalities
    SYMPTOMS

.

Becker muscular dystrophy (BMD)
Wolff-Parkinson-White (WPW) syndrome
BMD
WPW syndrome
WPW syndrome
intermittent WPW syndrome
BMD


Utility of oligonucleotide array-based comparative genomic hybridization for detection of target gene deletions.

direct DNA sequencing is the primary clinical technique for identifying mutations in human disease, but sequencing often does not detect intragenic or whole-gene deletions. Oligonucleotide array-based comparative genomic hybridization (CGH) is currently in clinical use to detect major changes in chromosomal copy number.

a custom oligonucleotide-based microarray was constructed to provide high-density coverage of an initial set of 130 nuclear genes involved in the pathogenesis of metabolic and mitochondrial disorders. Standard array CGH procedures were used to test patient DNA samples for regions of copy number change. Sequencing of regions of predicted breakpoints in genomic DNA and PCR analysis were used to confirm oligonucleotide array CGH data.

oligonucleotide array CGH identified intragenic exonic deletions in 2 cases: a heterozygous single-exon deletion of 4.5 kb in the SLC25A13 gene [solute carrier family 25, member 13 (citrin)] in an individual with citrin deficiency and a homozygous 10.5-kb deletion of exons 13-17 in the ABCB11 gene [PFIC2, ATP-binding cassette, sub-family B (MDR/TAP), member 11] in a patient with progressive familial intrahepatic cholestasis. In 2 females with OTC deficiency, we also found 2 large heterozygous deletions of approximately 7.4 Mb and 9 Mb on the short arm of the X chromosome extending from sequences telomeric to the DMD gene [dystrophin (muscular dystrophy, Duchenne and Becker types)] to sequences within or centromeric to the OTC gene (ornithine carbamoyltransferase).

these examples illustrate the successful use of custom oligonucleotide arrays to detect either whole-gene deletions or intragenic exonic deletions. This technology may be particularly useful as a complementary diagnostic test in the context of a recessive disease when only one mutant allele is found by sequencing.

    direct DNA sequencing
    PARACLINICAL

 is the primary clinical technique for identifying mutations in human disease, but sequencing often

    does not detect intragenic or whole-gene deletions
    NEG_FINDINGS

.

    Oligonucleotide array-based comparative genomic hybridization (CGH)
    PARACLINICAL

 is currently in clinical use to detect

    major changes in chromosomal copy number
    GENETICS

.

a

    custom oligonucleotide-based microarray
    MEDICATION

 was constructed to provide

    high-density
    MEDICATION

 coverage of an initial set of 130 nuclear genes involved in the pathogenesis of

    metabolic and mitochondrial disorders
    DIAGNOSIS

.

    Standard array CGH procedures
    PARACLINICAL

 were used to

    test patient DNA samples
    PARACLINICAL

 for regions of

    copy number change
    GENETICS

.

    Sequencing of regions of predicted breakpoints in genomic DNA
    PARACLINICAL

 and

    PCR analysis
    PARACLINICAL

 were used to confirm

    oligonucleotide array CGH data
    PARACLINICAL

.

    oligonucleotide array CGH
    PARACLINICAL

 identified

    intragenic exonic deletions
    GENETICS

 in 2 cases: a

    heterozygous single-exon deletion of 4.5 kb in the SLC25A13 gene [solute carrier family 25, member 13 (citrin)]
    GENETICS

 in an individual with

    citrin deficiency
    BIOCHEMICAL

 and a

    homozygous 10.5-kb deletion of exons 13-17 in the ABCB11 gene [PFIC2, ATP-binding cassette, sub-family B (MDR/TAP), member 11]
    GENETICS

 in a patient with

    progressive familial intrahepatic cholestasis
    DIAGNOSIS

. In 2

    females
    GENDER

 with

    OTC deficiency
    BIOCHEMICAL

, we also found

    2 large heterozygous deletions of approximately 7.4 Mb and 9 Mb on the short arm of the X chromosome extending from sequences telomeric to the DMD gene [dystrophin (muscular dystrophy, Duchenne and Becker types)] to sequences within or centromeric to the OTC gene (ornithine carbamoyltransferase)
    GENETICS

.

these examples illustrate the successful use of custom oligonucleotide arrays to detect either

    whole-gene deletions or intragenic exonic deletions
    GENETICS

. This technology may be particularly useful as a complementary diagnostic test in the context of a

    recessive disease
    DIAGNOSIS

 when only one mutant allele is found by sequencing.

custom oligonucleotide-based microarray
high-density


[Increased troponin I level in a Duchenne muscular dystrophy patient with normal coronarography].

Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by a progressive skeletal muscular weakness. As the respiratory care of such patients has been dramatically improved during the past few years, the DMD associated cardiomyopathy is becoming a new concern. We report a clinical case of a Troponin I level increase with normal coronarography occurring after an acute episode of respiratory failure. This report suggests the sensitivity of cardiomyocytes to hypoxemia in DMD patients.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    neuromuscular disease
    DIAGNOSIS

 characterized by a

    progressive skeletal muscular weakness
    SYMPTOMS

. As the respiratory care of such patients has been dramatically improved during the past few years, the

    DMD
    DIAGNOSIS

 associated

    cardiomyopathy
    DIAGNOSIS

 is becoming a new concern. We report a clinical case of a

    Troponin I level increase
    BIOCHEMICAL

 with

    normal coronarography
    NEG_FINDINGS

 occurring after an

    acute episode of respiratory failure
    SYMPTOMS

. This report suggests the sensitivity of

    cardiomyocytes to hypoxemia
    BIOCHEMICAL

 in

    DMD
    DIAGNOSIS

 patients.

Duchenne muscular dystrophy (DMD)
neuromuscular disease
DMD
cardiomyopathy
DMD

progressive skeletal muscular weakness
acute episode of respiratory failure

Troponin I level increase
cardiomyocytes to hypoxemia


A 2-bp deletion in exon 74 of the dystrophin gene does not clearly induce muscle weakness.

