Dystrophin analysis in duchenne muscular dystrophy: use in fetal diagnosis and in genetic counseling.

In this report we describe the use of dystrophin analysis both in the diagnosis of Duchenne muscular dystrophy (DMD) in an aborted fetus and in genetic counseling. Our consultand's initial carrier risk, as based on family history and creatine kinase determinations, was calculated as 0.6%. DNA analysis of her family (and fetus) modified this risk to 8.5%. Skeletal muscle of the 23-wk male abortus was found to be histologically indistinguishable from that of age-matched controls. However, immunoblot testing for dystrophin indicated that the fetus had indeed inherited dystrophin deficiency. The carrier risk of the consultand was thus elevated to 100%. Dystrophin assays should be employed whenever the diagnosis of fetal DMD is equivocal (e.g., cases in which a gene deletion cannot be identified). Assay results are crucial for genetic counseling for subsequent pregnancies and for studies of the early pathogenesis of muscular dystrophy.

In this report we describe the use of

    dystrophin analysis
    PARACLINICAL

 both in the diagnosis of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 in an

    aborted fetus
    DIAGNOSIS

 and in

    genetic counseling
    MEDICATION

. Our consultand's initial carrier risk, as based on family history and

    creatine kinase determinations
    PARACLINICAL

, was calculated as 0.6%.

    DNA analysis of her family (and fetus)
    PARACLINICAL

 modified this risk to 8.5%.

    Skeletal muscle of the 23-wk male abortus was found to be histologically indistinguishable from that of
    SYMPTOMS

 age-matched controls. However,

    immunoblot testing for dystrophin
    PARACLINICAL

 indicated that the

    fetus
    AGE

 had indeed

    inherited dystrophin deficiency
    BIOCHEMICAL

. The carrier risk of the consultand was thus elevated to 100%.

    Dystrophin assays
    PARACLINICAL

 should be employed whenever the diagnosis of

    fetal DMD
    DIAGNOSIS

 is equivocal (e.g., cases in which a

    gene deletion cannot be identified
    NEG_FINDINGS

). Assay results are crucial for

    genetic counseling
    MEDICATION

 for subsequent pregnancies and for studies of the early pathogenesis of

    muscular dystrophy
    DIAGNOSIS

.

Duchenne muscular dystrophy (DMD)
aborted fetus
fetal DMD
muscular dystrophy


Characterization of patients with glycerol kinase deficiency utilizing cDNA probes for the Duchenne muscular dystrophy locus.

Genomic DNA from five previously unreported patients with glycerol kinase deficiency (GKD), dystrophic myopathy, and adrenal insufficiency were studied with genomic probes and cDNA probes for the Duchenne muscular dystrophy (DMD) locus. These individuals, together with those reported by ourselves and others, show that patients with a contiguous gene syndrome involving the DMD, GK, and adrenal hypoplasia congenita (AHC) loci have a broader distribution of microdeletion breakpoints than those observed among patients with classical DMD. This study demonstrates the use of the DMD cDNA probes to delineate the centromeric deletion breakpoints for patients with Xp21 microdeletions extending beyond the DMD locus. It also shows the practical diagnostic application of the DMD cDNA probes when the diagnosis of GKD is entertained in a patient with known DMD and only DNA is available for study.

    Genomic DNA
    PARACLINICAL

 from five previously unreported patients with

    glycerol kinase deficiency (GKD)
    DIAGNOSIS

,

    dystrophic myopathy
    DIAGNOSIS

, and

    adrenal insufficiency
    SYMPTOMS

 were studied with

    genomic probes and cDNA probes for the Duchenne muscular dystrophy (DMD) locus
    PARACLINICAL

. These individuals, together with those reported by ourselves and others, show that patients with a

    contiguous gene syndrome involving the DMD, GK, and adrenal hypoplasia congenita (AHC) loci
    DIAGNOSIS

 have a

    broader distribution of microdeletion breakpoints
    GENETICS

 than those observed among patients with

    classical DMD
    DIAGNOSIS

. This study demonstrates the use of the

    DMD cDNA probes
    PARACLINICAL

 to delineate the centromeric deletion breakpoints for patients with

    Xp21 microdeletions extending beyond the DMD locus
    GENETICS

. It also shows the practical diagnostic application of the

    DMD cDNA probes
    PARACLINICAL

 when the diagnosis of

    GKD
    DIAGNOSIS

 is entertained in a patient with known

    DMD
    DIAGNOSIS

 and only DNA is available for study.


Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness.

We report the ophthalmological findings of a 6-year-old boy who has features of both Aland Island eye disease (also called Forsius-Eriksson ocular albinism) and incomplete congenital stationary night blindness, as defined by Miyake, leading us to suspect that they are the same entity. This child has a deletion of part of band 21 of the short arm of the X chromosome (Xp21) and three other X-linked disorders: congenital adrenal hypoplasia, glycerol kinase deficiency, and Duchenne type muscular dystrophy. The electroretinogram showed negative scotopic and abnormal photopic waveforms that were similar, if not identical, to the electroretinographic findings in both Aland Island eye disease and X-linked incomplete congenital stationary night blindness. Because of this similarity and the defective dark adaptometry that has been reported in patients with this disorder, we believe that Aland Island eye disease is more appropriately classified as a form of congenital night blindness than as a form of ocular albinism. From our case and review of the literature, Aland Island eye disease and incomplete congenital stationary night blindness appear indistinguishable. If further studies confirm that the disorders are the same, we recommend use of the term Aland Island eye disease or Forsius-Eriksson-Miyake syndrome. We also recommend that the gene symbols CSNB1 and CSNB2 be used for complete congenital stationary night blindness and Aland disease, respectively.

We report the

    ophthalmological
    PARACLINICAL

 findings of a

    6-year-old
    AGE

    boy
    GENDER

 who has

    features of both Aland Island eye disease (
    SYMPTOMS

also called

    Forsius-Eriksson ocular albinism
    DIAGNOSIS

) and

    incomplete congenital stationary night blindness
    SYMPTOMS

, as defined by Miyake, leading us to suspect that they are the same entity. This

    child
    AGE

 has a

    deletion of part of band 21 of the short arm of the X chromosome (Xp21)
    GENETICS

 and three other

    X-linked disorders
    GENETICS

:

    congenital adrenal hypoplasia
    DIAGNOSIS

,

    glycerol kinase deficiency
    BIOCHEMICAL

, and

    Duchenne type muscular dystrophy
    DIAGNOSIS

. The

    electroretinogram
    PARACLINICAL

 showed

    negative scotopic and abnormal photopic waveforms that were similar, if not identical, to the electroretinographic findings in both Aland Island eye disease
    SYMPTOMS

 and

    X-linked incomplete congenital stationary night blindness
    GENETICS

. Because of this similarity and the

    defective dark adaptometry
    SYMPTOMS

 that has been reported in patients with this disorder, we believe that

    Aland Island eye disease
    DIAGNOSIS

 is more appropriately classified as a form of

    congenital night blindness
    DIAGNOSIS

 than as a form of

    ocular albinism
    DIAGNOSIS

. From our case and review of the literature,

    Aland Island eye disease
    DIAGNOSIS

 and

    incomplete congenital stationary night blindness
    SYMPTOMS

 appear indistinguishable. If further studies confirm that the disorders are the same, we recommend use of the term

    Aland Island eye disease
    DIAGNOSIS

 or

    Forsius-Eriksson-Miyake syndrome
    DIAGNOSIS

. We also recommend that the gene symbols CSNB1 and CSNB2 be used for

    complete congenital stationary night blindness
    DIAGNOSIS

 and

    Aland disease
    DIAGNOSIS

, respectively.


