Unusual muscle pathology in McLeod syndrome.

Muscle pathology in McLeod syndrome is usually mild; patchy necrotic or regenerating fibres, occasional internal nuclei, and the absence of an inflammatory cell infiltrate are the usual findings. We report on a 29 year old man presenting with chronic fatiguability and excessive sweating in whom an open quadriceps muscle biopsy demonstrated grouped necrotic fibres accompanied by striking patchy mononuclear cell infiltrates. The diagnosis of McLeod syndrome was made on the basis of red blood cell acanthocytosis, raised serum creatine kinase, and weak expression of Kell blood group antigens. The quadriceps muscle infiltrate consisted principally of histologically typical macrophages. These cells had prominent nucleoli, displayed numerous mitoses, and were strongly CD68+. A small population of typical CD3+, CD43+ lymphocytes was also present. In addition, a small population of large atypical CD3+ cells was noted. Immunoperoxidase stains for CD20, CD30, CD79a, and CD56 were negative. Immunocytochemical studies for the common muscular dystrophies were normal. The muscle biopsy findings highlight a potential for confusion of this condition with idiopathic polymyositis. The expanding range of muscle pathology reported in McLeod syndrome, to which this case adds, may reflect variable involvement of the XK gene on chromosome Xp21, or of the adjacent loci of Duchenne muscular dystrophy and chronic granulomatous disease.

    Muscle pathology
    SYMPTOMS

 in

    McLeod syndrome
    DIAGNOSIS

 is usually mild;

    patchy necrotic or regenerating fibres
    SYMPTOMS

,

    occasional internal nuclei
    SYMPTOMS

, and the

    absence of an inflammatory cell infiltrate
    NEG_FINDINGS

 are the usual findings. We report on a

    29 year old
    AGE

    man
    GENDER

 presenting with

    chronic fatiguability
    SYMPTOMS

 and

    excessive sweating
    SYMPTOMS

 in whom an

    open quadriceps muscle biopsy
    PARACLINICAL

 demonstrated

    grouped necrotic fibres
    MICROSCOPIC

 accompanied by

    striking patchy mononuclear cell infiltrates
    MICROSCOPIC

. The diagnosis of

    McLeod syndrome
    DIAGNOSIS

 was made on the basis of

    red blood cell acanthocytosis
    BIOCHEMICAL

,

    raised serum creatine kinase
    BIOCHEMICAL

, and

    weak expression of Kell blood group antigens
    BIOCHEMICAL

.

    The quadriceps muscle infiltrate consisted principally of histologically typical macrophages
    MICROSCOPIC

.

    These cells had prominent nucleoli
    MICROSCOPIC

,

    displayed numerous mitoses
    MICROSCOPIC

,

    and were strongly CD68+
    MICROSCOPIC

. A

    small population of typical CD3+, CD43+ lymphocytes was also present
    MICROSCOPIC

. In addition, a

    small population of large atypical CD3+ cells
    MICROSCOPIC

 was noted.

    Immunoperoxidase stains for CD20, CD30, CD79a, and CD56 were negative
    NEG_FINDINGS

.

    Immunocytochemical studies for the common muscular dystrophies were normal
    NEG_FINDINGS

. The

    muscle biopsy
    PARACLINICAL

 findings highlight a potential for confusion of this condition with

    idiopathic polymyositis
    DIAGNOSIS

. The expanding range of muscle pathology reported in

    McLeod syndrome
    DIAGNOSIS

, to which this case adds, may reflect

    variable involvement of the XK gene on chromosome Xp21, or of the adjacent loci of Duchenne muscular dystrophy
    GENETICS

 and

    chronic granulomatous disease
    DIAGNOSIS

.

Muscle pathology
patchy necrotic or regenerating fibres
occasional internal nuclei
chronic fatiguability
excessive sweating

McLeod syndrome
McLeod syndrome
idiopathic polymyositis
McLeod syndrome
chronic granulomatous disease


[Tracheopulmonary-subcutaneous fistula associated with anaerobic subcutaneous abscess on mechanical ventilator support in a patient with Duchenne muscular dystrophy].

A 29-year-old Japanese man with Duchenne muscular dystrophy was placed on a mechanical ventilator support at 23 years of age and admitted to our hospital at 25 years of age. He had severe neck contracture deviated to the left side which resulted in dysphagia and microaspiration. At 29 years of age, he developed left lobar pneumonia accompanied by slight fever, back pain and a foul odor from the patient's sputum. Although the patient received broad spectrum antibiotics, pneumonia disseminated to the right lung. A week later, chest computed tomography was conducted which revealed tracheopulmonary-subcutaneous fistula, and a massive subcutaneous abscess with free air production. Drainage from the subcutaneous abscess was done through a chest tube; however, respiratory hypercapnia was not corrected and the patient died. From the culture of drained fluid, anaerobic bacteria including peptostreptococcus sp. were detected. This tracheopulmonary-subcutaneous fistula was thought to be caused by chronic microaspiration of mouth anaerobes, mechanical injury of the trachea under long term ventilator support, and decreased deep back muscle bulk with substitution of adipose tissue around the chest.

A

    29-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 was

    placed on a mechanical ventilator support
    MEDICATION

 at

    23 years of age
    AGE

 and admitted to our hospital at

    25 years of age
    AGE

.

    He
    GENDER

 had

    severe neck contracture deviated to the left side
    SYMPTOMS

 which resulted in

    dysphagia
    SYMPTOMS

 and

    microaspiration
    SYMPTOMS

. At

    29 years of age
    AGE

,

    he
    GENDER

 developed

    left lobar pneumonia
    SYMPTOMS

 accompanied by

    slight fever
    SYMPTOMS

,

    back pain
    SYMPTOMS

 and a

    foul odor from the patient's sputum
    SYMPTOMS

.

    Although the patient received broad spectrum antibiotics
    NEG_FINDINGS

,

    pneumonia disseminated to the right lung
    SYMPTOMS

. A week later,

    chest computed tomography
    PARACLINICAL

 was conducted which revealed

    tracheopulmonary-subcutaneous fistula
    SYMPTOMS

, and a

    massive subcutaneous abscess with free air production
    SYMPTOMS

.

    Drainage from the subcutaneous abscess was done through a chest tube
    MEDICATION

; however,

    respiratory hypercapnia was not corrected
    NEG_FINDINGS

 and the patient

    died
    SYMPTOMS

. From the

    culture of drained fluid
    PARACLINICAL

,

    anaerobic bacteria
    MICROSCOPIC

 including

    peptostreptococcus sp.
    BIOCHEMICAL

 were detected. This

    tracheopulmonary-subcutaneous fistula
    SYMPTOMS

 was thought to be caused by

    chronic microaspiration of mouth anaerobes
    MICROSCOPIC

,

    mechanical injury of the trachea under long term ventilator support
    SYMPTOMS

, and

    decreased deep back muscle bulk with substitution of adipose tissue around the chest
    SYMPTOMS

.


[Electrolyte abnormalities and metabolic acidosis in two Duchenne muscular dystrophy patients with advanced congestive heart failure].

We experienced two Duchenne muscular dystrophy patients with advanced congestive heart failure, who showed abrupt severe hyponatremia, hyperkalemia and metabolic acidosis. Two patients received respiratory management, parenteral nutrition, and drugs including angiotensin converting enzyme inhibitors (ACEI). The patient 1 who was 19 years old showed abdominal pain, hematuria, diarrhea and disorientation. Laboratory findings were as follows; Na 120 mEq/L, K 7.3 mEq/L, BUN > 140 mg/dl (scale over), ACTH 20.2 pg/ml, cortisol 25 micrograms/dl, renin 40.7 ng/ml/hr and aldosterone 203 ng/dl. Arterial blood gas analysis (ABG) showed metabolic acidosis (pH 7.232). Combination therapy with hydrocortisone, glucose-insulin therapy (GIT) and NaHCO3 successfully rescued this patient. The patient 2 (28 years of age) was admitted to our hospital because of congestive heart failure. Laboratory findings were as follows; Na 129 mEq/L, K 5.5 mEq/L, BUN 60 mg/dl, cortisol 21 micrograms/dl, renin 36 ng/ml/hr and aldosterone 47 ng/dl. He complained abdominal discomforts from the next day of admission. Ten days after the admission Na, K and BUN were 111 mEq/L, 6.2 mEq/L and 154 mg/dl, respectively. ABG showed compensated metabolic acidosis. He fell into shock during GIT therapy. Laboratory findings at that time were as follows; Na 108 mEq/L, K 3.2 mEq/L, ACTH 77.6 pg/ml, cortisol 24 micrograms/dl, renin 58 ng/ml/hr and aldosterone 24 ng/dl. Although hydrocortisone was introduced, he could not recover and died. There are some reports about life-threatening electrolyte abnormalities and metabolic acidosis in the patients receiving ACEI. These phenomena were more frequent in patients with renal dysfunction and/or congestive heart failure. Hyponatremia, hypovolemia, combination therapy with nonsteroidal anti-inflammatory drugs (NSAID) and/or potassium sparing diuretics were reported as risk factors. We could not prove the correlation between the acute changes in our cases and ACEI. However ACEI is suspicious, because many of these risk factors were observed in our cases. Aldosterone was extremely elevated in the patient 1 when potassium was severely elevated. On the other hand, the patient 2 showed lower aldosterone level after correction of potassium than that on admission. Potassium is regarded as a major secretion factor of aldosterone for patients receiving ACEI. The fact the patient 2 fell into shock during GIT, tells us that we should use steroid simultaneously when we try to correct potassium quickly in severe cases, because acute reduction of potassium may decrease aldosterone. Today, ACEI is a common drug for CHF, so we should pay attentions that ACEI could cause such acute changes. To prevent such acute changes, excessive restriction of water and sodium intake should be avoided. If possible, NSAID and potassium sparing diuretics also should be avoided. Steroid therapy must be introduced rapidly when needed.

We experienced two

    Duchenne muscular dystrophy
    DIAGNOSIS

 patients with

    advanced congestive heart failure
    DIAGNOSIS

, who showed

    abrupt severe hyponatremia
    BIOCHEMICAL

,

    hyperkalemia
    BIOCHEMICAL

 and

    metabolic acidosis
    BIOCHEMICAL

. Two patients received

    respiratory management
    MEDICATION

,

    parenteral nutrition
    MEDICATION

, and

    drugs including angiotensin converting enzyme inhibitors (ACEI)
    MEDICATION

. The patient 1 who was

    19 years old
    AGE

 showed

    abdominal pain
    SYMPTOMS

,

    hematuria
    SYMPTOMS

,

    diarrhea
    SYMPTOMS

 and

    disorientation
    SYMPTOMS

. Laboratory findings were as follows;

    Na 120 mEq/L, K 7.3 mEq/L
    BIOCHEMICAL

,

    BUN > 140 mg/dl (scale over)
    BIOCHEMICAL

,

    ACTH 20.2 pg/ml, cortisol 25 micrograms/dl, renin 40.7 ng/ml/hr
    BIOCHEMICAL

 and

    aldosterone 203 ng/dl
    BIOCHEMICAL

.

    Arterial blood gas analysis (ABG)
    PARACLINICAL

 showed

    metabolic acidosis (pH 7.232)
    BIOCHEMICAL

.