Duchenne muscular dystrophy (DMD) is caused by mutation of the dystrophin gene. Cases of dystrophinopathy with a 2-bp deletion in the dystrophin gene commonly result in DMD. We report here a case of dystrophinopathy in a 9-years-old boy with a 2-bp deletion in exon 74 of the dystrophin gene; however, the boy had no clear clinical signs of muscle weakness. Immunohistochemical studies with N-terminal (DYS3) and rod-domain anti-dystrophin (DYS1) antibodies revealed that the dystrophin signals were weaker than in the control sample (non-dystrophinopathy) at the sarcolemma of myofibers, and the studies with C-terminus anti-dystrophin antibody (DYS2) were negative. Our patient's mutation is located between the binding sites of alpha-syntrophin and alpha-dystrobrevin. These results suggest that this mutation does not clearly induce muscle weakness at least through the age of 9 years.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is caused by

    mutation of the dystrophin gene
    GENETICS

. Cases of

    dystrophinopathy
    DIAGNOSIS

 with a

    2-bp deletion in the dystrophin gene
    GENETICS

 commonly result in

    DMD
    DIAGNOSIS

. We report here a case of

    dystrophinopathy
    DIAGNOSIS

 in a

    9-years-old
    AGE

    boy
    GENDER

 with a

    2-bp deletion in exon 74 of the dystrophin gene
    GENETICS

; however, the

    boy
    GENDER

 had

    no clear clinical signs of muscle weakness
    NEG_FINDINGS

.

    Immunohistochemical studies with N-terminal (DYS3) and rod-domain anti-dystrophin (DYS1) antibodies
    PARACLINICAL

 revealed that

    the dystrophin signals were weaker than in the control sample (non-dystrophinopathy
    MICROSCOPIC

)

    at the sarcolemma of myofibers
    MICROSCOPIC

, and

    the studies with C-terminus anti-dystrophin antibody (DYS2) were negative
    NEG_FINDINGS

. Our patient's

    mutation is located between the binding sites of alpha-syntrophin and alpha-dystrobrevin
    GENETICS

. These results suggest that this mutation does

    not clearly induce muscle weakness
    NEG_FINDINGS

 at least through the

    age of 9 years
    AGE

.

Duchenne muscular dystrophy (DMD)
dystrophinopathy
DMD
dystrophinopathy


Two non-contiguous duplications in the DMD gene in a Spanish family.

DMD and BMD are X-linked myopathy diseases in most cases caused by intragenic deletions, but duplications also appear in a significant number of cases. We present a complex duplication pattern detected by MLPA, a recently formulated method applied here to amplify the 79 exons of the DMD gene. We found a double-duplication in two DMD-affected brothers and in their carrier mother, which consist of two non-contiguous duplications encompassing exons 2 to 7 and exons 50 to 55. Different models are presented to explain formation of this genetic variant.

    DMD
    DIAGNOSIS

 and

    BMD
    DIAGNOSIS

 are

    X-linked
    GENETICS

    myopathy diseases
    DIAGNOSIS

 in most cases caused by

    intragenic deletions
    GENETICS

, but

    duplications
    GENETICS

 also appear in a significant number of cases. We present a

    complex duplication pattern
    GENETICS

 detected by

    MLPA
    PARACLINICAL

, a recently formulated method applied here to

    amplify the 79 exons of the DMD gene
    PARACLINICAL

. We found a

    double-duplication in two DMD-affected brothers and in their carrier mother, which consist of two non-contiguous duplications encompassing exons 2 to 7 and exons 50 to 55
    FAMILY

. Different models are presented to explain formation of this genetic variant.

X-linked
intragenic deletions
duplications
complex duplication pattern


Preimplantation genetic diagnosis for Duchenne muscular dystrophy by multiple displacement amplification.

To evaluate the use of multiple displacement amplification (MDA) in preimplantation genetic diagnosis (PGD) for female carriers with Duchenne muscular dystrophy (DMD).

MDA was used to amplify a whole genome of single cells. Following the setup on single cells, the test was applied in two clinical cases of PGD. One mutant exon, six short tandem repeats (STR) markers within the dystrophin gene, and amelogenin were incorporated into singleplex polymerase chain reaction (PCR) assays on MDA products of single blastomeres.

Center for reproductive medicine in First Affiliated Hospital, Sun Yat-sen University, China.

Two female carriers with a duplication of exons 3-11 and a deletion of exons 47-50, respectively.

The MDA of single cells and fluorescent PCR assays for PGD.

The ability to analyze single blastomeres for DMD using MDA.

The protocol setup previously allowed for the accurate diagnosis of each embryo. Two clinical cases resulted in a healthy girl, which was the first successful clinical application of MDA in PGD for DMD.

We suggest that this protocol is reliable to increase the accuracy of the PGD for DMD.

To evaluate the use of

    multiple displacement amplification (MDA)
    PARACLINICAL

 in

    preimplantation genetic diagnosis (PGD)
    PARACLINICAL

 for

    female
    GENDER

 carriers with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

.

    MDA was used to amplify a whole genome of single cells
    PARACLINICAL

. Following the setup on single cells, the test was applied in two clinical cases of

    PGD
    DIAGNOSIS

.

    One mutant exon, six short tandem repeats (STR) markers within the dystrophin gene
    GENETICS

, and

    amelogenin
    GENETICS

 were incorporated into

    singleplex polymerase chain reaction (PCR) assays on MDA products of single blastomeres
    PARACLINICAL

.

    Center for reproductive medicine in First Affiliated Hospital
    MEDICATION

,

    Sun Yat-sen University
    MEDICATION

,

    China
    ETHNICITY

.

Two

    female
    GENDER

    carriers with a duplication of exons 3-11 and a deletion of exons 47-50
    FAMILY

, respectively.

The

    MDA of single cells
    MICROSCOPIC

 and

    fluorescent PCR assays for PGD
    PARACLINICAL

.

The ability to

    analyze single blastomeres
    PARACLINICAL

 for

    DMD
    DIAGNOSIS

    using MDA
    PARACLINICAL

.