A survey of manifesting carriers of Duchenne and Becker muscular dystrophy in Wales.

Manifesting carriers of Duchenne and Becker muscular dystrophy are uncommon but well described. Such patients are of particular importance with regard to the differential diagnosis from autosomal recessive limb-girdle muscular dystrophy. All mothers of affected males known to the Genetic Register of Muscular Dystrophy Families in Wales were contacted, and 167 out of a possible 190 were examined. It was estimated from pedigree and creatine kinase analysis that 119 out of the 167 were carriers of the Duchenne/Becker gene. Three manifesting carriers were identified, giving the proportion affected as 3/119 = 2.5%. We estimate the prevalence of manifesting carriers to be 1 in 100,000 of the female population, a figure comparable to the prevalence of autosomal recessive limb-girdle muscular dystrophy. During the period of the survey, several other women with similar clinical findings but without an appropriate family history were seen. We strongly suspect that some of these are also manifesting carriers of the Duchenne/Becker gene.

Manifesting carriers of

    Duchenne and Becker muscular dystrophy
    DIAGNOSIS

 are uncommon but well described. Such patients are of particular importance with regard to the

    differential diagnosis
    PARACLINICAL

 from

    autosomal recessive limb-girdle muscular dystrophy
    DIAGNOSIS

. All

    mothers
    GENDER

 of affected

    males
    GENDER

 known to the Genetic Register of

    Muscular Dystrophy
    DIAGNOSIS

 Families in

    Wales
    ETHNICITY

 were contacted, and 167 out of a possible 190 were examined. It was estimated from pedigree and

    creatine kinase analysis
    PARACLINICAL

 that 119 out of the 167 were

    carriers of the Duchenne/Becker gene
    GENETICS

. Three manifesting carriers were identified, giving the proportion affected as 3/119 = 2.5%. We estimate the prevalence of manifesting carriers to be 1 in 100,000 of the

    female
    GENDER

 population, a figure comparable to the prevalence of

    autosomal recessive limb-girdle muscular dystrophy
    DIAGNOSIS

. During the period of the survey, several other

    women
    GENDER

 with similar clinical findings but

    without an appropriate family history
    NEG_FINDINGS

 were seen. We strongly suspect that some of these are also manifesting carriers

    of the Duchenne/Becker gene
    GENETICS

.

carriers of the Duchenne/Becker gene
of the Duchenne/Becker gene


Screening for Duchenne muscular dystrophy.

A programme was introduced in Wales to screen all 18 month old boys who were not yet walking for raised creatine kinase activity within the existing community developmental screening programme. During an 18 month period 25 229 such boys were identified of whom 19 930 (79%) had a Denver developmental screening test and 338 (1.7%) of these were not walking. Two hundred and five of those who did not walk (61%) had creatine kinase activity assayed and two cases of Duchenne muscular dystrophy were detected. We conclude that screening boys of 18 months who do not walk is worthwhile if the opportunity arises, but that a population based screening programme of this type is not justified as detection rates will be unacceptably low.

A programme was introduced in

    Wales
    ETHNICITY

 to screen all

    18 month old
    AGE

    boys
    GENDER

 who were

    not yet walking
    NEG_FINDINGS

 for

    raised creatine kinase activity
    BIOCHEMICAL

 within the existing

    community developmental screening programme
    MEDICATION

. During an 18 month period 25 229 such

    boys
    GENDER

 were identified of whom 19 930 (79%) had a

    Denver developmental screening test
    PARACLINICAL

 and 338 (1.7%) of these were

    not walking
    NEG_FINDINGS

. Two hundred and five of those who

    did not walk
    NEG_FINDINGS

 (61%) had

    creatine kinase activity assayed
    BIOCHEMICAL

 and two cases of

    Duchenne muscular dystrophy
    DIAGNOSIS

 were detected. We conclude that screening

    boys of 18 months
    AGE

 who

    do not walk
    NEG_FINDINGS

 is worthwhile if the opportunity arises, but that a population based screening programme of this type is not justified as detection rates will be unacceptably low.

not yet walking
not walking
did not walk
do not walk

raised creatine kinase activity
creatine kinase activity assayed


Duchenne muscular dystrophy manifesting carriers.

Seven unrelated women were manifesting carriers of Duchenne muscular dystrophy. A manifesting carrier of Duchenne muscular dystrophy is defined as a female with a history of Duchenne muscular dystrophy in her pedigree who has symptomatic weakness. All were characterized by slowly progressive weakness that began in the second or third decade of life. Asymmetric weakness was present in only three of the seven patients. Serum creatine kinase values were elevated in all patients and none had an electrocardiogram indicating ventricular hypertrophy. The electromyogram and muscle biopsy specimens were reported as myopathic in all patients studied. In the absence of a male relative with Duchenne muscular dystrophy, clinical distinction from cases of autosomal recessive limb girdle muscular dystrophy may not be possible. The development of new techniques in molecular genetics should allow precise identification of manifesting carriers of Duchenne muscular dystrophy in the near future.

Seven unrelated

    women
    GENDER

 were manifesting carriers of

    Duchenne muscular dystrophy
    DIAGNOSIS

. A manifesting carrier of

    Duchenne muscular dystrophy
    DIAGNOSIS

 is defined as a

    female
    GENDER

    with a history of Duchenne muscular dystrophy in her pedigree
    FAMILY

 who has

    symptomatic weakness
    SYMPTOMS

. All were characterized by

    slowly progressive weakness
    SYMPTOMS

 that began

    in the second or third decade of life
    AGE

.

    Asymmetric weakness
    SYMPTOMS

 was present in only three of the seven patients.