    Combination therapy with hydrocortisone, glucose-insulin therapy (GIT) and NaHCO3
    MEDICATION

 successfully rescued this patient. The patient 2 (

    28 years of age
    AGE

) was admitted to our hospital because of

    congestive heart failure
    DIAGNOSIS

. Laboratory findings were as follows;

    Na 129 mEq/L, K 5.5 mEq/L
    BIOCHEMICAL

,

    BUN 60 mg/dl, cortisol 21 micrograms/dl, renin 36 ng/ml/hr and aldosterone 47 ng/dl
    BIOCHEMICAL

.

    He
    GENDER

 complained

    abdominal discomforts
    SYMPTOMS

 from the next day of admission. Ten days after the admission

    Na, K and BUN were 111 mEq/L, 6.2 mEq/L and 154 mg/dl, respectively
    BIOCHEMICAL

.

    ABG
    PARACLINICAL

 showed

    compensated metabolic acidosis
    BIOCHEMICAL

.

    He
    GENDER

    fell into shock
    SYMPTOMS

 during

    GIT therapy
    MEDICATION

. Laboratory findings at that time were as follows;

    Na 108 mEq/L, K 3.2 mEq/L
    BIOCHEMICAL

,

    ACTH 77.6 pg/ml, cortisol 24 micrograms/dl, renin 58 ng/ml/hr and aldosterone 24 ng/dl
    BIOCHEMICAL

.

    Although hydrocortisone was introduced
    NEG_FINDINGS

,

    he
    GENDER

    could not recover
    NEG_FINDINGS

 and

    died
    SYMPTOMS

. There are some reports about

    life-threatening electrolyte abnormalities
    SYMPTOMS

 and

    metabolic acidosis
    SYMPTOMS

 in the patients receiving

    ACEI
    MEDICATION

. These phenomena were more frequent in patients with

    renal dysfunction
    SYMPTOMS

 and/or

    congestive heart failure
    SYMPTOMS

.

    Hyponatremia
    BIOCHEMICAL

,

    hypovolemia
    BIOCHEMICAL

,

    combination therapy with nonsteroidal anti-inflammatory drugs (NSAID)
    MEDICATION

 and/or

    potassium sparing diuretics
    MEDICATION

 were reported as risk factors. We could not prove the correlation between the

    acute changes
    SYMPTOMS

 in our cases and

    ACEI
    MEDICATION

. However

    ACEI
    MEDICATION

 is suspicious, because many of these risk factors were observed in our cases.

    Aldosterone was extremely elevated
    BIOCHEMICAL

 in the patient 1 when

    potassium was severely elevated
    BIOCHEMICAL

. On the other hand, the patient 2 showed

    lower aldosterone level after correction of potassium than that on admission
    BIOCHEMICAL

.

    Potassium
    BIOCHEMICAL

 is regarded as a major

    secretion factor of aldosterone
    BIOCHEMICAL

 for patients receiving

    ACEI
    MEDICATION

. The fact the patient 2

    fell into shock
    SYMPTOMS

 during

    GIT
    MEDICATION

, tells us that we should use

    steroid simultaneously
    MEDICATION

 when we try to

    correct potassium quickly
    MEDICATION

 in severe cases, because

    acute reduction of potassium may decrease aldosterone
    BIOCHEMICAL

. Today,

    ACEI
    MEDICATION

 is a common drug for

    CHF
    DIAGNOSIS

, so we should pay attentions that

    ACEI
    MEDICATION

 could cause such

    acute changes
    SYMPTOMS

. To prevent such

    acute changes
    SYMPTOMS

,

    excessive restriction of water and sodium intake
    NEG_FINDINGS

 should be avoided. If possible,

    NSAID and potassium sparing diuretics
    MEDICATION

 also should be avoided.

    Steroid therapy
    MEDICATION

 must be introduced rapidly when needed.

Duchenne muscular dystrophy
advanced congestive heart failure
congestive heart failure
CHF


Preserving function in Duchenne dystrophy with long-term pulse prednisone therapy.

We report a case of a patient with Duchenne muscular dystrophy who was treated with intermittent pulse prednisone for severe asthma from age 3 to 17 yr and had remarkable preservation of skeletal muscle function. He had a maternal uncle with Duchenne muscular dystrophy who had the identical familial deletion mutation and died at age 19 of respiratory failure. Compared with his untreated uncle, our patient remains partially ambulatory at age 20. This case provides interesting, albeit anecdotal, evidence of considerable clinical benefit from pulse prednisone used on a much longer term basis than has been previously studied and promotes the need for further investigation on this type of therapy in Duchenne muscular dystrophy.

We report a case of a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 who was

    treated with intermittent pulse prednisone
    MEDICATION

 for

    severe asthma
    DIAGNOSIS

 from

    age 3 to 17 yr
    AGE

 and had

    remarkable preservation of skeletal muscle function
    SYMPTOMS

.

    He
    GENDER

    had a maternal uncle with Duchenne muscular dystrophy who had the identical familial deletion mutation
    FAMILY

 and

    died
    SYMPTOMS

 at

    age 19
    AGE

 of

    respiratory failure
    SYMPTOMS

.

    Compared with his untreated uncle
    FAMILY

, our patient remains

    partially ambulatory
    SYMPTOMS

 at

    age 20
    AGE

. This case provides interesting, albeit anecdotal, evidence of considerable clinical benefit from

    pulse prednisone used on a much longer term basis
    MEDICATION

 than has been previously studied and promotes the need for further investigation on this type of therapy in

    Duchenne muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy
severe asthma
Duchenne muscular dystrophy


[Improvement of obstructive sleep apnea by uvulopalatopharyngoplasty and tonsillectomy in a case of Duchenne muscular dystrophy].

A 10-year-old boy with Duchenne muscular dystrophy (DMD) underwent uvulopalatopharyngoplasty and tonsillectomy for obstructive sleep apnea (OSA). He has snored loudly during nocturnal sleep since infancy, and OSA developed one and a half years after he was wheel chair-bound at 8 years. Magnetic resonance imaging (MRI), conventional spirometry and overnight polysomnography were performed before and after the surgery. MRI before surgery revealed moderate tonsillar hypertrophy and a long uvula which narrowed the upper airway. After the surgery, his vital capacity (VC) was not changed (% VC; from 77 to 78%), but forced expiratory volume (FEV) was improved (FEV 1.0%; from 75 to 86%). A preoperative apnea index of 32.8/hour decreased to 0.8/hour postoperatively. REM-related falls in HbSaO2 improved remarkably. The present case suggests that subjects with DMD with tonsillar hypertrophy and a redundant uvula tend to develop noctrurnal OSA earlier than DMD cases with a normal tonsil and uvula. Assessment of respiratory function, particularly FEV 1.0%, is important for determining surgical indication of OSA in patients with DMD.

A

    10-year-old
    AGE

    boy
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 underwent

    uvulopalatopharyngoplasty
    MEDICATION

 and

    tonsillectomy
    MEDICATION

 for

    obstructive sleep apnea (OSA)
    DIAGNOSIS

.

    He
    GENDER

 has

    snored loudly during nocturnal sleep
    SYMPTOMS

 since

    infancy
    AGE

, and

    OSA
    DIAGNOSIS

 developed one and a half years after

    he
    GENDER

 was

    wheel chair-bound
    MEDICATION

    at 8 years
    AGE

.

    Magnetic resonance imaging (MRI)
    PARACLINICAL

,

    conventional spirometry
    PARACLINICAL

 and

    overnight polysomnography
    PARACLINICAL

 were performed before and after the

    surgery
    MEDICATION

.

    MRI
    PARACLINICAL

 before

    surgery
    MEDICATION

 revealed

    moderate tonsillar hypertrophy
    SYMPTOMS

 and a

    long uvula which narrowed the upper airway
    SYMPTOMS

. After

    the surgery
    MEDICATION

, his

    vital capacity (VC) was not changed (% VC; from 77 to 78%)
    NEG_FINDINGS

, but

    forced expiratory volume (FEV) was improved (FEV 1.0%; from 75 to 86%)
    SYMPTOMS

. A

    preoperative apnea index of 32.8/hour decreased to 0.8/hour postoperatively
    BIOCHEMICAL

.

    REM-related falls in HbSaO2 improved remarkably
    BIOCHEMICAL

. The present case suggests that subjects with

    DMD
    DIAGNOSIS

 with

    tonsillar hypertrophy
    SYMPTOMS

 and a

    redundant uvula
    SYMPTOMS

 tend to develop

    noctrurnal OSA
    SYMPTOMS

 earlier than

    DMD
    DIAGNOSIS

 cases with a

    normal tonsil and uvula
    NEG_FINDINGS

.

    Assessment of respiratory function, particularly FEV 1.0%
    PARACLINICAL

, is important for determining surgical indication of

    OSA
    DIAGNOSIS

 in patients with

    DMD
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
obstructive sleep apnea (OSA)
OSA
DMD
DMD
OSA
DMD

uvulopalatopharyngoplasty
tonsillectomy
wheel chair-bound
surgery
surgery
the surgery


[Mechanical ventilation in neuromuscular diseases: do not start too early, but certainly not too late].

Three patients had chronic respiratory disorders: a 42-year-old man with glycogenosis type II was tired, had headaches, poor pulmonary function values and, according to the arterial blood gas values, hypercapnia; a man aged 24 with Duchenne's muscular dystrophy had variable moderate dyspnoea with hypoxia and hypercapnia, and a man aged 64 years with an mitochondrial myopathy complained of dyspnoea and headache but had good blood gas values. The symptoms and abnormalities of the first patient were suppressed by nocturnal ventilatory support through a nasal mask system, the second preferred to refrain from ventilatory support and died a few weeks later and the symptoms of the third patient decreased without ventilatory support. Assessing a ventilatory disorder in patients with a neuromuscular disease is not always simple. Symptoms suggestive of nocturnal hypoventilation may occur in patients without respiratory insufficiency. It is also possible for patients with chronic respiratory insufficiency to be free of symptoms. Determinations of the arterial blood gas values are the most reliable method. Since normal daytime values do not exclude a nocturnal respiratory insufficiency, it is advisable in case of suspicion of nocturnal hypoventilation to measure the arterial blood gas values at night, as well. Nocturnal pulse oximetry does not always adequately reflect the degree of hypoventilation. In view of the positive effects of assisted respiration, adequate diagnostic examinations and early referral to a centre for home mechanical ventilation are advisable.

Three patients had

    chronic respiratory disorders
    DIAGNOSIS

: a

    42-year-old
    AGE

    man
    GENDER

 with

    glycogenosis type II
    DIAGNOSIS

 was

    tired
    SYMPTOMS

, had

    headaches
    SYMPTOMS

,

    poor pulmonary function values
    SYMPTOMS

 and, according to the

    arterial blood gas values
    PARACLINICAL

,

    hypercapnia
    BIOCHEMICAL

; a

    man
    GENDER

    aged 24
    AGE

 with

    Duchenne's muscular dystrophy
    DIAGNOSIS

 had

    variable moderate dyspnoea
    SYMPTOMS

 with

    hypoxia
    SYMPTOMS

 and

    hypercapnia
    BIOCHEMICAL

, and a

    man
    GENDER

    aged 64 years
    AGE

 with an

    mitochondrial myopathy
    DIAGNOSIS

 complained of

    dyspnoea
    SYMPTOMS

 and

    headache
    SYMPTOMS

 but had

    good blood gas values
    NEG_FINDINGS

. The

    symptoms and abnormalities
    SYMPTOMS

 of the first patient were suppressed by

    nocturnal ventilatory support through a nasal mask system
    MEDICATION

, the second

    preferred to refrain from ventilatory support
    NEG_FINDINGS

 and

    died
    SYMPTOMS

 a few weeks later and the symptoms of the third patient decreased

    without ventilatory support
    NEG_FINDINGS

. Assessing a

    ventilatory disorder
    DIAGNOSIS

 in patients with a

    neuromuscular disease
    DIAGNOSIS

 is not always simple.