The protocol setup previously allowed for the accurate diagnosis of each embryo. Two clinical cases resulted in a healthy

    girl
    GENDER

, which was the first successful clinical application of

    MDA
    MEDICATION

 in

    PGD
    MEDICATION

 for

    DMD
    DIAGNOSIS

.

We suggest that this protocol is reliable to increase the accuracy of the

    PGD
    PARACLINICAL

 for

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
PGD
DMD
DMD
DMD


Follow-up of three patients with a large in-frame deletion of exons 45-55 in the Duchenne muscular dystrophy (DMD) gene.

We review the clinical status of skeletal involvement and cardiac function in three unrelated patients harboring an in-frame deletion of exons 45 to 55 in the DMD gene followed up for 2 to 7 years. Two younger patients diagnosed as having X-linked dilated cardiomyopathy (XLDCM) developed congestive heart failure without overt skeletal myopathy. Heart failure recurred after viral infection but responded well to diuretics and angiotensin-converting enzyme inhibitors. One older patient diagnosed with Becker muscular dystrophy showed limb-girdle muscular atrophy and weakness at the age of 50, but did not have any cardiac symptoms. Skeletal muscle involvement in each patient remained unchanged, and cardiac function did not worsen in any of the patients during the study. In a younger XLDCM patient, the amount and molecular weight of mutant dystrophin were equally slightly decreased in both skeletal and cardiac muscles. Immunostaining for dystrophin and dystrophin-associated proteins was slightly reduced in both skeletal and cardiac muscle, with no discernible difference between the two. The phenotype of this dystrophinopathy can manifest as XLDCM in younger patients; however, careful attention to cardiac management may result in a favorable prognosis.

We review the clinical status of

    skeletal involvement
    SYMPTOMS

 and

    cardiac function
    SYMPTOMS

 in three unrelated patients harboring an

    in-frame deletion of exons 45 to 55 in the DMD gene
    GENETICS

 followed up for 2 to 7 years. Two

    younger
    AGE

 patients diagnosed as having

    X-linked dilated cardiomyopathy (XLDCM)
    DIAGNOSIS

 developed

    congestive heart failure
    SYMPTOMS

    without overt skeletal myopathy
    NEG_FINDINGS

.

    Heart failure
    SYMPTOMS

 recurred after

    viral infection
    DIAGNOSIS

 but responded well to

    diuretics
    MEDICATION

 and

    angiotensin-converting enzyme inhibitors
    MEDICATION

. One

    older
    AGE

 patient diagnosed with

    Becker muscular dystrophy
    DIAGNOSIS

 showed

    limb-girdle muscular atrophy
    SYMPTOMS

 and

    weakness
    SYMPTOMS

    at the age of 50
    AGE

, but

    did not have any cardiac symptoms
    NEG_FINDINGS

.

    Skeletal muscle involvement
    SYMPTOMS

 in each patient

    remained unchanged
    NEG_FINDINGS

, and

    cardiac function did not worsen
    NEG_FINDINGS

 in any of the patients during the study. In a

    younger
    AGE

    XLDCM
    DIAGNOSIS

 patient,

    the amount and molecular weight of mutant dystrophin were equally slightly decreased in both skeletal and cardiac muscles
    MICROSCOPIC

.

    Immunostaining for dystrophin and dystrophin-associated proteins was slightly reduced in both skeletal and cardiac muscle
    MICROSCOPIC

, with no discernible difference between the two. The phenotype of this

    dystrophinopathy
    DIAGNOSIS

 can manifest as

    XLDCM
    DIAGNOSIS

 in

    younger
    AGE

 patients; however, careful attention to

    cardiac management
    MEDICATION

 may result in a favorable prognosis.

skeletal involvement
cardiac function
congestive heart failure
Heart failure
limb-girdle muscular atrophy
weakness
Skeletal muscle involvement

X-linked dilated cardiomyopathy (XLDCM)
viral infection
Becker muscular dystrophy
XLDCM
dystrophinopathy
XLDCM

without overt skeletal myopathy
did not have any cardiac symptoms
remained unchanged
cardiac function did not worsen


Tandem duplications of two separate fragments of the dystrophin gene in a patient with Duchenne muscular dystrophy.

Mutations in the dystrophin gene result in the most common inherited muscle disease, Duchenne muscular dystrophy (DMD). Duplications spanning one or more exons have been found to be the second most common disease-causing mutation in the dystrophin gene. Although the duplicated exons are commonly thought to be arranged in tandem, rare noncontiguous exon duplications have been disclosed without clarifying their location or orientation. Here we present the first report that details the exact locations and orientations of noncontiguous duplications in the dystrophin gene. Multiplex ligation-dependent probe amplification analysis of the dystrophin gene of a Japanese boy with DMD revealed that his genomic DNA contained duplications of exons from two separate fragments of the gene: one from exon 45 to exon 48 and the other from exon 55 to exon 63. To clarify the locations and orientations of the duplicated exons, reverse transcription-nested PCR analysis of dystrophin mRNA was conducted. Interestingly, the extra copies of exons 45-48 and exons 55-63 were found to be properly oriented between exons 48 and 49 and exons 63 and 64, respectively. These results indicated that two tandem duplication events occurred in the dystrophin gene of this patient and should contribute to the understanding of the duplication mechanisms that contribute to the development of DMD.

    Mutations in the dystrophin gene
    GENETICS

 result in the most common

    inherited muscle disease
    DIAGNOSIS

,

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

.

    Duplications spanning one or more exons
    GENETICS

 have been found to be the second most common disease-causing mutation in the

    dystrophin gene
    GENETICS

. Although

    the duplicated exons
    GENETICS

 are commonly thought to be

    arranged in tandem
    GENETICS

,

    rare noncontiguous exon duplications
    GENETICS

 have been disclosed without clarifying their location or orientation. Here we present the first report that details the exact locations and orientations of

    noncontiguous duplications in the dystrophin gene
    GENETICS

.