    Serum creatine kinase values were elevated
    BIOCHEMICAL

 in all patients and

    none had an electrocardiogram indicating ventricular hypertrophy
    NEG_FINDINGS

. The

    electromyogram and muscle biopsy specimens
    PARACLINICAL

 were reported as

    myopathic
    DIAGNOSIS

 in all patients studied. In the

    absence of a male relative with Duchenne muscular dystrophy
    FAMILY

, clinical distinction from cases of

    autosomal recessive limb girdle muscular dystrophy
    DIAGNOSIS

 may not be possible. The development of new techniques in

    molecular genetics
    PARACLINICAL

 should allow precise identification of manifesting carriers of

    Duchenne muscular dystrophy
    DIAGNOSIS

 in the near future.

symptomatic weakness
slowly progressive weakness
Asymmetric weakness


Evidence for mutation by unequal sister chromatid exchange in the Duchenne muscular dystrophy gene.

We have studied three families each containing a male with Duchenne or Becker muscular dystrophy. Southern blot analysis using both genomic and cDNA probes revealed that an exon-containing segment of DNA within the gene is duplicated in the probands, their mothers, and, in two cases, their sisters. The grandpaternal origin of the duplication has been demonstrated in these families by RFLP and duplication analysis. The results suggest that unequal sister-chromatid exchange, which most likely occurred in the germ cell lineage of the proband's grandfather, is responsible for generating these duplications and that this type of intrachromosomal rearrangement, although rarely reported in humans, is not uncommon in the muscular dystrophy gene.

We have studied three families each containing a

    male
    GENDER

 with

    Duchenne or Becker muscular dystrophy
    DIAGNOSIS

.

    Southern blot analysis using both genomic and cDNA probes
    PARACLINICAL

 revealed that

    an exon-containing segment of DNA within the gene is duplicated in the probands
    GENETICS

, their mothers, and, in two cases,

    their sisters
    FAMILY

. The

    grandpaternal origin of the duplication
    FAMILY

 has been demonstrated in these families by

    RFLP and duplication analysis
    PARACLINICAL

. The results suggest that

    unequal sister-chromatid exchange, which most likely occurred in the germ cell lineage of the proband's grandfather
    FAMILY

, is responsible for generating

    these duplications
    GENETICS

 and that this type of

    intrachromosomal rearrangement
    GENETICS

, although rarely reported in humans, is not uncommon in the

    muscular dystrophy gene
    DIAGNOSIS

.

Duchenne or Becker muscular dystrophy
muscular dystrophy gene


Duchenne muscular dystrophy in monozygotic twins: deletion of 5' fragments of the gene.

A recombinant DNA study for deletion evaluation was performed in a 4 generation family with Duchenne muscular dystrophy (DMD) in twins. The patients were 6 years old, had a history of progressive difficulty in walking since age 4, and showed weak gluteals, iliopsoas, latissimus dorsi, rhomboids, lower trapezius, sternocleidomastoids, pseudohypertrophic calves, and tight heelcords. Both patients had high serum creatine kinase of 19,000 and 11,000 IU, respectively, and the muscle biopsy of the left vastus lateralis showed dystrophic alterations. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing also detected the same antigens in both twins: A2, B44, DR4, and DR5. Cytogenetic studies were consistent with 46, XY male individuals with normal banding pattern. By cDNA probes the entire DMD gene was surveyed for missing or abnormal-sized restriction fragments. Both twin boys showed absence of 8.5, 8.0, 4.6, 4.2, and 3.1 kb fragments on Hind III blots and absence of 13.5, 3.7, 2.9, and 1.4 kb fragments on Bgl II blots both hybridized with cDNA 1-2a corresponding to most 5' region of the DMD gene. The mother and other relatives of the patient did not show deletion. These findings strongly suggest that the deletion in the DMD monozygotic twins represents a new mutation.

A

    recombinant DNA study for deletion evaluation
    PARACLINICAL

 was performed in a

    4 generation family with Duchenne muscular dystrophy (DMD)
    FAMILY

    in twins
    FAMILY

. The patients were

    6 years old
    AGE

, had a history of

    progressive difficulty in walking
    SYMPTOMS

 since

    age 4
    AGE

, and showed

    weak gluteals, iliopsoas, latissimus dorsi, rhomboids, lower trapezius, sternocleidomastoids
    SYMPTOMS

,

    pseudohypertrophic calves
    SYMPTOMS

, and

    tight heelcords
    SYMPTOMS

. Both patients had

    high serum creatine kinase of 19,000 and 11,000 IU, respectively
    BIOCHEMICAL

, and the

    muscle biopsy of the left vastus lateralis
    PARACLINICAL

 showed

    dystrophic alterations
    SYMPTOMS

.

    Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd
    FAMILY

.

    HLA typing
    PARACLINICAL

 also

    detected the same antigens in both twins: A2, B44, DR4, and DR5
    GENETICS

.

    Cytogenetic studies
    PARACLINICAL

 were consistent with

    46, XY male
    GENETICS

 individuals with

    normal banding pattern
    NEG_FINDINGS

. By

    cDNA probes the entire DMD gene was surveyed for missing or abnormal-sized restriction fragments
    PARACLINICAL

. Both twin

    boys
    GENDER

 showed

    absence of 8.5, 8.0, 4.6, 4.2, and 3.1 kb fragments on Hind III blots
    GENETICS

 and

    absence of 13.5, 3.7, 2.9, and 1.4 kb fragments on Bgl II blots
    GENETICS

 both hybridized with

    cDNA 1-2a corresponding to most 5' region of the DMD gene
    GENETICS

.

    The mother and other relatives of the patient did not show deletion
    FAMILY

. These findings strongly suggest that

    the deletion in the DMD monozygotic twins
    FAMILY

 represents a

    new mutation
    GENETICS

.


Identification of a 220-kb insertion into the Duchenne gene in a family with an atypical course of muscular dystrophy.

Most known mutations in the gene region responsible for Duchenne or Becker muscular dystrophy are deletions of varying extent. Here we describe a 220-kb insertion within the DMD/BMD gene that cosegregates with a somewhat atypical course of muscular dystrophy in a pedigree. The insertion is demonstrated by field-inversion gel electrophoresis as an enlarged SfiI fragment hybridizing to probe J-Bir, while neighboring SfiI fragments (detected by probes PERT 87 and J-66) are unchanged. Hybridization with DMD c-DNA probes did not reveal alterations in coding sequences. In this pedigree, the altered SfiI fragments provide convenient markers for carrier identification.

Most known

    mutations in the gene region
    GENETICS

 responsible for

    Duchenne or Becker muscular dystrophy
    DIAGNOSIS

 are

    deletions
    GENETICS

 of varying extent. Here we describe a

    220-kb insertion within the DMD/BMD gene
    GENETICS

 that

    cosegregates with
    FAMILY

 a

    somewhat atypical course of muscular dystrophy
    SYMPTOMS

 in a pedigree. The insertion is demonstrated by

    field-inversion gel electrophoresis
    PARACLINICAL

 as an

    enlarged SfiI fragment hybridizing to probe J-Bir
    GENETICS

, while neighboring SfiI fragments (detected by probes PERT 87 and J-66) are unchanged.