    Symptoms suggestive of nocturnal hypoventilation
    SYMPTOMS

 may occur in patients

    without respiratory insufficiency
    NEG_FINDINGS

. It is also possible for patients with

    chronic respiratory insufficiency
    SYMPTOMS

 to be

    free of symptoms
    NEG_FINDINGS

.

    Determinations of the arterial blood gas values
    PARACLINICAL

 are the most reliable method. Since

    normal daytime values do not exclude a nocturnal respiratory insufficiency
    NEG_FINDINGS

, it is advisable in case of suspicion of

    nocturnal hypoventilation
    SYMPTOMS

 to

    measure the arterial blood gas values at night
    PARACLINICAL

, as well.

    Nocturnal pulse oximetry
    PARACLINICAL

 does not always adequately reflect the degree of

    hypoventilation
    SYMPTOMS

. In view of the positive effects of

    assisted respiration
    MEDICATION

, adequate diagnostic examinations and

    early referral to a centre for home mechanical ventilation
    MEDICATION

 are advisable.

chronic respiratory disorders
glycogenosis type II
Duchenne's muscular dystrophy
mitochondrial myopathy
ventilatory disorder
neuromuscular disease


Rapacuronium administration to two children with Duchenne's muscular dystrophy.

Children with Duchenne's muscular dystrophy should not be exposed to succinylcholine because of the risk of hyperkalemic cardiac arrest and rhabdomyolysis. This report describes the response to rapacuronium bromide in two patients with Duchenne's muscular dystrophy. Both patients had a recovery index 2 times longer than that reported in children with normal neuromuscular function.

    Children
    AGE

 with

    Duchenne's muscular dystrophy
    DIAGNOSIS

 should not be exposed to

    succinylcholine
    MEDICATION

 because of the risk of

    hyperkalemic cardiac arrest
    SYMPTOMS

 and

    rhabdomyolysis
    DIAGNOSIS

. This report describes the response to

    rapacuronium bromide
    MEDICATION

 in two patients with

    Duchenne's muscular dystrophy
    DIAGNOSIS

. Both patients had a

    recovery index 2 times longer than that
    BIOCHEMICAL

 reported in

    children
    AGE

 with

    normal neuromuscular function
    NEG_FINDINGS

.

Duchenne's muscular dystrophy
rhabdomyolysis
Duchenne's muscular dystrophy


[A patient presented with atypical paroxysmal kinesigenic choreoathetosis and Becker muscular dystrophy].

A 22-year-old man had choreatic movements in upper limbs, neck and trunk for over twelve years which were associated with dystonia in lower limbs upon initiating voluntary movements. The choreatic movement lasted for a few seconds and the dystonia lasted for a few minutes. He also had high serum CK levels and hypertrophic calf muscles. His muscle strength and deep tendon reflexes were normal. His choreatic movements fulfill the criteria for paroxysmal kinesigenic choreoathetosis (PKC). However, it was unclear what the symptom of dystonia was due to. From a muscle biopsy and DNA analysis, he was diagnosed as having Becker muscular dystrophy. Administration of anticonvulsant improved the dystonia as well as the choreatic movement, which showed that the dystonia was a symptom of PKC. Coincidence of choreatic movements and dystonias which had different lasting time in a patient of PKC was atypical and had not previously reported.

A

    22-year-old
    AGE

    man
    GENDER

 had

    choreatic movements in upper limbs, neck and trunk for over twelve years
    SYMPTOMS

 which were associated with

    dystonia in lower limbs
    SYMPTOMS

 upon

    initiating voluntary movements
    SYMPTOMS

. The

    choreatic movement lasted for a few seconds
    SYMPTOMS

 and the

    dystonia lasted for a few minutes
    SYMPTOMS

.

    He
    GENDER

 also had

    high serum CK levels
    BIOCHEMICAL

 and

    hypertrophic calf muscles
    SYMPTOMS

. His

    muscle strength and deep tendon reflexes were normal
    NEG_FINDINGS

. His

    choreatic movements
    SYMPTOMS

 fulfill the criteria for

    paroxysmal kinesigenic choreoathetosis (PKC)
    DIAGNOSIS

. However, it was unclear what the symptom of

    dystonia
    DIAGNOSIS

 was due to. From a

    muscle biopsy
    PARACLINICAL

 and

    DNA analysis
    PARACLINICAL

,

    he
    GENDER

 was diagnosed as having

    Becker muscular dystrophy
    DIAGNOSIS

.

    Administration of anticonvulsant
    MEDICATION

    improved the dystonia as well as the choreatic movement
    SYMPTOMS

, which showed that the

    dystonia
    DIAGNOSIS

 was a symptom of

    PKC
    DIAGNOSIS

.

    Coincidence of choreatic movements and dystonias which had different lasting time
    SYMPTOMS

 in a patient of

    PKC
    DIAGNOSIS

 was atypical and had not previously reported.


Becker muscular dystrophy combined with X-linked Charcot-Marie-Tooth neuropathy.

A man was identified with two X-chromosomal neuromuscular disorders, X-linked Charcot-Marie-Tooth disease (CMTX) and Becker muscular dystrophy (BMD). The neuropathy could be tracked in the family and was found to be caused by a mutation in the connexin32 gene on Xq13. 1. The muscular dystrophy was sporadic owing to a de novo deletion in the dystrophin gene located in band Xp21.2. Although these genetic alterations of the same X-chromosome are considered as physically independent, their combination resulted in a unique phenotype with severe wasting of proximal as well as distal muscles and rapid progression of both conditions.

A

    man
    GENDER

 was identified with two

    X-chromosomal neuromuscular disorders
    GENETICS

,

    X-linked Charcot-Marie-Tooth disease (CMTX)
    DIAGNOSIS

 and

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

. The

    neuropathy could be tracked in the family
    FAMILY

 and was found to be caused by a

    mutation in the connexin32 gene on Xq13. 1
    GENETICS

. The

    muscular dystrophy
    DIAGNOSIS

 was

    sporadic
    GENETICS

 owing to a

    de novo deletion in the dystrophin gene located in band Xp21.2
    GENETICS

. Although these

    genetic alterations of the same X-chromosome
    GENETICS

 are considered as physically independent, their combination resulted in a unique phenotype with

    severe wasting of proximal as well as distal muscles
    SYMPTOMS

 and

    rapid progression of both conditions
    SYMPTOMS

.


[Carrier's detection in families affected by Duchenne/Becker muscular dystrophy in which DNA from affected individuals is not available].

Carrier/noncarrier status of the mutated dystrophin gene was established in 9 females from four families with Duchenne/Becker muscular dystrophy, in which samples of DNA from the affected members were not available. Analysis of extra- and intragenic polymorphic segments of the dystrophin gene enabled identification of two female carriers and exclusion of carriership in four females. In three cases the results were not informative because of recombination in the analysed segment of the gene.

Carrier/noncarrier status of

    the mutated dystrophin gene
    GENETICS

 was established in 9

    females
    GENDER

 from four families with

    Duchenne/Becker muscular dystrophy
    DIAGNOSIS

, in which

    samples of DNA from the affected members were not available
    NEG_FINDINGS

.

    Analysis of extra- and intragenic polymorphic segments of the dystrophin gene
    PARACLINICAL

 enabled identification of two

    female
    GENDER

 carriers and

    exclusion of carriership
    NEG_FINDINGS

 in four

    females
    GENDER

. In three cases the

    results were not informative
    NEG_FINDINGS

 because of

    recombination in the analysed segment of the gene
    GENETICS

.


[Detecting carriers of a deletion in the dystrophin gene in families with a single case of Duchenne/Becker muscular dystrophy].

A search for female mutation carriers was performed in 40 families with an isolated case of Duchenne/Becker muscular dystrophy due to a deletion in the dystrophin gene. Intragenic restriction sites and microsatellite sequences (CA repeats) were analysed in females possible carriers of the deletion. Application of this approach enabled us the detection of the deletion in 19 females in 9 families and exclusion of the deletion in 41 females in 23 families. The results of DNA analysis in the remaining 8 families were not informative.

A search for

    female
    GENDER

 mutation carriers was performed in 40 families with an

    isolated case of Duchenne/Becker muscular dystrophy
    DIAGNOSIS

 due to a

    deletion in the dystrophin gene
    GENETICS

.

    Intragenic restriction sites and microsatellite sequences (CA repeats) were analysed
    PARACLINICAL

 in

    females
    GENDER

 possible carriers of the deletion. Application of this approach enabled us the detection of the deletion in 19

    females
    GENDER

 in 9 families and exclusion of the deletion in 41

    females
    GENDER

 in 23 families. The results of

    DNA analysis
    PARACLINICAL

 in the remaining 8 families

    were not informative
    NEG_FINDINGS

.


[Anesthetic complications. The incidence of severe anesthetic complications in patients and families with progressive muscular dystrophy of the Duchenne and Becker types].

During the last 30 years a great number of case reports presented severe anaesthetic complications with sudden cardiac arrest in patients with muscular dystrophies, mostly unsuspected at the time of the event. As succinylcholine was involved in the majority of the intractable incidents with lethal outcome the Food and Drug Administration (FDA) of the United States recommended a warning of the administration of succinylcholine in young children and adolescents in 1992 and an extensive international discussion on the routine use of succinylcholine in paediatric anaesthesia. Epidemiological studies on this issue are rare. We projected an inquiry about the incidence rate and type of severe anaesthetic complications in an utmost large number of patients and families with Duchenne (DMD) and Becker type (BMD) muscular dystrophy.

With the approval of the ethic committee of the university Witten/Herdecke and informed consent of the participants we investigated all patients and families who were diagnosed, controlled and treated for DMD or BMD as inpatients or outpatients in a "Muscle Centre" since 1983. The questionnaire asked for the number of patients per family, classification of the disease DMD or BMD, number and date of anaesthetics in the patients and eventual complications, anaesthetics and eventual complications in the parents, siblings and relatives and the occurrence of malignant hyperthermia (MH) in the family or relatives. Statistical assessments were done by Fisher's exact test for stratified 2 x 2 tables and Zelen's test for homogeneity of odds ratios.

200 out of 224 questionnaires could be evaluated. The diagnosis was confirmed by molecular genetic and immunohistochemical investigations. In 147 families it turned out to be DMD, in 53 families BMD. The 212 male and 9 female patients in the 200 families were given 444 anaesthetics. Sudden cardiac arrest occurred in 6 patients, all successfully resuscitated. Nine less severe incidents consisted of fever, symptoms of rhabdomyolysis (CK-elevation, dark coloured urine, hyperkalemia) and masseter spasm. The statistical assessment revealed that the occurrence of an event was highly dependent whether the diagnosis of muscular dystrophy was established or not (p < 0.0001, Fisher's exact test). All six cardiac arrests occurred in the 45 families with undiagnosed disease and no event happened in the 134 families with already known DMD/BMD. There was evidence that the number of anaesthetics without prior establishment of the diagnosis decreased after 1992 (p = 0.004, Fisher's exact test).