    Multiplex ligation-dependent probe amplification analysis of the dystrophin gene
    PARACLINICAL

 of a

    Japanese
    ETHNICITY

    boy
    GENDER

 with

    DMD
    DIAGNOSIS

 revealed that

    his
    GENDER

    genomic DNA contained duplications of exons from two separate fragments of the gene: one from exon 45 to exon 48 and the other from exon 55 to exon 63
    PARACLINICAL

. To clarify the locations and orientations of

    the duplicated exons
    GENETICS

,

    reverse transcription-nested PCR analysis of dystrophin mRNA
    PARACLINICAL

 was conducted. Interestingly,

    the extra copies of exons 45-48 and exons 55-63 were found to be properly oriented between exons 48 and 49 and exons 63 and 64, respectively
    GENETICS

. These results indicated that

    two tandem duplication events occurred in the dystrophin gene
    GENETICS

 of this patient and should contribute to the understanding of the duplication mechanisms that contribute to the development of

    DMD
    DIAGNOSIS

.

inherited muscle disease
Duchenne muscular dystrophy (DMD)
DMD
DMD


Novel SHOX gene mutation in a short boy with Becker muscular dystrophy: double trouble in two adjacent genes.

Short stature is a well-recognized feature of Duchenne muscular dystrophy, whilst it has been reported rarely in Becker muscular dystrophy (BMD). Here we report two brothers with BMD, who exhibited a very different growth pattern. Whereas in the short brother (-2.2 SDS) molecular investigation revealed a G367A mutation in the short stature homeobox containing (SHOX) gene located in the Xp22.3 region, no abnormality was found in the brother with normal height (-0.1 SDS). Our data suggest that abnormal growth observed in a boy with BMD may be related to an additional genetic alteration, already known as correlated with short stature.

    Short stature
    SYMPTOMS

 is a well-recognized feature of

    Duchenne muscular dystrophy
    DIAGNOSIS

, whilst it has been reported rarely in

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

. Here we report two

    brothers
    GENDER

 with

    BMD
    DIAGNOSIS

, who exhibited a very different growth pattern. Whereas in the

    short brother
    SYMPTOMS

    (-2.2 SDS
    SYMPTOMS

)

    molecular investigation
    PARACLINICAL

 revealed a

    G367A mutation in the short stature homeobox containing (SHOX) gene located in the Xp22.3 region
    GENETICS

,

    no abnormality was found in the brother with normal height (-0.1 SDS)
    NEG_FINDINGS

. Our data suggest that

    abnormal growth
    SYMPTOMS

 observed in a

    boy
    GENDER

 with

    BMD
    DIAGNOSIS

 may be related to an additional

    genetic alteration
    GENETICS

, already known as correlated with

    short stature
    SYMPTOMS

.

Short stature
short brother
(-2.2 SDS
abnormal growth
short stature

Duchenne muscular dystrophy
Becker muscular dystrophy (BMD)
BMD
BMD


DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy.

The degenerative muscle diseases Duchenne (DMD) and Becker muscular dystrophy result from mutations in the DMD gene, which encodes the dystrophin protein. Recent improvements in mutational analysis techniques have resulted in the increasing identification of deep intronic point mutations, which alter splicing such that intronic sequences are included in the messenger RNA as "pseudoexons." We sought to test the hypothesis that the clinical phenotype correlates with splicing efficiency of these mutations, and to test the feasibility of antisense oligonucleotide (AON)-mediated pseudoexon skipping.

We identified three pseudoexon insertion mutations in dystrophinopathy patients, two of whom had tissue available for further analysis. For these two out-of-frame pseudoexon mutations (one associated with Becker muscular dystrophy and one with DMD), mutation-induced splicing was tested by quantitative reverse transcription polymerase chain reaction; pseudoexon skipping was tested using AONs composed of 2'-O-methyl-modified bases on a phosphorothioate backbone to treat cultured primary myoblasts.

Variable amounts of pseudoexon inclusion correlates with the severity of the dystrophinopathy phenotype in these two patients. AON treatment directed at the pseudoexon results in the expression of full-length dystrophin in a DMD myoblast line.

Both DMD and Becker muscular dystrophy can result from out-of-frame pseudoexons, with the difference in phenotype being due to variable efficiency of the newly generated splicing signal. AON-mediated pseudoexon skipping therapy is a viable approach to these patients and would be predicted to result in increased expression of wild-type dystrophin protein.

The

    degenerative muscle diseases Duchenne (DMD)
    DIAGNOSIS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 result from

    mutations in the DMD gene
    GENETICS

, which encodes

    the dystrophin protein
    GENETICS

. Recent improvements in mutational analysis techniques have resulted in the increasing identification of

    deep intronic point mutations
    GENETICS

, which

    alter splicing such that intronic sequences are included in the messenger RNA as "pseudoexons
    GENETICS

." We sought to test the hypothesis that the clinical phenotype correlates with splicing efficiency of these mutations, and to test the feasibility of

    antisense oligonucleotide (AON)-mediated pseudoexon skipping
    MEDICATION

.

We identified three

    pseudoexon insertion mutations
    GENETICS

 in

    dystrophinopathy
    DIAGNOSIS

 patients, two of whom had tissue available for further analysis. For these two

    out-of-frame pseudoexon mutations
    GENETICS

 (one associated with

    Becker muscular dystrophy
    DIAGNOSIS

 and one with

    DMD
    DIAGNOSIS

),

    mutation-induced splicing was tested
    PARACLINICAL

 by

    quantitative reverse transcription polymerase chain reaction
    PARACLINICAL

;

    pseudoexon skipping
    GENETICS

 was tested using

    AONs composed of 2'-O-methyl-modified bases on a phosphorothioate backbone
    MEDICATION

 to treat

    cultured primary myoblasts
    MICROSCOPIC

.

    Variable amounts of pseudoexon inclusion
    MICROSCOPIC

 correlates with the severity of the

    dystrophinopathy
    SYMPTOMS

 phenotype in these two patients.

    AON treatment directed at the pseudoexon
    MEDICATION

 results in the expression of full-length dystrophin in a

    DMD myoblast line
    MICROSCOPIC

.