    Hybridization with DMD c-DNA probes
    PARACLINICAL

    did not reveal alterations in coding sequences
    NEG_FINDINGS

. In this pedigree, the

    altered SfiI fragments
    GENETICS

 provide convenient markers for carrier identification.


Genetic abnormalities in Duchenne and Becker dystrophies: clinical correlations.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are two allelic forms of an X-linked muscle disorder exhibiting phenotypic heterogeneity. We studied 49 individuals clinically diagnosed as having classic DMD, female DMD, mild DMD "outliers," and BMD. The patients' DNA was analyzed and alterations detected were correlated with particular phenotypes. We found that 14 of 32 classic DMD patients have an internal deletion in the same, relatively small, region of the gene; therefore this region may undergo deletions at a higher rate than the remainder of the gene. We could detect no alterations in the DNA in the remaining 18 patients. Selected patients from both groups failed to show muscle dystrophin. Seven of 11 patients with a mild DMD or BMD phenotype showed deletions at the 5' end of the gene. The other 4 patients failed to show deletions. Three of the patients with both a mild phenotype and a deletion at the 5' end had normal or low amounts of a dystrophin of smaller molecular weight. Patients with classic DMD who had a detectable deletion had a milder clinical course than those without. Contrary to a previous report, no patient in the population of clinically precisely defined DMD boys showed a deletion at the 5' end; thus, the outlier and BMD patients may be genetically different from boys with classic DMD. This correlation may be of diagnostic and prognostic significance.

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 are two allelic forms of an

    X-linked
    GENETICS

    muscle disorder
    DIAGNOSIS

 exhibiting phenotypic heterogeneity. We studied 49 individuals clinically diagnosed as having

    classic DMD
    DIAGNOSIS

,

    female DMD
    DIAGNOSIS

,

    mild DMD
    DIAGNOSIS

 "outliers," and

    BMD
    DIAGNOSIS

. The patients'

    DNA was analyzed
    PARACLINICAL

 and alterations detected were correlated with particular phenotypes. We found that 14 of 32

    classic DMD
    DIAGNOSIS

 patients have an

    internal deletion in the same, relatively small, region of the gene
    GENETICS

; therefore this region

    may undergo deletions at a higher rate than the remainder of the gene
    GENETICS

. We could detect

    no alterations in the DNA
    NEG_FINDINGS

 in the remaining 18 patients. Selected patients from both groups

    failed to show muscle dystrophin
    NEG_FINDINGS

. Seven of 11 patients with a

    mild DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

 phenotype showed

    deletions at the 5' end of the gene
    GENETICS

. The other 4 patients

    failed to show deletions
    NEG_FINDINGS

. Three of the patients with both a

    mild phenotype
    SYMPTOMS

 and a

    deletion at the 5' end
    GENETICS

 had

    normal or low amounts of a dystrophin of smaller molecular weight
    NEG_FINDINGS

. Patients with

    classic DMD
    DIAGNOSIS

 who had a

    detectable deletion
    GENETICS

 had a

    milder clinical course
    SYMPTOMS

 than those without. Contrary to a previous report, no patient in the population of clinically precisely defined

    DMD
    DIAGNOSIS

    boys
    GENDER

 showed a

    deletion at the 5' end
    GENETICS

; thus, the outlier and

    BMD
    DIAGNOSIS

 patients may be genetically different from

    boys
    GENDER

 with

    classic DMD
    DIAGNOSIS

. This correlation may be of diagnostic and prognostic significance.

Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
muscle disorder
classic DMD
female DMD
mild DMD
BMD
classic DMD
mild DMD
BMD
classic DMD
DMD
BMD
classic DMD


Use of DNA probes in detecting carriers of Duchenne muscular dystrophy: selected case studies.

Detection of Duchenne muscular dystrophy carriers by genetic analysis is illustrated by four case studies. The technique is most useful in obligate families, in excluding carrier status in isolated cases, and in families in which the affected child demonstrates a molecular deletion. A major limitation of this technique is that the accuracy of carrier status in isolated (i.e., no family history) cases is limited by the probability that the affected child may represent a new mutation. To improve the carrier risk estimate generated by the DNA data, particularly in isolated cases, we suggest that measuring creatine kinase activities in the serum and performing the genetic analysis on the nonaffected males may be helpful.

Detection of

    Duchenne muscular dystrophy
    DIAGNOSIS

 carriers by

    genetic analysis
    PARACLINICAL

 is illustrated by four case studies. The technique is most useful in

    obligate families
    GENETICS

, in excluding carrier status in isolated cases, and in families in which

    the affected child demonstrates a molecular deletion
    FAMILY

. A major limitation of this technique is that the accuracy of carrier status in isolated (i.e.,

    no family history
    NEG_FINDINGS

) cases is limited by the probability that the

    affected child may represent a new mutation
    FAMILY

. To improve the carrier risk estimate generated by the DNA data, particularly in isolated cases, we suggest that

    measuring creatine kinase activities in the serum
    PARACLINICAL

 and performing the

    genetic analysis
    PARACLINICAL

 on the nonaffected

    males
    GENDER

 may be helpful.


Dilated cardiomyopathy with regional myocardial hypoperfusion in Becker's muscular dystrophy.

We describe two cases of Becker's muscular dystrophy, both of which presented with a dilated cardiomyopathy with alterations of myocardial perfusion and hypokinesia in the anteroseptal and apical ventricular walls. To the best of our knowledge, only one case with similar cardiologic characteristics has been reported previously. Myocardial involvement in this disease is comparable to that found in the Duchenne form of dystrophy. The possible mechanisms underscoring its induction are discussed.

We describe two cases of

    Becker's muscular dystrophy
    DIAGNOSIS

, both of which presented with a

    dilated cardiomyopathy
    SYMPTOMS

 with

    alterations of myocardial perfusion
    SYMPTOMS

 and

    hypokinesia in the anteroseptal and apical ventricular walls
    SYMPTOMS

. To the best of our knowledge, only one case with similar

    cardiologic characteristics
    SYMPTOMS

 has been reported previously.

    Myocardial involvement
    SYMPTOMS

 in this disease is comparable to that found in the

    Duchenne form of dystrophy
    DIAGNOSIS

. The possible mechanisms underscoring its induction are discussed.

Becker's muscular dystrophy
Duchenne form of dystrophy


[Asymmetrical patchy muscle involvement in manifesting carriers of Duchenne muscular dystrophy--computed tomographical and histological study].