Our results demonstrate that severe incidents and cardiac arrests occurred only in young children with undiagnosed DMD or BMD who received inhalational agents and succinylcholine. A cardiac arrest in 6 out of 200 families was found much more frequently than in the normal paediatric population (about 1:1000 to 1:3000). The decrease of events after 1992 (warning of the FDA) and disappearance of sudden cardiac arrests in our group of patients might be due to the world wide discussion on routine use of succinylcholine in children or the much earlier establishment of the diagnosis in our population. An early diagnosis of DMD and BMD and the avoidance of the triggering agents succinylcholine and volatile anaesthetics can reduce the risk of severe anaesthetic complications.

During the last 30 years a great number of case reports presented

    severe anaesthetic complications
    SYMPTOMS

 with

    sudden cardiac arrest
    SYMPTOMS

 in patients with

    muscular dystrophies
    DIAGNOSIS

, mostly unsuspected at the time of the event. As

    succinylcholine
    MEDICATION

 was involved in the majority of the

    intractable incidents
    SYMPTOMS

 with

    lethal outcome
    SYMPTOMS

 the Food and Drug Administration (FDA) of the United States recommended a warning of the

    administration of succinylcholine
    MEDICATION

 in

    young children and adolescents
    AGE

 in 1992 and an extensive international discussion on the routine use of

    succinylcholine
    MEDICATION

 in

    paediatric
    AGE

    anaesthesia
    MEDICATION

. Epidemiological studies on this issue are rare. We projected an inquiry about the incidence rate and type of

    severe anaesthetic complications
    SYMPTOMS

 in an utmost large number of patients and families with

    Duchenne (DMD) and Becker type (BMD) muscular dystrophy
    DIAGNOSIS

.

With the approval of the ethic committee of the university

    Witten/Herdecke
    PARACLINICAL

 and informed consent of the participants we investigated all patients and families who were diagnosed, controlled and treated for

    DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

 as inpatients or

    outpatients
    MEDICATION

 in a "

    Muscle Centre
    MEDICATION

" since 1983. The questionnaire asked for the number of patients per family, classification of the disease

    DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

, number and date of

    anaesthetics
    MEDICATION

 in the patients and eventual complications,

    anaesthetics and eventual complications in the parents, siblings and relatives
    MEDICATION

 and the occurrence of

    malignant hyperthermia (MH)
    SYMPTOMS

    in the family or relatives
    FAMILY

. Statistical assessments were done by Fisher's exact test for stratified 2 x 2 tables and Zelen's test for homogeneity of odds ratios.

200 out of 224 questionnaires could be evaluated. The diagnosis was confirmed by

    molecular genetic and immunohistochemical investigations
    PARACLINICAL

. In 147 families it turned out to be

    DMD
    DIAGNOSIS

, in 53 families

    BMD
    DIAGNOSIS

. The 212

    male
    GENDER

 and 9

    female
    GENDER

 patients in the 200 families were given

    444 anaesthetics
    MEDICATION

.

    Sudden cardiac arrest
    SYMPTOMS

 occurred in 6 patients, all successfully

    resuscitated
    MEDICATION

. Nine less severe incidents consisted of

    fever
    SYMPTOMS

,

    symptoms of rhabdomyolysis (CK-elevation
    SYMPTOMS

,

    dark coloured urine
    BIOCHEMICAL

,

    hyperkalemia)
    BIOCHEMICAL

 and

    masseter spasm
    SYMPTOMS

. The statistical assessment revealed that the occurrence of an event was highly dependent whether the diagnosis of

    muscular dystrophy
    DIAGNOSIS

 was established or not (p < 0.0001, Fisher's exact test). All six

    cardiac arrests
    SYMPTOMS

 occurred in the 45 families with

    undiagnosed disease
    DIAGNOSIS

 and no event happened in the 134 families with already known

    DMD/BMD
    DIAGNOSIS

. There was evidence that the number of

    anaesthetics
    MEDICATION

 without prior establishment of the diagnosis decreased after 1992 (p = 0.004, Fisher's exact test).

Our results demonstrate that

    severe incidents
    SYMPTOMS

 and

    cardiac arrests
    SYMPTOMS

 occurred only in

    young
    AGE

    children
    AGE

 with

    undiagnosed DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

 who received

    inhalational agents and succinylcholine
    MEDICATION

. A

    cardiac arrest
    SYMPTOMS

 in 6 out of 200 families was found much more frequently than in the normal paediatric population (about 1:1000 to 1:3000). The decrease of events after 1992 (warning of the FDA) and disappearance of

    sudden cardiac arrests
    SYMPTOMS

 in our group of patients might be due to the world wide discussion on routine use of

    succinylcholine
    MEDICATION

 in

    children
    AGE

 or the much earlier establishment of the diagnosis in our population. An early diagnosis of

    DMD
    DIAGNOSIS

 and

    BMD
    DIAGNOSIS

 and the

    avoidance of the triggering agents succinylcholine and volatile anaesthetics
    MEDICATION

 can reduce the risk of

    severe anaesthetic complications
    SYMPTOMS

.


Oral creatine supplementation in Duchenne muscular dystrophy: a clinical and 31P magnetic resonance spectroscopy study.

The decrease in intracellular creatine concentration in Duchenne muscular dystrophy may contribute to the deterioration of intracellular energy homeostasis and may thus be one of the factors aggravating muscle weakness and degeneration. Oral creatine supplementation should have potential in alleviating the clinical symptoms. To test this hypothesis, creatine was orally administered over a period of 155 days to a 9-year-old patient with Duchenne muscular dystrophy. In accordance with previous investigations on normal subjects and trained athletes, the patient experienced improved muscle performance during creatine supplementation. Further evidence supporting this hypothesis derived from plasma creatine kinase and lactate dehydrogenase activities and repeated 31P magnetic resonance spectroscopy of the gastrocnemius muscle. These preliminary observations indicate a potential role for creatine supplementation in the symptomatic therapy of patients with muscle disease.

The

    decrease in intracellular creatine concentration
    BIOCHEMICAL

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

 may contribute to the

    deterioration of intracellular energy homeostasis
    BIOCHEMICAL

 and may thus be one of the factors aggravating

    muscle weakness and degeneration
    SYMPTOMS

.

    Oral creatine supplementation
    MEDICATION

 should have potential in alleviating the clinical symptoms. To test this hypothesis,

    creatine was orally administered over a period of 155 days
    MEDICATION

 to a

    9-year-old
    AGE

 patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

. In accordance with previous investigations on normal subjects and trained

    athletes
    GENDER

, the patient experienced

    improved muscle performance
    SYMPTOMS

 during

    creatine supplementation
    MEDICATION

. Further evidence supporting this hypothesis derived from

    plasma creatine kinase and lactate dehydrogenase activities
    BIOCHEMICAL

 and

    repeated 31P magnetic resonance spectroscopy of the gastrocnemius muscle
    PARACLINICAL

. These preliminary observations indicate a potential role for

    creatine supplementation
    MEDICATION

 in the

    symptomatic therapy
    MEDICATION

 of patients with

    muscle disease
    DIAGNOSIS

.

Duchenne muscular dystrophy
Duchenne muscular dystrophy
muscle disease

muscle weakness and degeneration
improved muscle performance


Perturbation in dystrophin-associated glycoprotein complex in a boy with Becker muscular dystrophy.

We report on a boy with a BMD phenotype presenting with a deletion of exons 45-49 in the DMD gene. Immunofluorescence and Western blot analysis of a skeletal muscle sample revealed, as expected, truncated dystrophin with loss in the central rod domain, but with an unusual severe deficiency in the sarcoglycan complex, as in severe DMD. We discuss possible neighboring between dystrophin and associated proteins within their complex organization at the muscle membrane.

We report on a

    boy
    GENDER

 with a

    BMD
    DIAGNOSIS

 phenotype presenting with a

    deletion of exons 45-49 in the DMD gene
    GENETICS

.

    Immunofluorescence and Western blot analysis of a skeletal muscle sample
    PARACLINICAL

 revealed, as expected,

    truncated dystrophin with loss in the central rod domain
    MICROSCOPIC

, but with an

    unusual severe deficiency in the sarcoglycan complex
    BIOCHEMICAL

, as in

    severe DMD
    DIAGNOSIS

. We discuss possible neighboring between dystrophin and associated proteins within their complex organization at the muscle membrane.


An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22.

We present four subjects from one family and one subject (with an affected sibling who had died) from a second, unrelated family, with early onset, Duchenne-like, muscular dystrophy who presented with proximal girdle weakness, calf and generalized muscle hypertrophy, selective wasting of the sternomastoid muscles, rigidity of the spine and contractures of the tendo Achilles. Intellect was normal. Serum creatine kinase was grossly elevated and the muscle biopsies showed a dystrophic picture. All five subjects have developed early respiratory failure due to severe diaphragmatic involvement; two have already died aged 4 and 7 years of age and the remaining three are dependent on night time ventilation. There has been very little deterioration over time in the skeletal muscle function, and the survivors remain ambulant, the oldest being 11 years. Immunocytochemical studies of the muscle biopsy showed a normal pattern for dystrophin and the dystrophin-associated glycoproteins, but a reduction of the laminin alpha2 chain of merosin. Magnetic resonance imaging of the brain was normal. The disease did not link to the LAMA2 locus for laminin alpha2 on chromosome 6q, so that these families seem to represent a new form of autosomal recessive muscular dystrophy with a secondary merosin deficiency. The primary protein deficiency has not yet been identified.

We present four subjects from one family and one subject

    (with an affected sibling who had died) from a second, unrelated family
    FAMILY

, with

    early onset, Duchenne-like, muscular dystrophy
    DIAGNOSIS

 who presented with

    proximal girdle weakness
    SYMPTOMS

,

    calf and generalized muscle hypertrophy
    SYMPTOMS

,

    selective wasting of the sternomastoid muscles
    SYMPTOMS

,

    rigidity of the spine
    SYMPTOMS

 and

    contractures of the tendo Achilles
    SYMPTOMS

.

    Intellect was normal
    NEG_FINDINGS

.

    Serum creatine kinase was grossly elevated
    BIOCHEMICAL

 and the

    muscle biopsies
    PARACLINICAL

 showed a

    dystrophic picture
    MICROSCOPIC

. All five subjects have developed

    early respiratory failure
    SYMPTOMS

 due to

    severe diaphragmatic involvement
    SYMPTOMS

; two have already

    died
    SYMPTOMS

    aged 4 and 7 years of age
    AGE

 and the remaining three are

    dependent on night time ventilation
    MEDICATION

. There has been

    very little deterioration over time in the skeletal muscle function
    NEG_FINDINGS

, and the survivors remain

    ambulant
    SYMPTOMS

, the

    oldest being 11 years
    AGE

.

    Immunocytochemical studies of the muscle biopsy
    PARACLINICAL

 showed a

    normal pattern for dystrophin and the dystrophin-associated glycoproteins
    NEG_FINDINGS

, but a

    reduction of the laminin alpha2 chain of merosin
    BIOCHEMICAL

.

    Magnetic resonance imaging of the brain was normal
    NEG_FINDINGS

. The disease

    did not link to the LAMA2 locus for laminin alpha2 on chromosome 6q
    NEG_FINDINGS

, so that these families seem to represent a new form of

    autosomal recessive muscular dystrophy
    DIAGNOSIS

 with a

    secondary merosin deficiency
    BIOCHEMICAL

. The primary

    protein deficiency
    BIOCHEMICAL

 has not yet been identified.


Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families.