Both

    DMD
    DIAGNOSIS

 and

    Becker muscular dystrophy
    DIAGNOSIS

 can result from

    out-of-frame pseudoexons
    GENETICS

, with the difference in phenotype being due to variable efficiency

    of the newly generated splicing signal
    GENETICS

.

    AON-mediated pseudoexon skipping therapy
    MEDICATION

 is a viable approach to these patients and would be predicted to result in

    increased expression of wild-type dystrophin protein
    BIOCHEMICAL

.


Muscle pain as the only presenting symptom in a girl with dystrophinopathy.

We present a family with dystrophinopathy in whom the proband is a female aged 4.5 years, who presented with exertional muscle pain without weakness. Familial analysis identified a maternal nephew of the proband who demonstrated a similar clinical picture, with asymptomatic cardiomyopathy. A DNA analysis revealed an in-frame deletion in the proximal part of domain II of the dystrophin gene. Extensive familial analysis indicated that the asymptomatic maternal grandfather transmitted the deletion. This is the first report of a young female patient with exertional muscle pain as the only early presenting symptom of dystrophinopathy.

We present a

    family with dystrophinopathy
    FAMILY

 in whom the proband is a

    female
    GENDER

    aged 4.5 years
    AGE

, who presented with

    exertional muscle pain
    SYMPTOMS

    without weakness
    NEG_FINDINGS

.

    Familial analysis
    PARACLINICAL

 identified

    a maternal nephew of the proband who demonstrated a similar clinical picture
    FAMILY

, with

    asymptomatic cardiomyopathy
    SYMPTOMS

. A

    DNA analysis
    PARACLINICAL

 revealed an

    in-frame deletion in the proximal part of domain II of the dystrophin gene
    GENETICS

.

    Extensive familial analysis
    PARACLINICAL

 indicated

    that the asymptomatic maternal grandfather transmitted the deletion
    FAMILY

. This is the first report of a

    young
    AGE

    female
    GENDER

 patient with

    exertional muscle pain
    SYMPTOMS

 as the only early presenting symptom of

    dystrophinopathy
    DIAGNOSIS

.

exertional muscle pain
asymptomatic cardiomyopathy
exertional muscle pain


Paternal inheritance or a de novo mutation in a Duchenne Muscular Dystrophy pedigree from South India.

A six year old boy presented with classical features of Duchenne Muscular Dystrophy (DMD) and was confirmed by absent dystrophin staining on muscle biopsy. In the paternal line there were 5 affected individuals across two generations with classical DMD. There was no family history of the illness in the maternal line. Molecular genetics analysis by PCR of the exons showed a deletion in exon 45 in two affected individuals. Microsatellite analysis showed that though the deletion was observed in the same locus in exon 45 it is a new independent mutation.

A

    six year old
    AGE

    boy
    GENDER

 presented with

    classical features of Duchenne Muscular Dystrophy (DMD)
    SYMPTOMS

 and was confirmed by

    absent dystrophin staining
    BIOCHEMICAL

 on

    muscle biopsy
    PARACLINICAL

.

    In the paternal line there were 5 affected individuals across two generations with classical DMD
    FAMILY

. There was

    no family history of the illness in the maternal line
    FAMILY

.

    Molecular genetics analysis by PCR of the exons
    PARACLINICAL

 showed a

    deletion in exon 45 in two affected individuals
    GENETICS

.

    Microsatellite analysis
    PARACLINICAL

 showed that

    though the deletion was observed in the same locus in exon 45 it is a new independent mutation
    GENETICS

.


[Complex glycerol kinase deficiency in three children].

Glycerol kinase deficiency (GKD), a rare X-linked recessive disorder, is classified into two types: isolated and complex. Complex GKD is an Xp21 contiguous gene deletion involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Its clinical features depend on the involved loci. GKD can be confirmed by an elevated urinary glycerol concentration tested by gas chromatography mass spectrometry (GC/MS). The three cases reported here were all male, presenting symptoms from neonatal period. The predominant clinical profile was characterized by hypoadrenocorticism, glyceroluria and Duchenne muscular dystrophy. After receiving a low fat diet and glucocorticoid replacement, they improved with relieved symptoms of hypoadrenocorticism. But they had significant developmental delays and myasthenia. In the follow-up two of them died of adrenal crisis.

    Glycerol kinase deficiency (GKD)
    DIAGNOSIS

, a

    rare X-linked recessive disorder
    GENETICS

, is classified into two types: isolated and complex.

    Complex GKD
    DIAGNOSIS

 is an

    Xp21 contiguous gene deletion involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci
    GENETICS

 or both. Its clinical features depend on the involved loci.

    GKD
    DIAGNOSIS

 can be confirmed by an

    elevated urinary glycerol concentration
    BIOCHEMICAL

 tested by

    gas chromatography mass spectrometry (GC/MS)
    PARACLINICAL

. The three cases reported here were all

    male
    GENDER

, presenting symptoms from

    neonatal
    AGE

    period
    AGE

. The predominant clinical profile was characterized by

    hypoadrenocorticism
    BIOCHEMICAL

,

    glyceroluria
    BIOCHEMICAL

 and

    Duchenne muscular dystrophy
    DIAGNOSIS

. After

    receiving a low fat diet and glucocorticoid replacement
    MEDICATION

, they improved with

    relieved symptoms of hypoadrenocorticism
    SYMPTOMS

. But they had

    significant developmental delays
    SYMPTOMS

 and

    myasthenia
    SYMPTOMS

. In the follow-up two of them

    died
    SYMPTOMS

 of

    adrenal crisis
    SYMPTOMS

.

Glycerol kinase deficiency (GKD)
Complex GKD
GKD
Duchenne muscular dystrophy

elevated urinary glycerol concentration
hypoadrenocorticism
glyceroluria


Postoperative hyperthermia, rhabdomyolysis, critical temperature, and death in a former premature infant after his ninth general anesthetic.