Two cases of manifesting carriers of Duchenne muscular dystrophy (DMD) were described. Case 1. The 41 year-old woman presented gait disturbance at the age of 40. She had two sons. The first son died of pneumonia soon after birth. The second son developed DMD and died of heart failure when he was 17 years old. Neurological examination revealed mild muscle weakness in neck flexors, gluteus maximus (left side dominance) and hamstrings (right side dominance) as well as bilateral calf pseudohypertrophy. Electromyography showed myopathic changes and serum creatine kinase (CK) was elevated (1941IU/l). The karyotype was 46XX. Computed tomography (CT) of skeletal muscles showed that the following muscles were partly replaced by fatty tissue: bilateral paravertebral muscles, left gluteus maximus, left quadriceps femoris, right adductor magnus, long head of right biceps femoris, bilateral peroneus longus and medial head of left gastrocnemius. Histological examination of left quadriceps femoris revealed only minimal change of focal endomysial proliferation and fiber size variation, demonstrating no necrotic fiber or no abnormalities in fiber type. Case 2. The 42 year-old woman was admitted to the hospital complaining of dyspnea and palpitation. The disease was initially diagnosed as myocardial infarction based on cardiomegaly, ECG abnormality (Q in aVL, V5,6., ST depression and negative T in V5,6, ST elevation in I, aVL) and elevated serum CK. However, the diagnosis was rejected due to the lack of subsequent changes in ECG and the continued elevation of serum CK even after her complaints had disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of manifesting carriers of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 were described. Case 1. The

    41 year-old
    AGE

    woman
    GENDER

 presented

    gait disturbance
    SYMPTOMS

 at the

    age of 40
    AGE

.

    She
    GENDER

    had two sons
    FAMILY

.

    The first son died of pneumonia soon after birth
    FAMILY

. The

    second son developed DMD
    FAMILY

    and died of heart failure
    FAMILY

 when

    he
    GENDER

 was

    17 years old
    AGE

.

    Neurological examination
    PARACLINICAL

 revealed

    mild muscle weakness in neck flexors, gluteus maximus (left side dominance) and hamstrings (right side dominance)
    SYMPTOMS

 as well as

    bilateral calf pseudohypertrophy
    SYMPTOMS

.

    Electromyography
    PARACLINICAL

 showed

    myopathic changes
    SYMPTOMS

 and

    serum creatine kinase (CK) was elevated (1941IU/l)
    BIOCHEMICAL

. The

    karyotype was 46XX
    GENETICS

.

    Computed tomography (CT) of skeletal muscles
    PARACLINICAL

 showed that

    the following muscles were partly replaced by fatty tissue: bilateral paravertebral muscles, left gluteus maximus, left quadriceps femoris, right adductor magnus, long head of right biceps femoris, bilateral peroneus longus and medial head of left gastrocnemius
    SYMPTOMS

.

    Histological examination of left quadriceps femoris
    PARACLINICAL

 revealed

    only minimal change of focal endomysial proliferation and fiber size variation
    SYMPTOMS

, demonstrating

    no necrotic fiber
    NEG_FINDINGS

 or

    no abnormalities in fiber type
    NEG_FINDINGS

. Case 2. The

    42 year-old
    AGE

    woman
    GENDER

 was admitted to the hospital complaining of

    dyspnea
    SYMPTOMS

 and

    palpitation
    SYMPTOMS

. The disease was initially diagnosed as

    myocardial infarction
    SYMPTOMS

 based on

    cardiomegaly
    SYMPTOMS

,

    ECG abnormality (Q in aVL, V5,6., ST depression and negative T in V5,6, ST elevation in I, aVL)
    SYMPTOMS

 and

    elevated serum CK
    BIOCHEMICAL

. However, the diagnosis

    was rejected
    NEG_FINDINGS

 due to the

    lack of subsequent changes in ECG
    NEG_FINDINGS

 and the

    continued elevation of serum CK
    BIOCHEMICAL

 even after her complaints had disappeared.(ABSTRACT TRUNCATED AT 250 WORDS)

no necrotic fiber
no abnormalities in fiber type
was rejected
lack of subsequent changes in ECG


[Duchenne muscular dystrophy in a girl with chromosomal translocation].

It is reported the case of an 8-year-old girl with clinical and laboratory findings suggestive of Duchenne muscular dystrophy who had a chromosome translocation involving the X chromosome, 46,X,t(Bp+,Xq-). A review about Duchenne muscular dystrophy in females is made, with emphasis about chromosome abnormalities, mainly chromosome translocations.

It is reported the case of an

    8-year-old
    AGE

    girl
    GENDER

 with

    clinical and laboratory findings
    SYMPTOMS

 suggestive of

    Duchenne muscular dystrophy
    DIAGNOSIS

 who had a

    chromosome translocation involving the X chromosome, 46,X,t(Bp+,Xq-)
    GENETICS

. A review about

    Duchenne muscular dystrophy
    DIAGNOSIS

 in

    females
    GENDER

 is made, with emphasis about

    chromosome abnormalities
    GENETICS

, mainly

    chromosome translocations
    GENETICS

.

Duchenne muscular dystrophy
Duchenne muscular dystrophy


Identification of carriers of Duchenne muscular dystrophy: value of molecular analysis.

Currently, molecular methods are the most accurate diagnostic tools for carrier detection and prenatal diagnosis of Duchenne muscular dystrophy (DMD). This report illustrates the value of molecular diagnosis as opposed to previous diagnostic methods, the need for frequent re-evaluations as new methodologies develop, and the necessity for in-depth genetic counseling. In Family 1, the proposita was predicted to be a carrier by an indirect assay (abnormal in vitro muscle ribosomal protein synthesis). DNA analysis using restriction fragment length polymorphisms (RFLPs) indicated that she was not a carrier. She gave birth to a predicted non-affected male, who inherited the gene in question. In Family 2 the proposita, an obligate carrier, was initially evaluated by RFLP analysis. Two pregnancies were monitored by first trimester chorionic villous sampling. Re-evaluation indicated that all affected individuals, including one of the embryos, carried a deletion of the dystrophin gene. The identification of an RFLP within the region containing the deletion allowed unambiguous determination of the carrier status of all individuals.

Currently,

    molecular methods
    PARACLINICAL

 are the most accurate diagnostic tools for carrier detection and

    prenatal diagnosis
    PARACLINICAL

 of

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. This report illustrates the value of

    molecular diagnosis
    PARACLINICAL

 as opposed to previous diagnostic methods, the need for frequent re-evaluations as new methodologies develop, and the necessity for in-depth genetic counseling. In Family 1, the

    proposita
    FAMILY

 was predicted to be a carrier by an indirect assay (

    abnormal in vitro muscle ribosomal protein synthesis
    BIOCHEMICAL

).