This study reports three children from three unrelated families, aged from 9 to 12 years, who were investigated because of the incidental finding of elevated serum creatine kinase (CK) levels and were found to have a dystrophinopathy. The molecular defect consisted of a deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32-44 or 48-51 or 48-53. In each family we found the same deletion in at least one adult male relative aged from 40 to 77 years, who was either completely asymptomatic or had very mild muscle involvement (thin muscles and/or mild scoliosis), with normal or borderline CK levels. This study suggests once again that deletions of the central rod domain of dystrophin may be associated with elevation of serum CK as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution.

This study reports three

    children
    AGE

 from three unrelated families,

    aged from 9 to 12 years
    AGE

, who were investigated because of the incidental finding of

    elevated serum creatine kinase (CK) levels
    BIOCHEMICAL

 and were found to have a

    dystrophinopathy
    DIAGNOSIS

. The

    molecular defect
    GENETICS

 consisted of a

    deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32-44 or 48-51 or 48-53
    GENETICS

. In each family we

    found the same deletion in at least one adult
    FAMILY

    male
    GENDER

 relative

    aged from 40 to 77 years
    AGE

, who was either

    completely asymptomatic
    NEG_FINDINGS

 or had

    very mild muscle involvement (thin muscles and/or mild scoliosis)
    SYMPTOMS

, with

    normal or borderline CK levels
    NEG_FINDINGS

. This study suggests once again that

    deletions of the central rod domain of dystrophin
    GENETICS

 may be associated with

    elevation of serum CK
    BIOCHEMICAL

 as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution.

completely asymptomatic
normal or borderline CK levels


Complete skipping of exon 66 due to novel mutations of the dystrophin gene was identified in two Japanese families of Duchenne muscular dystrophy with severe mental retardation.

Severe mental retardation is a rare complication of Duchenne muscular dystrophy (DMD). Here we report that two DMD cases showing severe mental retardation exhibit the same exon skipping event induced by different intron mutations. In the two Japanese DMD patients studied, the complete sequence of exon 66 of the dystrophin gene was found to be absent from the dystrophin mRNA, creating a premature stop codon in exon 67. Novel point mutations at the consensus sequence of the splice donor site of intron 66 (T9857(+2) to C in one case and G9857(+5) to T in the other case) were found to be the cause of complete exon skipping. Remarkably, severe mental retardation cosegregated with an exon 66-skipping event in their families. Furthermore, pachygyria was disclosed by magnetic resonance imaging (MRI) examination of the brain of one case. Our results suggested that exon 66 skipping should be examined in DMD cases with a severe form of mental retardation.

    Severe mental retardation
    SYMPTOMS

 is a rare complication of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. Here we report that two

    DMD
    DIAGNOSIS

 cases showing

    severe mental retardation
    SYMPTOMS

 exhibit the same

    exon skipping event
    GENETICS

 induced by

    different intron mutations
    GENETICS

. In the two

    Japanese
    ETHNICITY

    DMD
    DIAGNOSIS

 patients studied,

    the complete sequence of exon 66 of the dystrophin gene was found to be absent from the dystrophin mRNA, creating a premature stop codon in exon 67
    GENETICS

.

    Novel point mutations at the consensus sequence of the splice donor site of intron 66 (T9857(+2) to C in
    GENETICS

 one case

    and G9857(+5) to T in
    GENETICS

 the other case

    )
    GENETICS

 were found to be the cause of

    complete exon skipping
    GENETICS

. Remarkably,

    severe mental retardation
    SYMPTOMS

    cosegregated with an exon 66-skipping event in their families
    FAMILY

. Furthermore,

    pachygyria
    SYMPTOMS

 was disclosed by

    magnetic resonance imaging (MRI) examination of the brain
    PARACLINICAL

 of one case. Our results suggested that

    exon 66 skipping
    PARACLINICAL

 should be examined in

    DMD
    DIAGNOSIS

 cases with a

    severe form of mental retardation
    SYMPTOMS

.

Severe mental retardation
severe mental retardation
severe mental retardation
pachygyria
severe form of mental retardation

Duchenne muscular dystrophy (DMD)
DMD
DMD
DMD


Maternal contamination at fetal muscle biopsy.

Duchenne muscular dystrophy (DMD) can be diagnosed by fetal muscle biopsy and immunohistochemical staining showing the absence of dystrophin. We report a case of fetal muscle biopsy in which the needle gun was successfully fired within the fetal gluteal muscle but the sample was contaminated by maternal tissue. This was attributed to the design of the biopsy needle, allowing transient opening of the biopsy core as the needle penetrated the maternal rectus sheath, muscle, and myometrium. Histology showed tissue suggestive of maternal origin, confirmed by DNA analysis. Repeat sampling revealed fetal muscle with normal dystrophin expression. We recommend that care be taken during needle insertion to avoid maternal contamination, and tests be used to confirm the fetal source of the sample.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 can be diagnosed by

    fetal muscle biopsy
    PARACLINICAL

 and

    immunohistochemical staining
    PARACLINICAL

 showing the

    absence of dystrophin
    BIOCHEMICAL

. We report a case of

    fetal muscle biopsy
    PARACLINICAL

 in which the needle gun was successfully fired within the

    fetal gluteal muscle
    AGE

 but the sample was

    contaminated by maternal tissue
    MICROSCOPIC

. This was attributed to the design of the biopsy needle, allowing

    transient opening of the biopsy core
    MEDICATION

 as the

    needle penetrated the maternal rectus sheath, muscle, and myometrium
    MEDICATION

.

    Histology
    PARACLINICAL

 showed

    tissue suggestive of maternal origin
    MICROSCOPIC

, confirmed by

    DNA analysis
    PARACLINICAL

.

    Repeat sampling
    PARACLINICAL

 revealed

    fetal muscle
    MICROSCOPIC

 with

    normal dystrophin expression
    NEG_FINDINGS

. We recommend that care be taken during needle insertion to avoid

    maternal contamination
    SYMPTOMS

, and tests be used to confirm the fetal source of the sample.


Hypertrophic muscular dystrophy in a young dog.

Hypertrophic muscular dystrophy was diagnosed in a 10-month-old male Rat Terrier with hypersalivation, dysphagia, gait abnormalities, and generalized weakness. Serum creatine kinase activity was high, and electromyography revealed myotonic discharges. Histologic examination of a muscle biopsy specimen revealed muscle fiber degeneration, clusters of basophilic regenerating fibers, and endomysial fibrosis. Staining for dystrophin, a sarcolemmal protein, was decreased, compared with that in muscle specimens from clinically normal dogs. Treatment with mexiletene hydrochloride and procainamide hydrochloride resulted in temporary improvement in clinical signs, but the disease became refractory to treatment, and the dog was euthanatized. Clinical and histologic characteristics of this dystrophin deficiency-related muscular dystrophy were similar to those of X-linked muscular dystrophy in dogs, hypertrophic muscular dystrophy in cats, and Duchenne muscular dystrophy in humans.

    Hypertrophic muscular dystrophy
    DIAGNOSIS

 was diagnosed in a

    10-month-old
    AGE

    male
    GENDER

    Rat Terrier
    ETHNICITY

 with

    hypersalivation
    SYMPTOMS

,

    dysphagia
    SYMPTOMS

,

    gait abnormalities
    SYMPTOMS

, and

    generalized weakness
    SYMPTOMS

.

    Serum creatine kinase activity was high
    BIOCHEMICAL

, and

    electromyography
    PARACLINICAL

 revealed

    myotonic discharges
    SYMPTOMS

.

    Histologic examination of a muscle biopsy specimen
    PARACLINICAL

 revealed

    muscle fiber degeneration
    MICROSCOPIC

,

    clusters of basophilic regenerating fibers
    MICROSCOPIC

, and

    endomysial fibrosis
    MICROSCOPIC

.

    Staining for dystrophin, a sarcolemmal protein, was decreased
    BIOCHEMICAL

, compared with that in muscle specimens from

    clinically normal dogs
    NEG_FINDINGS

.

    Treatment with mexiletene hydrochloride and procainamide hydrochloride
    MEDICATION

 resulted in

    temporary improvement in clinical signs
    SYMPTOMS

, but the disease became

    refractory to treatment
    NEG_FINDINGS

, and the

    dog
    GENDER

 was

    euthanatized
    MEDICATION

. Clinical and histologic characteristics of this

    dystrophin deficiency-related muscular dystrophy
    DIAGNOSIS

 were similar to those of

    X-linked muscular dystrophy
    DIAGNOSIS

 in

    dogs
    GENDER

,

    hypertrophic muscular dystrophy
    DIAGNOSIS

 in

    cats
    GENDER

, and

    Duchenne muscular dystrophy
    DIAGNOSIS

 in

    humans
    GENDER

.

hypersalivation
dysphagia
gait abnormalities
generalized weakness
myotonic discharges
temporary improvement in clinical signs

clinically normal dogs
refractory to treatment


An atypical kindred with X-linked adrenal hypoplasia congenita, normal puberty, and normal Dax-1 promoter and coding sequence.

We report a Chinese kindred with an atypical sex-linked form of isolated adrenal hypoplasia without hypogonadotropic hypogonadism. Evidence of sex linkage was supported by DNA analysis using three polymorphic markers from the X-chromosome: a restriction fragment length polymorphism 200 kb centromeric of the DAX-1 gene, a tetranucleotide repeat marker in the DAX-1 promoter (DAX-P), and a microsatellite in the Duchenne muscular dystrophy locus (3'-19). This pedigree therefore presents the novel phenotype of sex-linked hypoadrenalism without hypogonadotropic hypogonadism, with evidence of possible linkage to the DAX-1 gene. However, all three affected individuals were examined for mutations in the DAX-1 gene, and found to have no sequence anomalies in the coding region, splice sites or 5' non-coding region. This presentation may be due to a defect in the DAX-1 gene outside its known coding region, possibly modulated by functional polymorphisms at other loci, and/or environmental effects, or to a defect in a novel gene on the X chromosome which selectively influences adrenal development.

We report a

    Chinese
    ETHNICITY

    kindred
    FAMILY

 with an

    atypical sex-linked form of isolated adrenal hypoplasia
    SYMPTOMS

    without hypogonadotropic hypogonadism
    NEG_FINDINGS

. Evidence of

    sex linkage
    GENETICS

 was supported by

    DNA analysis
    PARACLINICAL

 using three

    polymorphic markers from the X-chromosome
    GENETICS

: a

    restriction fragment length polymorphism 200 kb centromeric of the DAX-1 gene, a tetranucleotide repeat marker in the DAX-1 promoter (DAX-P)
    GENETICS

, and a

    microsatellite in the Duchenne muscular dystrophy locus (3'-19)
    GENETICS

. This pedigree therefore presents the novel phenotype of

    sex-linked hypoadrenalism
    SYMPTOMS

    without hypogonadotropic hypogonadism
    NEG_FINDINGS

, with evidence of

    possible linkage to the DAX-1 gene
    GENETICS

. However, all three affected individuals were examined for

    mutations in the DAX-1 gene
    NEG_FINDINGS

, and found to have

    no sequence anomalies in the coding region, splice sites or 5' non-coding region
    NEG_FINDINGS

. This presentation may be due to a

    defect in the DAX-1 gene outside its known coding region
    GENETICS

, possibly modulated by

    functional polymorphisms at other loci
    GENETICS

, and/or environmental effects, or to a

    defect in a novel gene on the X chromosome
    GENETICS

 which selectively influences

    adrenal development
    GENETICS

.


A female carrier of Duchenne muscular dystrophy complicated with cardiomyopathy.