An 8-mo-old infant born at 24-wk of gestation died unexpectedly 12 h after his ninth uneventful general anesthetic. Preoperatively, he required low-flow nasal oxygen due to bronchopulmonary dysplasia, chronic diuretic therapy, and IV alimentation. As planned preoperatively, the infant remained tracheally intubated after his elective surgery and went to the Neonatal Intensive Care Unit in stable condition. However, over the next 6 h, he developed fever. The diagnosis of postoperative sepsis was considered. One hour before his death his temperature reached 43 degrees C. Autopsy documented Duchenne's muscular dystrophy and renal tubules containing myoglobin.

An

    8-mo-old
    AGE

    infant
    AGE

    born at 24-wk of gestation
    MEDICATION

    died
    SYMPTOMS

 unexpectedly 12 h after his

    ninth uneventful general anesthetic
    MEDICATION

.

    Preoperatively
    MEDICATION

,

    he
    GENDER

 required

    low-flow nasal oxygen
    MEDICATION

 due to

    bronchopulmonary dysplasia
    DIAGNOSIS

,

    chronic diuretic therapy
    MEDICATION

, and

    IV alimentation
    MEDICATION

. As planned preoperatively, the

    infant
    AGE

    remained tracheally intubated after his elective surgery
    MEDICATION

 and

    went to the Neonatal Intensive Care Unit
    MEDICATION

 in stable condition. However, over the next 6 h,

    he
    GENDER

 developed

    fever
    SYMPTOMS

. The diagnosis of

    postoperative sepsis
    DIAGNOSIS

 was considered. One hour before his

    death
    SYMPTOMS

 his temperature reached 43 degrees C.

    Autopsy
    PARACLINICAL

 documented

    Duchenne's muscular dystrophy
    DIAGNOSIS

 and

    renal tubules containing myoglobin
    MICROSCOPIC

.

bronchopulmonary dysplasia
postoperative sepsis
Duchenne's muscular dystrophy


Enhancing success in transition service coordinators: use of transformational leadership.

The lifespan of children with special healthcare needs has been extended because of improved technology and medical advances. Successful transition to the adult arena of healthcare, social services, and education by adolescents with special healthcare needs (ASHCN) is lacking. The transition service coordinator (TSC) is a multifaceted role of advanced practice nursing that provides highly specialized transition services to adolescents with special healthcare needs. The use of key concepts from the transformational leadership theory may improve healthcare outcomes.

This article applies to pediatric and adult primary care and case management services that serve adolescents with special healthcare needs.

Employing key concepts of transformational leadership theory will enhance the success of the TSC to improve both collaboration among stakeholders in the transitional team and young adults' transition to the world of adult services.

Enhanced communication resulting in improved sharing of information, understanding of the stakeholder roles, and provision of formal linkages between pediatric and adult medical providers is a significant outcome affecting the ASHCN. Improved collaboration will produce a smooth transition for the ASHCN to the world of adult social services education, and employment. Incorporating the transformational leadership dimensions of idealized influence, inspirational motivation intellectual stimulation, and individualized consideration will enhance the ability of the TSC to improve collaboration among stakeholders in the transitional team and the quality of services for the ASHCN.

The lifespan of

    children
    AGE

 with

    special healthcare needs
    AGE

 has been extended because of improved technology and medical advances.

    Successful transition to the adult arena of healthcare, social services, and education
    MEDICATION

 by

    adolescents
    AGE

 with special healthcare needs (ASHCN) is lacking. The

    transition service coordinator (TSC)
    MEDICATION

 is a multifaceted role of

    advanced practice nursing
    MEDICATION

 that provides

    highly specialized transition services to adolescents
    MEDICATION

 with

    special healthcare needs
    MEDICATION

. The use of key concepts from the

    transformational leadership theory
    MEDICATION

 may improve healthcare outcomes.

This article applies to

    pediatric and adult primary care and case management services
    MEDICATION

 that serve

    adolescents
    AGE

 with

    special healthcare needs
    AGE

.

Employing key concepts of

    transformational leadership theory
    MEDICATION

 will enhance the success of the TSC to improve both collaboration among stakeholders in the

    transitional team
    MEDICATION

 and

    young adults
    AGE

'

    transition to the world of adult services
    MEDICATION

.

Enhanced communication resulting in improved sharing of information, understanding of the stakeholder roles, and provision of

    formal linkages between pediatric and adult medical providers
    MEDICATION

 is a significant outcome affecting the ASHCN. Improved collaboration will produce a smooth transition for the ASHCN to the world of

    adult social services education, and employment
    MEDICATION

. Incorporating the transformational leadership dimensions of

    idealized influence
    MEDICATION

, inspirational

    motivation intellectual stimulation
    MEDICATION

, and

    individualized consideration
    MEDICATION

 will enhance the ability of the TSC to improve collaboration among stakeholders in the transitional team and the quality of services for the ASHCN.


Charcot-Marie-Tooth neuropathy type 1A combined with Duchenne muscular dystrophy.

We report a 24-year-old male with an unusual combination of two inherited neuromuscular disorders--Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD). A phenotypic presentation of this patient included features of both these disorders. Nerve conduction studies revealed demyelinating peripheral neuropathy. Electromyography showed a profound myogenic pattern. The serum creatine kinase level was highly elevated. Muscle biopsy revealed a dystrophic picture with deficient dystrophin immunostaining. CMT1A duplication on chromosome 17p11.2 was found. The frame-shift mutation c.3609-3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene by analysing mRNA isolated from the muscle tissue. The patient inherited both these mutations from his mother. The combination of CMT1A and DMD has not been reported as yet.

We report a

    24-year-old
    AGE

    male
    GENDER

 with an

    unusual combination of two inherited neuromuscular disorders--Charcot-Marie-Tooth (CMT) disease type 1A and Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. A phenotypic presentation of this patient included

    features of both these disorders
    SYMPTOMS

.

    Nerve conduction studies
    PARACLINICAL

 revealed

    demyelinating peripheral neuropathy
    SYMPTOMS

.

    Electromyography
    PARACLINICAL

 showed a

    profound myogenic pattern
    SYMPTOMS

. The

    serum creatine kinase level was highly elevated
    BIOCHEMICAL

.