    DNA analysis using restriction fragment length polymorphisms (RFLPs)
    PARACLINICAL

 indicated that

    she
    GENDER

 was

    not a carrier
    NEG_FINDINGS

.

    She
    GENDER

    gave birth to a predicted non-affected male, who inherited the gene in question
    FAMILY

. In Family 2 the

    proposita, an obligate carrier
    FAMILY

, was initially evaluated by

    RFLP analysis
    PARACLINICAL

. Two pregnancies were monitored by

    first trimester chorionic villous sampling
    PARACLINICAL

.

    Re-evaluation
    PARACLINICAL

 indicated that all affected individuals, including one of the embryos, carried a

    deletion of the dystrophin gene
    GENETICS

. The identification of an

    RFLP within the region containing the deletion
    GENETICS

 allowed unambiguous determination of the carrier status of all individuals.


Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients.

Five male Japanese patients with complex glycerol kinase deficiency (CGKD) and their relatives were studied clinically, cytogenetically, and molecular-genetically. All patients had muscular dystrophy or muscle weakness, mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency. High-resolution GTG-banded chromosomes showed a microdeletion in the Xp21 region in all four patients examined and in all five mothers. Southern hybridizations, after digestions by restriction endonucleases, with various cloned DNAs (D2, 99-6, B24, C7, L1-4, cDMD13-14, J66-HI, P20, J-Bir, ERT87-30, ERT87-15, ERT87-8, ERT87-1, XJ-1.1, 754, cx5.7, and OTC-1) that are located around Xp21 also showed a deletion in the genome of all patients and mothers. Although the deletion differed in size among patients, a segment commonly absent was located between the genomic sequences corresponding to L1-4 and cDMD13-14. This finding indicated that the gene coding for glycerol kinase (GK) is located within this segment. A comparison of the clinical manifestations of the present five patients and reported CGKD or Duchenne muscular dystrophy (DMD) patients with DNA deletion suggests the existence of a certain gene responsible for gonadotropin deficiency (GTD). The result of the present study and results of previous studies suggest that genes for ornithine transcarbamylase (OTC), DMD, and GK and putative genes responsible for congenital adrenal hypoplasia (AHC) and GTD are arranged from telomere to centromere as pter--GTD--AHC--GK--DMD--OTC--cen.

Five

    male
    GENDER

    Japanese
    ETHNICITY

 patients with

    complex glycerol kinase deficiency (CGKD)
    DIAGNOSIS

 and their relatives were studied clinically, cytogenetically, and

    molecular-genetically
    PARACLINICAL

. All patients had

    muscular dystrophy
    SYMPTOMS

 or

    muscle weakness
    SYMPTOMS

,

    mental retardation
    SYMPTOMS

,

    congenital adrenal hypoplasia
    SYMPTOMS

, and

    glycerol kinase deficiency
    BIOCHEMICAL

.

    High-resolution GTG-banded chromosomes
    PARACLINICAL

 showed a

    microdeletion in the Xp21 region
    GENETICS

 in all four patients examined and in all five

    mothers
    GENDER

.

    Southern hybridizations
    PARACLINICAL

, after

    digestions by restriction endonucleases
    PARACLINICAL

, with various cloned DNAs (D2, 99-6, B24, C7, L1-4, cDMD13-14, J66-HI, P20, J-Bir,

    ERT87-30, ERT87-15, ERT87-8, ERT87-1
    MEDICATION

,

    XJ-1.1, 754, cx5.7, and OTC-1) that are located around Xp21
    GENETICS

 also showed a

    deletion in the genome
    GENETICS

 of all patients and

    mothers
    GENDER

. Although the deletion differed in size among patients,

    a segment commonly absent was located between the genomic sequences corresponding to L1-4 and cDMD13-14
    GENETICS

. This finding indicated that the

    gene coding for glycerol kinase (GK) is located within this
    GENETICS

 segment. A comparison of the clinical manifestations of the present five patients and reported

    CGKD
    DIAGNOSIS

 or

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 patients with

    DNA deletion
    GENETICS

 suggests the existence of a certain gene responsible for

    gonadotropin deficiency (GTD)
    DIAGNOSIS

. The result of the present study and results of previous studies suggest that

    genes for ornithine transcarbamylase (OTC), DMD, and GK
    GENETICS

 and

    putative genes responsible for congenital adrenal hypoplasia (AHC) and GTD
    GENETICS

 are arranged from telomere to centromere as pter--GTD--AHC--GK--DMD--OTC--cen.

muscular dystrophy
muscle weakness
mental retardation
congenital adrenal hypoplasia


Molecular analysis of male-viable deletions and duplications allows ordering of 52 DNA probes on proximal Xq.

While performing a systematic search for chromosomal microdeletions in patients with clinically complex X-linked syndromes, we have observed that large male-viable deletions and duplications are clustered in heterochromatic regions of the X chromosome. Apart from the Xp21 band, where numerous deletions have been found that encompass the Duchenne muscular dystrophy gene, an increasing number of deletions and duplications have been observed that span (part of) the Xq21 segment. To refine the molecular and genetic map of this region, we have employed 52 cloned single-copy DNA sequences from the Xcen-q22 segment to characterize two partly overlapping tandem duplications and two interstitial deletions on the proximal long arm of the human X chromosome. Together with a panel of somatic cell hybrids that had been described earlier, these four rearrangements enabled us to order the 52 probes into nine different groups and to narrow the regional assignment of several genes, including those for tapetochoroidal dystrophy and anhidrotic ectodermal dysplasia.

While performing a systematic search for

    chromosomal microdeletions
    GENETICS

 in patients with clinically complex

    X-linked syndromes
    GENETICS

, we have observed that

    large male-viable deletions and duplications
    GENETICS

 are

    clustered in heterochromatic regions of the X chromosome
    GENETICS

. Apart from the

    Xp21 band
    GENETICS

, where numerous deletions have been found that encompass the

    Duchenne muscular dystrophy gene
    DIAGNOSIS

, an increasing number of

    deletions and duplications
    GENETICS

 have been observed that

    span (part of) the Xq21 segment
    GENETICS

. To refine the molecular and genetic map of this region, we have employed

    52 cloned single-copy DNA sequences from the Xcen-q22 segment
    PARACLINICAL

 to characterize two

    partly overlapping tandem duplications and two interstitial deletions on the proximal long arm of the human X chromosome
    GENETICS

. Together with a panel of somatic cell hybrids that had been described earlier, these four rearrangements enabled us to order the 52 probes into nine different groups and to narrow the regional assignment of several genes, including those for

    tapetochoroidal dystrophy
    DIAGNOSIS

 and

    anhidrotic ectodermal dysplasia
    DIAGNOSIS

.