A 45-year-old female carrier of Duchenne muscular dystrophy (DMD) complicated with cardiomyopathy is described. She had no symptoms of muscle weakness or heart failure. Her chest X-ray film revealed marked cardiomegaly. Echocardiogram showed marked enlargement and severe hypokinesis of the left ventricle. In myocardial scintigraphic images, perfusion defects of the myocardium were revealed. Dystrophin immunostaining of myocardial biopsy specimens showed a mosaic pattern of dystrophin-negative and -positive fibers. Cardiomyopathy is sometimes the only clinical symptom in female carriers of DMD. They are thought to be in a high risk group for developing heart failure.

A

    45-year-old
    AGE

    female
    GENDER

 carrier of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 complicated with

    cardiomyopathy
    DIAGNOSIS

 is described.

    She
    GENDER

 had

    no symptoms of muscle weakness or heart failure
    NEG_FINDINGS

.

    Her
    GENDER

    chest X-ray film
    PARACLINICAL

 revealed

    marked cardiomegaly
    SYMPTOMS

.

    Echocardiogram
    PARACLINICAL

 showed

    marked enlargement and severe hypokinesis of the left ventricle
    SYMPTOMS

. In

    myocardial scintigraphic images
    PARACLINICAL

,

    perfusion defects of the myocardium
    SYMPTOMS

 were revealed.

    Dystrophin immunostaining of myocardial biopsy specimens
    PARACLINICAL

 showed a

    mosaic pattern of dystrophin-negative and -positive fibers
    MICROSCOPIC

.

    Cardiomyopathy
    SYMPTOMS

 is sometimes the only clinical symptom in

    female
    GENDER

 carriers of

    DMD
    DIAGNOSIS

. They are thought to be in a high risk group for developing

    heart failure
    SYMPTOMS

.

Duchenne muscular dystrophy (DMD)
cardiomyopathy
DMD


Noval mutation (Y184C) in exon 4 of the beta-sarcoglycan gene identified in a Portuguese patient. Mutations in brief no. 177. Online.

We report a novel beta-sarcoglycan gene mutation identified in a 21-year-old Portuguese male with a progressive myopathy of intermediate severity, who had been misdiagnosed as Becker Muscular Dystrophy (BMD) based on clinical observations and muscle immunocytochemical anaylsis with dystrophin antibodies only. Since no detectable deletions or duplications were found in the dystrophin gene, we screened for mutations in the sarcoglycan genes by PCR-SSCP. The patient's sample showed a band of increased mobility in exon 4 of the beta-sarcoglycan gene which, upon sequencing, was found to represent a homozygous A-->G transversion at nucleotide 551, resulting in a tyrosine to cysteine substitution at position 184 (Y184C). Carrier status was ascertained in both parents and a sister. These aberrant conformers were not detected in 85 unrelated control individuals screened by PCR-SSCP analysis. All seven beta-sarcoglycan mutations reported to date are associated with a severe phenotype and occur in exons 3 and 4, which correspond to the immediate extracellular domain of the protein. This region contains five conserved cysteine residues. In our patient, the presence of an extra cysteine residue could interefere with intra- and/or inter-molecular disulphide bond formation. The intermediate phenotype could perhaps result from the assembly of both normal and abnormal complexes, depending on the formation of the disulphide bonds.

We report a

    novel beta-sarcoglycan gene mutation
    GENETICS

 identified in a

    21-year-old
    AGE

    Portuguese
    ETHNICITY

    male
    GENDER

 with a

    progressive myopathy of intermediate severity
    SYMPTOMS

, who had been

    misdiagnosed as Becker Muscular Dystrophy (BMD)
    NEG_FINDINGS

 based on clinical observations and

    muscle immunocytochemical anaylsis
    PARACLINICAL

 with

    dystrophin antibodies
    PARACLINICAL

 only. Since

    no detectable deletions or duplications were found in the dystrophin gene
    NEG_FINDINGS

, we screened for

    mutations in the sarcoglycan genes
    GENETICS

 by

    PCR-SSCP
    PARACLINICAL

. The patient's sample showed a

    band of increased mobility in exon 4 of the beta-sarcoglycan gene
    GENETICS

 which, upon sequencing, was found to represent a

    homozygous A-->G transversion at nucleotide 551, resulting in a tyrosine to cysteine substitution at position 184 (Y184C)
    GENETICS

.

    Carrier status was ascertained in both parents and a sister
    FAMILY

. These aberrant conformers were not detected in 85 unrelated control individuals screened by

    PCR-SSCP analysis
    PARACLINICAL

. All seven

    beta-sarcoglycan mutations
    GENETICS

 reported to date are associated with a severe phenotype and occur

    in exons 3 and 4, which correspond to the immediate extracellular domain of the protein
    GENETICS

. This region contains

    five conserved cysteine residues
    GENETICS

. In our patient, the presence of an

    extra cysteine residue
    GENETICS

 could interefere with intra- and/or

    inter-molecular disulphide bond formation
    BIOCHEMICAL

. The intermediate phenotype could perhaps result from the assembly of both normal and abnormal complexes, depending on the formation of the disulphide bonds.


[Epidural anesthesia and general anesthesia using the cuffed oropharyngeal airway for an obese patient with Duchenne's muscular dystrophy].

Duchenne's muscular dystrophy is a genetic disorder whose features include abnormal responses to muscular relaxants and possible respiratory dysfunction after general anesthesia. The purpose of this report is to describe one management strategy used successfully to anesthetize an obese man with this disorder for atypical mastectomy. The anesthetic management during surgery involves epidural anesthesia using 2% mepivacaine and general anesthesia using the cuffed oropharyngeal airway. Postoperatively 0.25% bupivacaine was infused for epidural analgesia. The patient was observed in the intensive care unit until the first postoperative day and showed an uncomplicated intra- and post-operative course.

    Duchenne's muscular dystrophy
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 whose features include

    abnormal responses to muscular relaxants
    SYMPTOMS

 and possible

    respiratory dysfunction
    SYMPTOMS

 after

    general anesthesia
    MEDICATION

. The purpose of this report is to describe one management strategy used successfully to

    anesthetize
    MEDICATION

 an

    obese
    AGE

    man
    GENDER

 with this disorder for

    atypical mastectomy
    MEDICATION

. The

    anesthetic management during surgery
    MEDICATION

 involves

    epidural anesthesia using 2% mepivacaine
    MEDICATION

 and

    general anesthesia using the cuffed oropharyngeal airway
    MEDICATION

.

    Postoperatively 0.25% bupivacaine was infused for epidural analgesia
    MEDICATION

. The patient was

    observed in the intensive care unit
    MEDICATION

 until the first postoperative day and showed an uncomplicated intra- and post-operative course.


Response to vecuronium in a patient with facioscapulohumeral muscular dystrophy.

Increased sensitivity to vecuronium has been noted in patients with Duchenne muscular dystrophy. We report the response to vecuronium in a patient with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disorder with an incidence of 10-20 cases per million. In this patient, sensitivity to an initial dose of vecuronium (0.02 + 0.08 mg kg-1) was normal, but recovery was faster and the effect of incremental doses of vecuronium (0.02 mg kg-1) was less than expected. Onset time and 25% recovery of T1/T0 after the intubating dose of vecuronium were 240 s and 22 min, respectively. Recovery index (spontaneous recovery of T1/T0 from 25% to 75%) was 9 min.

    Increased sensitivity to vecuronium
    SYMPTOMS

 has been noted in patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

. We report the response to

    vecuronium
    MEDICATION

 in a patient with

    facioscapulohumeral muscular dystrophy (FSHD)
    DIAGNOSIS

, an

    autosomal dominant disorder
    GENETICS

 with an incidence of 10-20 cases per million. In this patient,

    sensitivity to an initial dose of vecuronium (0.02 + 0.08 mg kg-1) was normal
    NEG_FINDINGS

, but recovery was faster and the effect of incremental

    doses of vecuronium (0.02 mg kg-1) was less than expected
    MEDICATION

. Onset time and

    25% recovery of T1/T0
    SYMPTOMS

 after the

    intubating dose of vecuronium
    MEDICATION

 were 240 s and 22 min, respectively.

    Recovery index (spontaneous recovery of T1/T0 from 25% to 75%)
    SYMPTOMS

 was 9 min.


Cardiac involvement in Becker's muscular dystrophy, necessitating heart transplantation, 6 years before apparent skeletal muscle involvement.

In Becker's muscular dystrophy cardiac abnormalities usually occur after onset of neuromuscular symptoms. We describe a Becker muscular dystrophy patient in whom chronic heart failure, necessitating cardiac transplantation, was the initial manifestation. Neuromuscular symptoms occurred not earlier than 6 years after the initial cardiac symptoms and 5 years after heart transplantation. In conclusion, severe heart failure due to dilated cardiomyopathy may be the initial manifestation of Becker's muscular dystrophy and may predate neuromuscular symptoms for years.

In

    Becker's muscular dystrophy
    DIAGNOSIS

    cardiac abnormalities
    SYMPTOMS

 usually occur after onset of

    neuromuscular symptoms
    SYMPTOMS

. We describe a

    Becker muscular dystrophy
    DIAGNOSIS

 patient in whom

    chronic heart failure
    SYMPTOMS

, necessitating

    cardiac transplantation
    MEDICATION

, was the initial manifestation.

    Neuromuscular symptoms
    SYMPTOMS

 occurred not earlier than 6 years after the

    initial cardiac symptoms
    SYMPTOMS

 and 5 years after

    heart transplantation
    MEDICATION

. In conclusion,

    severe heart failure
    SYMPTOMS

 due to

    dilated cardiomyopathy
    SYMPTOMS

 may be the initial manifestation of

    Becker's muscular dystrophy
    DIAGNOSIS

 and may predate

    neuromuscular symptoms
    SYMPTOMS

 for years.

Becker's muscular dystrophy
Becker muscular dystrophy
Becker's muscular dystrophy

cardiac abnormalities
neuromuscular symptoms
chronic heart failure
Neuromuscular symptoms
initial cardiac symptoms
severe heart failure
dilated cardiomyopathy
neuromuscular symptoms

cardiac transplantation
heart transplantation


IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies.

We report three boys with adrenal hypoplasia congenita (AHC) and additional findings that represent a new syndrome, IMAGe: Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after birth with growth retardation and severe adrenal insufficiency. Each of the three patients had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all three and epiphyseal dysplasia in two. The patients had documented or suspected hypercalciuria and/or hypercalcemia, resulting in nephrocalcinosis in one and in prenatal liver and spleen calcifications in another. AHC presents most often either as an isolated abnormality, caused by mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome, caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes. All three patients with the IMAGe association had normal creatine kinase levels and no evidence of glycerol kinase deficiency. Sequence analysis of DNA from these patients revealed no mutation in the DAX1- or steroidogenic factor-1-coding sequences, nor was a deletion of DAX1 detected. Identification of the molecular basis of the IMAGe association will give new insight into the pathogenesis of this syndromic relationship involving bone, adrenal cortical, and pituitary development.

We report three

    boys
    GENDER

 with

    adrenal hypoplasia congenita (AHC)
    DIAGNOSIS

 and additional findings that represent a new syndrome, IMAGe:

    Intrauterine growth retardation
    SYMPTOMS

,

    Metaphyseal dysplasia
    SYMPTOMS

,

    AHC
    DIAGNOSIS

, and

    Genital anomalies
    SYMPTOMS

. Each presented

    shortly after birth
    AGE

 with

    growth retardation
    SYMPTOMS

 and

    severe adrenal insufficiency
    SYMPTOMS

. Each of the three patients had

    mild dysmorphic features
    SYMPTOMS

,

    bilateral cryptorchidism
    SYMPTOMS

, a

    small penis
    SYMPTOMS

, and

    hypogonadotropic hypogonadism
    SYMPTOMS

.