    Muscle biopsy
    PARACLINICAL

 revealed a

    dystrophic picture
    SYMPTOMS

 with

    deficient dystrophin immunostaining
    BIOCHEMICAL

.

    CMT1A duplication on chromosome 17p11.2
    GENETICS

 was found. The

    frame-shift mutation c.3609-3612delTAAAinsCTT (p.K1204LfsX11) was detected in the dystrophin gene
    GENETICS

 by

    analysing mRNA isolated from the muscle tissue
    PARACLINICAL

.

    The patient inherited both these mutations from his mother
    FAMILY

. The

    combination of CMT1A and DMD
    DIAGNOSIS

 has not been reported as yet.

features of both these disorders
demyelinating peripheral neuropathy
profound myogenic pattern
dystrophic picture


Myoglobinuria in boys with Duchenne muscular dystrophy on corticosteroid therapy.

Myoglobinuria is a recognised complication of Duchenne muscular dystrophy (DMD), but has only once been reported in ambulant boys on corticosteroid therapy [Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediatr Neurol 2002;6(3):153-9.]. We present three prednisolone-treated boys with myoglobinuria and in two cases this was recurrent. All three showed improved motor performance in response to the introduction of corticosteroids. The greater activity of steroid-treated individuals may place their dystrophin-deficient muscles under greater mechanical stress, predisposing to further muscle fibre damage and consequent myoglobinuria. Families and physicians need to have an increased awareness of this possibility and of the appropriate management of myoglobinuria.

    Myoglobinuria
    BIOCHEMICAL

 is a recognised complication of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

, but has only once been reported in

    ambulant
    AGE

    boys
    GENDER

 on

    corticosteroid therapy
    MEDICATION

 [Dubowitz V, Kinali M, Main M, Mercuri E, Muntoni F.

    Remission of clinical signs
    SYMPTOMS

 in

    early Duchenne muscular dystrophy
    DIAGNOSIS

 on

    intermittent low-dosage prednisolone therapy
    MEDICATION

. Eur J Paediatr Neurol 2002;6(3):153-9.]. We present three

    prednisolone-treated
    MEDICATION

    boys
    GENDER

 with

    myoglobinuria
    BIOCHEMICAL

 and in two cases this was recurrent. All three showed

    improved motor performance
    SYMPTOMS

 in response to the

    introduction of corticosteroids
    MEDICATION

. The greater activity of

    steroid-treated
    MEDICATION

 individuals may place their

    dystrophin-deficient muscles under greater mechanical stress
    SYMPTOMS

, predisposing to further

    muscle fibre damage
    SYMPTOMS

 and consequent

    myoglobinuria
    BIOCHEMICAL

. Families and physicians need to have an increased awareness of this possibility and of the appropriate management of

    myoglobinuria
    BIOCHEMICAL

.

Myoglobinuria myoglobinuria myoglobinuria myoglobinuria

Duchenne muscular dystrophy (DMD)
early Duchenne muscular dystrophy


Nephrolithiasis in patients with duchenne muscular dystrophy.

To present the first series of patients with Duchenne muscular dystrophy (DMD) and nephrolithiasis.

A retrospective chart review was done to identify patients with DMD who were referred for urologic consultation because of nephrolithiasis from June 2004 to April 2006.

Four patients were identified with DMD and nephrolithiasis. Of the 4 patients, 2 underwent treatment, and their stones were obtained for analysis. The other 2 patients had stones diagnosed by computed tomography. Their stones were passed but not retrieved. Stone analysis for the available patients revealed a mixed calcareous composition. All 4 patients had had a relatively small stone burden. The patients ranged in age from 18 to 31 years.

Stone disease appears to have many of the same characteristics in patients with DMD as it does in the general population. Risk factors, including immobilization and corticosteroid use, are present. Additional studies are needed before conclusions can be made regarding the associations between DMD and nephrolithiasis.

To present the first series of patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    nephrolithiasis
    DIAGNOSIS

.

A retrospective chart review was done to identify patients with

    DMD
    DIAGNOSIS

 who were referred for

    urologic consultation
    PARACLINICAL

 because of

    nephrolithiasis
    DIAGNOSIS

 from June 2004 to April 2006.

Four patients were identified with

    DMD
    DIAGNOSIS

 and

    nephrolithiasis
    DIAGNOSIS

. Of the 4 patients, 2 underwent

    treatment
    MEDICATION

, and their stones were obtained for analysis. The other 2 patients had

    stones
    DIAGNOSIS

 diagnosed by

    computed tomography
    PARACLINICAL

. Their

    stones were passed but not retrieved
    NEG_FINDINGS

.

    Stone analysis
    PARACLINICAL

 for the available patients revealed a

    mixed calcareous composition
    MICROSCOPIC

. All 4 patients had had a

    relatively small stone burden
    SYMPTOMS

. The patients

    ranged in age from 18 to 31 years
    AGE

.

    Stone disease
    DIAGNOSIS

 appears to have many of the same characteristics in patients with

    DMD
    DIAGNOSIS

 as it does in the general population. Risk factors, including

    immobilization
    MEDICATION

 and

    corticosteroid use
    MEDICATION

, are present. Additional studies are needed before conclusions can be made regarding the associations between

    DMD
    DIAGNOSIS

 and

    nephrolithiasis
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
nephrolithiasis
DMD
nephrolithiasis
DMD
nephrolithiasis
stones
Stone disease
DMD
DMD
nephrolithiasis

treatment
immobilization
corticosteroid use


Language disturbances in a group of participants suffering from Duchenne muscular dystrophy: a pilot study.

Results from several studies suggest that the process of language acquisition may be altered in patients suffering from Duchenne Muscular Dystrophy. In this study, a group of 8 male participants with Duchenne Muscular Dystrophy (M age = 16 yr., SD = 4.7) underwent an extensive neuropsychological and language assessment. They also performed a discourse production task. Results showed mild mental retardation associated with a specific deficit in Verbal rather than Performance IQ. At the linguistic assessment, 7 of 8 participants showed moderate to severe difficulties on oral language processing with particularly impaired morphosyntactic competence.