Duchenne muscular dystrophy gene
tapetochoroidal dystrophy
anhidrotic ectodermal dysplasia


Neonatal rhabdomyolysis as a presentation of muscular dystrophy.

We report a unique presentation of X-linked recessive dystrophy as neonatal rhabdomyolysis. There was induration of the proximal musculature in an otherwise well neonate and striking CK elevation, without myoglobinuria. Muscle biopsy at age 1 year showed dystrophic alterations, and X chromosome analysis showed a deletion within or adjacent to the Duchenne/Becker locus.

We report a unique presentation of

    X-linked recessive dystrophy
    GENETICS

 as

    neonatal
    AGE

    rhabdomyolysis
    DIAGNOSIS

. There was

    induration of the proximal musculature
    SYMPTOMS

 in an

    otherwise well neonate
    NEG_FINDINGS

 and

    striking CK elevation
    BIOCHEMICAL

,

    without myoglobinuria
    NEG_FINDINGS

.

    Muscle biopsy
    PARACLINICAL

 at

    age 1 year
    AGE

 showed

    dystrophic alterations
    MICROSCOPIC

, and

    X chromosome analysis
    PARACLINICAL

 showed

    a deletion within or adjacent to the Duchenne/Becker locus
    GENETICS

.

otherwise well neonate
without myoglobinuria


Inherited deletion of subband Xp21.13 in a male with Duchenne muscular dystrophy.

The chromosomes of a male patient who suffers from Duchenne muscular dystrophy (DMD) with a molecular deletion were examined with an improved high resolution R type replication banding technique. High resolution cytogenetic analysis of the proband revealed a deletion of the Xp21.13 subband. His healthy mother was heterozygous for the deletion, which is subject to random X inactivation in lymphocytes. The X chromosomes of the proband's grandmother were normal, suggesting that the deletion of the Xp21.13 subband in the mother was a new mutation. The finding of a very small, cytologically visible Xp21.1 deletion in a male DMD patient with a molecular deletion emphasises the importance of resolving the fine structure in the Xp21 region.

The chromosomes of a

    male
    GENDER

 patient who suffers from

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 with a

    molecular deletion
    GENETICS

 were examined with an improved high

    resolution R type replication banding technique
    PARACLINICAL

.

    High resolution cytogenetic analysis of the proband
    PARACLINICAL

 revealed a

    deletion of the Xp21.13 subband
    GENETICS

.

    His
    GENDER

    healthy mother was heterozygous for the deletion, which is subject to random X inactivation in lymphocytes
    FAMILY

.

    The X chromosomes of the proband's grandmother were normal
    FAMILY

, suggesting that the

    deletion of the Xp21.13 subband in the mother was a new mutation
    GENETICS

. The finding of a

    very small, cytologically visible Xp21.1 deletion
    SYMPTOMS

 in a

    male
    GENDER

    DMD
    DIAGNOSIS

 patient with a

    molecular deletion
    GENETICS

 emphasises the importance of resolving the fine structure in the Xp21 region.


Noninvasive nasal mask-assisted ventilation in respiratory failure of Duchenne muscular dystrophy.

The effects of noninvasive nasal mask-assisted ventilation were studied in two patients with chronic respiratory failure due to Duchenne's muscular dystrophy. Observations were made with continuous recordings of transcutaneous CO2 and O2 and ear oximetry. In one case, the mean tcPCO2 fell from 72 mm Hg to 43 mm Hg. The tcPO2 increased from 38 mm Hg to 62 mm Hg without supplementary oxygen. In the second case, hypercapnia associated with supplementary oxygen was corrected, and at five months' follow-up, hypoxemia was corrected without supplementary oxygen. Prolonged therapy during sleep has resulted in sustained clinical improvement for more than 18 months.

The effects of

    noninvasive nasal mask-assisted ventilation
    MEDICATION

 were studied in two patients with

    chronic respiratory failure
    SYMPTOMS

 due to

    Duchenne's muscular dystrophy
    DIAGNOSIS

. Observations were made with

    continuous recordings of transcutaneous CO2 and O2
    PARACLINICAL

 and

    ear oximetry
    PARACLINICAL

. In one case, the

    mean tcPCO2 fell from 72 mm Hg to 43 mm Hg
    BIOCHEMICAL

. The

    tcPO2 increased from 38 mm Hg to 62 mm Hg
    BIOCHEMICAL

    without supplementary oxygen
    NEG_FINDINGS

. In the second case,

    hypercapnia associated with supplementary oxygen
    NEG_FINDINGS

 was corrected, and at five months'

    follow-up
    PARACLINICAL

,

    hypoxemia was corrected
    SYMPTOMS

    without supplementary oxygen
    NEG_FINDINGS

.

    Prolonged therapy during sleep
    MEDICATION

 has resulted in

    sustained clinical improvement for more than 18 months
    SYMPTOMS

.


Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy.

A deficiency of the protein dystrophin has recently been shown to be the probable cause of Duchenne's muscular dystrophy. We sought to determine the relation between the clinical phenotype and the status of dystrophin in muscle-biopsy specimens from 103 patients with various neuromuscular disorders. We found very low levels (less than 3 percent of normal levels) or no dystrophin in the severe Duchenne phenotype (35 of 38 patients), low concentrations of dystrophin in the intermediate (outlier) phenotype (4 of 7), and dystrophin of abnormal molecular weight in the mild Becker phenotype (12 of 18). Normal levels of dystrophin of normal molecular weight were found in nearly all the patients (38 of 40) with 20 other neuromuscular disorders we studied. These data show the clinical consequences of both quantitative alterations (in Duchenne's and intermediate dystrophy) in a single protein. The biochemical assay for dystrophin should prove helpful in delineating myopathies that overlap clinically with Duchenne's and Becker's dystrophies, and it shows promise as an accurate diagnostic tool.

A

    deficiency of the protein dystrophin
    BIOCHEMICAL

 has recently been shown to be the probable cause of

    Duchenne's muscular dystrophy
    DIAGNOSIS

. We sought to determine the relation between the clinical phenotype and the status of dystrophin in

    muscle-biopsy specimens
    PARACLINICAL

 from 103 patients with various

    neuromuscular disorders
    DIAGNOSIS

. We found

    very low levels (less than 3 percent of normal levels) or no dystrophin in the severe Duchenne
    BIOCHEMICAL

 phenotype (35 of 38 patients),

    low concentrations of dystrophin in the intermediate (outlier) phenotype
    BIOCHEMICAL

 (4 of 7), and

    dystrophin of abnormal molecular weight
    BIOCHEMICAL

    in the mild Becker phenotype
    MICROSCOPIC

 (12 of 18).