    Skeletal surveys
    PARACLINICAL

 revealed

    metaphyseal dysplasia
    SYMPTOMS

 in all three and

    epiphyseal dysplasia
    SYMPTOMS

 in two. The patients had documented or suspected

    hypercalciuria
    BIOCHEMICAL

 and/or

    hypercalcemia
    BIOCHEMICAL

, resulting in

    nephrocalcinosis
    BIOCHEMICAL

 in one and in

    prenatal liver and spleen calcifications
    SYMPTOMS

 in another.

    AHC
    DIAGNOSIS

 presents most often either as an isolated abnormality, caused by

    mutations in the DAX1 gene
    GENETICS

, or as part of an

    Xp21 contiguous gene syndrome
    GENETICS

, caused by a

    deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes
    GENETICS

. All three patients with the

    IMAGe association
    DIAGNOSIS

 had

    normal creatine kinase levels
    NEG_FINDINGS

 and

    no evidence of glycerol kinase deficiency
    NEG_FINDINGS

.

    Sequence analysis of DNA from
    PARACLINICAL

 these patients revealed

    no mutation in the DAX1- or steroidogenic factor-1-coding sequences
    NEG_FINDINGS

, nor was a

    deletion of DAX1 detected
    NEG_FINDINGS

. Identification of the molecular basis of the

    IMAGe association
    DIAGNOSIS

 will give new insight into the pathogenesis of this

    syndromic relationship
    DIAGNOSIS

 involving

    bone, adrenal cortical, and pituitary development
    SYMPTOMS

.

adrenal hypoplasia congenita (AHC)
AHC
AHC
IMAGe association
IMAGe association
syndromic relationship


Duchenne muscular dystrophy and concomitant metastatic alveolar rhabdomyosarcoma.

The authors report the concomitant occurrence of Duchenne muscular dystrophy (DMD) and alveolar rhabdomyosarcoma (RMS). A 4-year-old boy presented with symptoms involving his neuromuscular system that affected primarily his left hip and leg. Duchenne muscular dystrophy was diagnosed. Seven months later, metastatic alveolar RMS in the ipsilateral pelvis was documented. The diagnosis of one major disorder affecting striated muscle (DMD) may have prevented the early detection of another (RMS).

The authors report the

    concomitant occurrence of Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    alveolar rhabdomyosarcoma (RMS)
    DIAGNOSIS

. A

    4-year-old
    AGE

    boy
    GENDER

 presented with

    symptoms involving his neuromuscular system that affected primarily his left hip and leg
    SYMPTOMS

.

    Duchenne muscular dystrophy
    DIAGNOSIS

 was diagnosed. Seven months later,

    metastatic alveolar RMS in the ipsilateral pelvis
    DIAGNOSIS

 was documented. The diagnosis of one

    major disorder affecting striated muscle (DMD)
    DIAGNOSIS

 may have prevented the early detection of another (

    RMS)
    DIAGNOSIS

.


Clinical characteristics of aged Becker muscular dystrophy patients with onset after 30 years.

To elucidate the clinical characteristics of aged patients with Becker muscular dystrophy (BMD), 4 patients with this disease who were over 50 years were examined. The ages at onset in all patients were later than 30 years. All were proven to have a deletion around exons 45-55 of the Duchenne muscular dystrophy (DMD) gene. Two patients became wheelchair bound in their 40s or beyond, while the other 2 (aged 73 and 69, respectively) were still able to walk at the time of examination. Three of 4 patients had no obvious hypertrophy in their calves, which is known to be one of the characteristic clinical features in the juvenile BMD patients. Serum creatine kinase levels were elevated in all patients, but not markedly (mean 444.8 +/- 230.3 U/l; normal value < 180 U/l). Dilated cardiomyopathy was clinically apparent in 2 patients. We emphasize that some BMD patients are free of muscular symptoms until their 50s and are still self-supporting in their 60s or 70s.

To elucidate the clinical characteristics of

    aged
    AGE

 patients with

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

, 4 patients with this disease who were

    over 50 years
    AGE

 were examined. The

    ages at onset
    AGE

 in all patients were

    later than 30 years
    AGE

. All were proven to have a

    deletion around exons 45-55 of the Duchenne muscular dystrophy (DMD) gene
    GENETICS

. Two patients became

    wheelchair bound
    MEDICATION

    in their 40s or beyond
    AGE

, while the other 2 (

    aged 73
    AGE

 and

    69
    AGE

, respectively) were

    still able to walk
    NEG_FINDINGS

 at the time of examination. Three of 4 patients had

    no obvious hypertrophy in their calves
    NEG_FINDINGS

, which is known to be one of the characteristic clinical features in the

    juvenile
    AGE

    BMD
    DIAGNOSIS

 patients.

    Serum creatine kinase levels were elevated
    BIOCHEMICAL

 in all patients, but

    not markedly (mean 444.8 +/- 230.3 U/l; normal value < 180 U/l)
    BIOCHEMICAL

.

    Dilated cardiomyopathy
    SYMPTOMS

 was clinically apparent in 2 patients. We emphasize that some

    BMD
    DIAGNOSIS

 patients are

    free of muscular symptoms
    NEG_FINDINGS

 until

    their 50s
    AGE

 and are still self-supporting in

    their 60s or 70s
    AGE

.

still able to walk
no obvious hypertrophy in their calves
free of muscular symptoms


Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families.

Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen's disease, one (Q658X) in a family with Becker's disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease.

    Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35
    GENETICS

, lead to

    recessive and dominant myotonia congenita
    DIAGNOSIS

. We report four novel mutations identified in this gene, after

    clinical, electromyographic, and genetic studies
    PARACLINICAL

 performed on 13 unrelated families. Two of the

    four mutations (2512insCTCA and A218T)
    GENETICS

 were identified in

    families with Thomsen's disease
    FAMILY

, one (

    Q658X)
    GENETICS

 in a

    family with Becker's disease
    FAMILY

, and the fourth (

    R669C)
    GENETICS

 in a presumably sporadic patient with the

    Becker
    DIAGNOSIS

 phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease.


Fetal muscle biopsy as a diagnostic tool in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a relentless progressive disorder, leading to severe disability during childhood and death in adolescence or early adulthood. In most families, prenatal diagnosis is readily achieved by molecular detection of DNA deletions using chorionic villi or amniocytes, or by linkage analysis. In some cases, however, molecular methods fail to provide a definitive diagnosis and in such cases in utero fetal muscle biopsy may serve as a diagnostic option. We describe three families in whom fetal muscle biopsy was performed, focusing on the prenatal diagnostic dilemmas, the indications and timing for in utero fetal muscle biopsy, and the difficulties encountered.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 is a

    relentless progressive disorder
    DIAGNOSIS

, leading to

    severe disability
    SYMPTOMS

    during childhood
    AGE

 and

    death
    SYMPTOMS

    in adolescence or early adulthood
    AGE

. In most families,

    prenatal diagnosis
    PARACLINICAL

 is readily achieved by

    molecular detection of DNA deletions using chorionic villi or amniocytes
    PARACLINICAL

, or by

    linkage analysis
    PARACLINICAL

. In some cases, however,

    molecular methods fail to
    NEG_FINDINGS

 provide a definitive diagnosis and in such cases

    in utero fetal muscle biopsy
    PARACLINICAL

 may serve as a diagnostic option. We describe three families in whom

    fetal muscle biopsy
    PARACLINICAL

 was performed, focusing on the prenatal diagnostic dilemmas, the indications and timing for

    in utero fetal muscle biopsy
    PARACLINICAL

, and the difficulties encountered.

Duchenne muscular dystrophy (DMD)
relentless progressive disorder


[Effective milrinone therapy to a Duchenne muscular dystrophy patient with advanced congestive heart failure].

We experienced a Duchenne muscular dystrophy (DMD) patient with severe congestive heart failure (CHF) successfully treated with milrinone. He had been diagnosed as having CHF since 24 years of age when he began to have mechanical ventilation with a nasal mask at home. Although angiotensin converting enzyme (ACE) inhibitor was effective for his CHF, cardiac function worsened year by year. Respiratory infection triggered the exacerbation of CHF at the end of 1997 (27 years old). On admission to our hospital on January 7, 1998, PaO2 was 48 mmHg and cardiothoracic ratio (CTR) was 62%. Both ventricles were dilated and ventricular wall motility was markedly reduced on ultrasonocardiography. Ejection fraction of the left ventricle (LVEF) was 5%. Serum brain natriuretic peptide (BNP) was 760 pg/ml. Continuous intravenous infusion of milrinone was started on January 8 at the rate of 0.25-0.35 microgram/kg/min. His general condition improved and LVEF increased up to 15% on January 27. No serious side effects were observed. Even after milrinone withdrawal, his cardiac condition remained stable until the end of February 1998. Temporary deteriorated CHF due to urinary tract infection was successfully treated by chemotherapy and milrinone. Subsequently he was discharged on March 13 and could stay in his home for 7 weeks uneventfully with milrinone infusion therapy. When he was readmitted to the hospital for evaluation of CHF on April 30, CTR was 44%, LVEF was 20% and BNP was 44 pg/ml. CHF is one of the life threatening complications for DMD. Although catecholamine is a well utilized agent for advanced CHF, it has limited effect in DMD, because beta receptors are down-regulated due to long-lasting cardiac dysfunction. Increased heart rate and arrhytmia are also serious problems during catecholamine therapy. Milrinone is a type III phosphodiesterase inhibitor having inotropic and vasodilatic actions with modest increase of heart rate and little torelance. Milrinone is probably effective in improving CHF of DMD and has less side effects as compared to catecholamine. We concluded that milrinone might improve quality of lives of DMD patients with advanced CHF, although further cumultative studies are necessary to confirm its effectiveness and safety.

We experienced a

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patient with

    severe congestive heart failure (CHF)
    DIAGNOSIS

 successfully treated with

    milrinone
    MEDICATION

.

    He
    GENDER

 had been diagnosed as having

    CHF
    DIAGNOSIS

 since

    24 years of age
    AGE

 when

    he
    GENDER

 began to have

    mechanical ventilation with a nasal mask
    MEDICATION

 at home. Although

    angiotensin converting enzyme (ACE) inhibitor
    MEDICATION

 was effective for his

    CHF
    DIAGNOSIS

,

    cardiac function worsened
    SYMPTOMS

 year by year.

    Respiratory infection
    SYMPTOMS

 triggered the

    exacerbation of CHF
    SYMPTOMS

 at the end of

    1997
    AGE

 (

    27 years old
    AGE

). On admission to our hospital on January 7, 1998,

    PaO2 was 48 mmHg
    BIOCHEMICAL

 and

    cardiothoracic ratio (CTR) was 62%
    SYMPTOMS

.

    Both ventricles were dilated
    SYMPTOMS

 and

    ventricular wall motility was markedly reduced
    SYMPTOMS

 on

    ultrasonocardiography
    PARACLINICAL

.

    Ejection fraction of the left ventricle (LVEF) was 5%
    SYMPTOMS

.

    Serum brain natriuretic peptide (BNP) was 760 pg/ml
    BIOCHEMICAL

.

    Continuous intravenous infusion of milrinone
    MEDICATION

 was started on January 8

    at the rate of 0.25-0.35 microgram/kg/min
    MEDICATION

. His

    general condition improved
    SYMPTOMS

 and

    LVEF increased up to 15%
    SYMPTOMS

 on January 27.