Results from several studies suggest that the process of language acquisition may be altered in patients suffering from

    Duchenne Muscular Dystrophy
    DIAGNOSIS

. In this study, a group of 8

    male
    GENDER

 participants with

    Duchenne Muscular Dystrophy
    DIAGNOSIS

 (

    M age = 16 yr., SD = 4.7)
    AGE

 underwent an

    extensive neuropsychological and language assessment
    PARACLINICAL

. They also performed a

    discourse production task
    PARACLINICAL

. Results showed

    mild mental retardation
    SYMPTOMS

 associated with a specific

    deficit in Verbal rather than Performance IQ
    SYMPTOMS

. At the

    linguistic assessment
    PARACLINICAL

, 7 of 8 participants showed

    moderate to severe difficulties on oral language processing
    SYMPTOMS

 with particularly

    impaired morphosyntactic competence
    SYMPTOMS

.

Duchenne Muscular Dystrophy
Duchenne Muscular Dystrophy


[Contiguous gene deletion syndrome in Xp21: the association between glycerol kinase deficiency, congenital suprarenal hypoplasia and Duchenne's muscular dystrophy].

Complex glycerol kinase (GK) deficiency is a contiguous deletion of genes in Xp21 with loss of the locus for GK, for congenital adrenal hypoplasia (AHC) and/or for Duchenne's muscular dystrophy (DMD). We report the case of a 7-year-old patient with this rare disease.

Our patient was a full-term male, with normal gestation and delivery, and no relevant family history. At the age of 11 days he presented a clinical picture of salt loss with lethargy, vomiting, metabolic acidosis, hypoglycaemia, hyponatraemia and hyperpotassaemia. Fluid therapy and treatment with corticoids was established. The patient's condition developed with moderate mental retardation and progressive muscular weakness. In the physical examination, the skull and face were seen to be 'hourglass' shaped. Decompensations associated to infectious processes and fasting hypoglycaemia, hydroelectrolytic disorders and ketoacidosis are all frequent. Lab findings showed a drop in cortisol levels, elevation of muscle enzymes, 'pseudohypertriglyceridaemia' and raised levels of glycerol in plasma and urine. Karyotype and neuroimaging tests were normal. A myopathic pattern was observed in the electromyogram. The genetic study confirmed the deletion in Xp21 of the genes responsible for DMD, the GK deficit and AHC.

Early identification of this disease makes it possible to foresee the acute metabolic decompensations and to establish suitable genetic counselling. CK and triglyceride counts should be performed in all male patients that present a suprarenal hypoplasia; if levels are high, then it is necessary to confirm the raised glycerol values and to carry out a confirmatory genetic study.

    Complex glycerol kinase (GK) deficiency
    BIOCHEMICAL

 is a

    contiguous deletion of genes in Xp21 with loss of the locus for GK
    GENETICS

, for

    congenital adrenal hypoplasia (AHC)
    DIAGNOSIS

 and/or for

    Duchenne's muscular dystrophy (DMD)
    DIAGNOSIS

. We report the case of a

    7-year-old
    AGE

 patient with this rare disease.

Our patient was a

    full-term male
    AGE

, with

    normal gestation and delivery
    NEG_FINDINGS

, and

    no relevant family history
    NEG_FINDINGS

. At the

    age of 11 days
    AGE

    he
    GENDER

 presented a clinical picture of

    salt loss
    SYMPTOMS

 with

    lethargy
    SYMPTOMS

,

    vomiting
    SYMPTOMS

,

    metabolic acidosis
    BIOCHEMICAL

,

    hypoglycaemia
    BIOCHEMICAL

,

    hyponatraemia
    BIOCHEMICAL

 and

    hyperpotassaemia
    BIOCHEMICAL

.

    Fluid therapy
    MEDICATION

 and

    treatment with corticoids
    MEDICATION

 was established. The patient's condition developed with

    moderate mental retardation
    SYMPTOMS

 and

    progressive muscular weakness
    SYMPTOMS

. In the physical examination,

    the skull and face were seen to be 'hourglass' shaped
    SYMPTOMS

.

    Decompensations associated to infectious processes
    SYMPTOMS

 and

    fasting hypoglycaemia
    BIOCHEMICAL

,

    hydroelectrolytic disorders
    SYMPTOMS

 and

    ketoacidosis
    BIOCHEMICAL

 are all frequent.

    Lab findings
    PARACLINICAL

 showed a

    drop in cortisol levels
    BIOCHEMICAL

,

    elevation of muscle enzymes
    BIOCHEMICAL

, '

    pseudohypertriglyceridaemia
    BIOCHEMICAL

    '
    SYMPTOMS

 and

    raised levels of glycerol in plasma and urine
    BIOCHEMICAL

.

    Karyotype and neuroimaging tests were normal
    NEG_FINDINGS

. A

    myopathic pattern
    SYMPTOMS

 was observed in the

    electromyogram
    PARACLINICAL

. The

    genetic study
    PARACLINICAL

 confirmed the

    deletion in Xp21 of the genes responsible for DMD
    GENETICS

, the

    GK deficit
    BIOCHEMICAL

 and

    AHC
    DIAGNOSIS

.

Early identification of this disease makes it possible to foresee the

    acute metabolic decompensations
    SYMPTOMS

 and to establish suitable

    genetic counselling
    MEDICATION

.

    CK and triglyceride counts
    PARACLINICAL

 should be performed in all

    male
    GENDER

 patients that present a

    suprarenal hypoplasia
    SYMPTOMS

; if

    levels are high
    BIOCHEMICAL

, then it is necessary to confirm the

    raised glycerol values
    BIOCHEMICAL

 and to carry out a

    confirmatory genetic study
    PARACLINICAL

.

congenital adrenal hypoplasia (AHC)
Duchenne's muscular dystrophy (DMD)
AHC

Fluid therapy
treatment with corticoids
genetic counselling