    No serious side effects
    NEG_FINDINGS

 were observed.

    Even after milrinone withdrawal
    NEG_FINDINGS

, his

    cardiac condition remained stable
    SYMPTOMS

 until the end of February 1998.

    Temporary deteriorated CHF
    SYMPTOMS

 due to

    urinary tract infection
    SYMPTOMS

 was successfully treated by

    chemotherapy and milrinone
    MEDICATION

. Subsequently

    he
    GENDER

 was discharged on March 13 and

    could stay in his home for 7 weeks
    MEDICATION

 uneventfully with

    milrinone infusion therapy
    MEDICATION

. When

    he
    GENDER

 was readmitted to the hospital for evaluation of

    CHF
    DIAGNOSIS

 on April 30,

    CTR was 44%
    SYMPTOMS

,

    LVEF was 20%
    SYMPTOMS

 and

    BNP was 44 pg/ml
    BIOCHEMICAL

.

    CHF
    DIAGNOSIS

 is one of the life threatening complications for

    DMD
    DIAGNOSIS

. Although

    catecholamine
    MEDICATION

 is a well utilized agent for

    advanced CHF
    DIAGNOSIS

, it has limited effect in

    DMD
    DIAGNOSIS

, because

    beta receptors are down-regulated
    BIOCHEMICAL

 due to

    long-lasting cardiac dysfunction
    SYMPTOMS

.

    Increased heart rate
    SYMPTOMS

 and

    arrhytmia
    SYMPTOMS

 are also serious problems during

    catecholamine therapy
    MEDICATION

.

    Milrinone
    MEDICATION

 is a

    type III phosphodiesterase inhibitor
    MEDICATION

 having

    inotropic and vasodilatic actions
    SYMPTOMS

 with

    modest increase of heart rate
    SYMPTOMS

 and

    little torelance
    NEG_FINDINGS

.

    Milrinone
    MEDICATION

 is probably effective in improving

    CHF
    DIAGNOSIS

 of

    DMD
    DIAGNOSIS

 and has less side effects as compared to

    catecholamine
    MEDICATION

. We concluded that

    milrinone
    MEDICATION

 might improve quality of lives of

    DMD
    DIAGNOSIS

 patients with

    advanced CHF
    DIAGNOSIS

, although further cumultative studies are necessary to confirm its effectiveness and safety.

Duchenne muscular dystrophy (DMD)
severe congestive heart failure (CHF)
CHF
CHF
CHF
CHF
DMD
advanced CHF
DMD
CHF
DMD
DMD
advanced CHF

No serious side effects
Even after milrinone withdrawal
little torelance


A simple explanation for a case of incompatibility with the reading frame theory in Duchenne muscular dystrophy: failure to detect an aberrant restriction fragment in Southern blot analysis.

According to the translational reading frame theory, Duchenne muscular dystrophy (DMD) patients harbor out-of-frame deletion mutations in the dystrophin gene. We identified a Japanese DMD case who appeared to have an in-frame deletion of exons 46-54 that was disclosed by Southern blot analysis using a dystrophin cDNA as a probe. Analysis of dystrophin mRNA in skeletal muscle revealed the presence of an out-of-frame deletion of exons 46-53. In agreement with this result, the region encompassing exon 54 could be amplified from genomic DNA by polymerase chain reaction (PCR). Furthermore, re-analysis by Southern blot using an exon specific probe disclosed that a HindIII fragment containing exon 54 was present at aberrant size, leading to the incorrect conclusion that exon 54 had been deleted. Thus, this particular DMD case does not constitute an exception to the reading frame theory.

According to the translational reading frame theory,

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patients harbor

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

. We identified a

    Japanese
    ETHNICITY

    DMD
    DIAGNOSIS

 case who appeared to have an

    in-frame deletion of exons 46-54
    GENETICS

 that was disclosed by

    Southern blot analysis using a dystrophin cDNA as a probe
    PARACLINICAL

.

    Analysis of dystrophin mRNA in skeletal muscle
    PARACLINICAL

 revealed the

    presence of an out-of-frame deletion of exons 46-53
    GENETICS

. In agreement with this result, the

    region encompassing exon 54 could be amplified from genomic DNA by polymerase chain reaction (PCR)
    PARACLINICAL

. Furthermore,

    re-analysis by Southern blot using an exon specific probe
    PARACLINICAL

 disclosed that a

    HindIII fragment containing exon 54 was present at aberrant size
    GENETICS

, leading to the

    incorrect conclusion that exon 54 had been deleted
    NEG_FINDINGS

. Thus, this particular

    DMD
    DIAGNOSIS

 case does not constitute an exception to the reading frame theory.

Duchenne muscular dystrophy (DMD)
DMD
DMD


Multiple episodes of thrombosis in a patient with Becker muscular dystrophy with marked expression of utrophin on the muscle cell membrane.

We previously reported a patient with Becker muscular dystrophy (BMD) who exhibited a benign clinical phenotype and marked expression of utrophin on the muscle cell membrane. The patient developed multiple episodes of thrombosis (middle cerebral and femoral arteries) in the course of the disease. We re-examined the biopsy muscle specimen from the patient immunohistochemically as to the expression of procoagulant or anticoagulant factors. We found a lower expression of thrombomodulin on the muscle cell membrane in the BMD patient compared with other BMD or Duchenne muscular dystrophy (DMD) patients. Although utrophin up-regulation in muscle is thought to prevent the muscle wasting in dystrophin-deficient DMD or BMD, the data obtained in the present study indicate that up-regulated utrophin may have an unexpected influence on the function of the vascular or coagulation system.

We previously reported a patient with

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 who exhibited a

    benign clinical phenotype
    SYMPTOMS

 and

    marked expression of utrophin on the muscle cell membrane
    MICROSCOPIC

. The patient developed

    multiple episodes of thrombosis (middle cerebral and femoral arteries)
    SYMPTOMS

 in the course of the disease. We

    re-examined the biopsy muscle specimen
    PARACLINICAL

 from the patient immunohistochemically as to the

    expression of procoagulant or anticoagulant factors
    BIOCHEMICAL

. We found a

    lower expression of thrombomodulin on the muscle cell membrane
    BIOCHEMICAL

 in the

    BMD
    DIAGNOSIS

 patient compared with other

    BMD
    DIAGNOSIS

 or

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patients. Although

    utrophin up-regulation
    BIOCHEMICAL

    in muscle
    MICROSCOPIC

 is thought to prevent the

    muscle wasting
    SYMPTOMS

 in

    dystrophin-deficient DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

, the data obtained in the present study indicate that

    up-regulated utrophin
    GENETICS

 may have an unexpected influence on the function of the vascular or

    coagulation system
    BIOCHEMICAL

.

Becker muscular dystrophy (BMD)
BMD
BMD
Duchenne muscular dystrophy (DMD)
dystrophin-deficient DMD
BMD


Botulinum toxin for amelioration of knee contracture in Duchenne muscular dystrophy.

An 11-year-old non-ambulant boy with Duchenne muscular dystrophy developed tightness in his left knee flexors, which caused difficulties in standing exercises. Botulinum toxin A (BTX-A) was injected into the medial and lateral hamstring muscles and the range of motion increased by 20 degrees but after 5 months, when the pharmacological effect of BTX-A had vanished, an increase of only 5 degrees in range compared with the initial finding was left. It is concluded that there may be a role for BTX-A in controlling contractures in Duchenne muscular dystrophy.

An

    11-year-old
    AGE

    non-ambulant
    NEG_FINDINGS

    boy
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 developed

    tightness in his left knee flexors
    SYMPTOMS

, which caused

    difficulties in standing exercises
    NEG_FINDINGS

.

    Botulinum toxin A (BTX-A) was injected into the medial and lateral hamstring muscles
    MEDICATION

 and the

    range of motion increased by 20 degrees
    SYMPTOMS

 but after 5 months, when

    the pharmacological effect of BTX-A had vanished
    NEG_FINDINGS

,

    an increase of only 5 degrees in range compared with the initial finding was left
    SYMPTOMS

. It is concluded that there may be a role for

    BTX-A
    MEDICATION

 in controlling

    contractures
    SYMPTOMS

 in

    Duchenne muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy
Duchenne muscular dystrophy


A case of McLeod syndrome with unusually severe myopathy.

A 51-year-old man developed weakness and muscle atrophy in the legs at the age of 41, later followed by choreiform involuntary movements. Neurological and laboratory examinations revealed severe muscle weakness and atrophy, and areflexia in all the extremities, acanthocytosis and an elevated serum creatine kinase level. Together with these findings, the weak expression of Kell blood group antigens and the absence of the Kx antigen led to a definite diagnosis of McLeod syndrome for his condition. Brain magnetic resonance imaging revealed marked atrophy of the head of the caudate nuclei. Although immunocytochemical analysis of dystrophin in muscle specimens from our patient revealed normal staining, we found prominent fiber size variability, central nuclei, and connective tissue proliferation as well as necrotic and regenerating fibers, which are as a whole compatible with the myopathology of muscular dystrophy. Moreover, muscle computerized tomography of the lower extremities revealed the 'selectivity pattern' characteristically reported in muscular dystrophies including Duchenne type muscular dystrophy. The muscular symptoms and pathology in McLeod syndrome have been reported to be mild, but the present case clearly shows that the muscular features in this condition may be much more severe than previously thought.

A

    51-year-old
    AGE

    man
    GENDER

 developed

    weakness and muscle atrophy in the legs
    SYMPTOMS

 at the

    age of 41
    AGE

, later followed by

    choreiform involuntary movements
    SYMPTOMS

.

    Neurological and laboratory examinations
    PARACLINICAL

 revealed

    severe muscle weakness and atrophy
    SYMPTOMS

, and

    areflexia in all the extremities
    SYMPTOMS

,

    acanthocytosis
    BIOCHEMICAL

 and an

    elevated serum creatine kinase level
    BIOCHEMICAL

. Together with these findings, the

    weak expression of Kell blood group antigens
    BIOCHEMICAL

 and the

    absence of the Kx antigen
    BIOCHEMICAL

 led to a definite diagnosis of

    McLeod syndrome
    DIAGNOSIS

 for his condition.

    Brain magnetic resonance imaging
    PARACLINICAL

 revealed

    marked atrophy of the head of the caudate nuclei
    SYMPTOMS

. Although

    immunocytochemical analysis of dystrophin in muscle specimens
    PARACLINICAL

 from our patient

    revealed normal staining
    NEG_FINDINGS

, we found

    prominent fiber size variability, central nuclei, and connective tissue proliferation
    MICROSCOPIC

 as well as

    necrotic and regenerating fibers
    MICROSCOPIC

, which are as a whole compatible with the

    myopathology of muscular dystrophy
    DIAGNOSIS

. Moreover,

    muscle computerized tomography of the lower extremities
    PARACLINICAL

 revealed

    the 'selectivity pattern' characteristically reported in muscular dystrophies
    SYMPTOMS

 including

    Duchenne type muscular dystrophy
    DIAGNOSIS

. The

    muscular symptoms and pathology
    SYMPTOMS

 in

    McLeod syndrome
    DIAGNOSIS

 have been reported to be mild, but the present case clearly shows that the

    muscular features
    SYMPTOMS

 in this condition may be much more severe than previously thought.

McLeod syndrome
myopathology of muscular dystrophy
Duchenne type muscular dystrophy
McLeod syndrome