    Normal levels of dystrophin of normal molecular weight
    NEG_FINDINGS

 were found in nearly all the patients (38 of 40) with 20 other

    neuromuscular disorders
    DIAGNOSIS

 we studied. These data show the clinical consequences of both quantitative alterations (in

    Duchenne's and intermediate dystrophy
    DIAGNOSIS

) in a single protein. The

    biochemical assay for dystrophin
    PARACLINICAL

 should prove helpful in delineating

    myopathies
    DIAGNOSIS

 that overlap clinically with

    Duchenne's and Becker's dystrophies
    DIAGNOSIS

, and it shows promise as an accurate diagnostic tool.

Duchenne's muscular dystrophy
neuromuscular disorders
neuromuscular disorders
Duchenne's and intermediate dystrophy
myopathies
Duchenne's and Becker's dystrophies


Localization of the McLeod locus (XK) within Xp21 by deletion analysis.

The McLeod phenotype is an X-linked, recessive disorder in which the red blood cells demonstrate acanthocytic morphology and weakened antigenicity in the Kell blood group system. The phenotype is associated with a reduction of in vivo red cell survival, but the permanent hemolytic state is usually compensated by erythropoietic hyperplasia. The McLeod phenotype is accompanied by either a subclinical myopathy and elevated creatine kinase (CK) or X-linked chronic granulomatous disease (CGD). Seven males with the McLeod red-blood-cell phenotype and associated myopathy but not CGD, one male with the McLeod phenotype associated with CGD, and two males known to possess large deletions of the Duchenne muscular dystrophy (DMD) locus were studied. DNA isolated from each patient was screened for the presence or absence of various cloned sequences located in the Xp21 region of the human X chromosome. Two of the seven males who have only the McLeod phenotype and are cousins exhibit deletions for four Xp21 cloned fragments but are not deleted for any portion of either the CGD or the DMD loci. Comparison of the cloned segments absent from these two McLeod cousins with those absent from the two DMD boys and the CGD/McLeod patient leads to the submapping of various cloned DNA segments within the Xp21 region. The results place the locus for the McLeod phenotype within a 500-kb interval distal from the CGD locus toward the DMD locus.

The

    McLeod phenotype
    DIAGNOSIS

 is an

    X-linked, recessive disorder
    GENETICS

 in which

    the red blood cells demonstrate acanthocytic morphology
    MICROSCOPIC

 and

    weakened antigenicity in the Kell blood group system
    BIOCHEMICAL

. The phenotype is associated with a

    reduction of in vivo red cell survival
    BIOCHEMICAL

, but the

    permanent hemolytic state
    BIOCHEMICAL

 is usually compensated by

    erythropoietic hyperplasia
    BIOCHEMICAL

. The

    McLeod phenotype
    DIAGNOSIS

 is accompanied by either a

    subclinical myopathy
    SYMPTOMS

 and

    elevated creatine kinase (CK)
    BIOCHEMICAL

 or

    X-linked
    GENETICS

    chronic granulomatous disease (CGD)
    DIAGNOSIS

. Seven

    males
    GENDER

 with the

    McLeod red-blood-cell phenotype
    MICROSCOPIC

 and

    associated myopathy
    SYMPTOMS

 but

    not CGD
    NEG_FINDINGS

, one

    male
    GENDER

 with the

    McLeod phenotype associated with CGD
    SYMPTOMS

, and two

    males
    GENDER

 known to possess

    large deletions of the Duchenne muscular dystrophy (DMD) locus
    GENETICS

 were studied.

    DNA isolated from
    PARACLINICAL

 each patient was

    screened for the presence or absence of various cloned sequences located in the Xp21 region of the human X chromosome
    PARACLINICAL

. Two of the seven

    males
    GENDER

 who have

    only the McLeod phenotype
    SYMPTOMS

    and are cousins
    FAMILY

 exhibit

    deletions for four Xp21 cloned fragments
    GENETICS

    but are not deleted for any portion of either the CGD or the DMD loci
    NEG_FINDINGS

.

    Comparison of the cloned segments absent from these two McLeod cousins with those absent from the two DMD boys
    PARACLINICAL

 and the

    CGD/McLeod
    DIAGNOSIS

 patient leads to the submapping of various cloned

    DNA segments within the Xp21 region
    GENETICS

. The results place the locus for the

    McLeod phenotype
    DIAGNOSIS

 within a

    500-kb interval distal from the CGD locus toward the DMD locus
    GENETICS

.

McLeod phenotype
McLeod phenotype
chronic granulomatous disease (CGD)
CGD/McLeod
McLeod phenotype

subclinical myopathy
associated myopathy
McLeod phenotype associated with CGD
only the McLeod phenotype


Direct method for prenatal diagnosis and carrier detection in Duchenne/Becker muscular dystrophy using the entire dystrophin cDNA.

DNA sequence polymorphisms (RFLPs) have been widely used as genetic markers for identification of the X chromosome that carries the mutation for Duchenne muscular dystrophy (DMD) in affected families, but serious limitations and pitfalls are associated with this approach [Darras et al., 1987]. The complementary DNA (cDNA) of the DMD gene has recently been isolated and shown to detect partial gene deletions in a large proportion of patients [Koenig et al., 1987]. Two prenatal studies are presented to illustrate how the unambiguous identification of deletion mutations by cDNA probes permits direct DNA-based diagnoses with high accuracy and in otherwise uninformative families. In a single proband family, DNA marker analysis had determined that the Xp21 chromosomal region present in the affected male was also carried by a male fetus in a subsequent pregnancy. Analysis of this family's DNA with probes covering the entire 14 kb cDNA revealed a small deletion in the affected male that was not present in the fetus nor in the mother. In the second family the fetus was a female deletion carrier identified by comparing intensities of restriction fragments. Since 1/3 of all DMD patients are thought to result from new mutations and most families have only single affected males, the cloned cDNA probes now available are likely to revolutionize DNA-based diagnostic studies in this disorder. More reliable, more rapid and less expensive than linkage studies with DNA polymorphisms, this method will be informative in the more than 50% of DMD/BMD cases that have deletion mutations.

    DNA sequence polymorphisms (RFLPs)
    PARACLINICAL

 have been widely used as genetic markers for identification of the

    X chromosome that carries the mutation for Duchenne muscular dystrophy (DMD)
    GENETICS

 in affected families, but serious limitations and pitfalls are associated with this approach [Darras et al., 1987]. The

    complementary DNA (cDNA) of the DMD gene
    PARACLINICAL

 has recently been isolated and shown to detect

    partial gene deletions
    GENETICS

 in a large proportion of patients [Koenig et al., 1987]. Two prenatal studies are presented to illustrate how the unambiguous identification of

    deletion mutations
    GENETICS

 by

    cDNA probes
    PARACLINICAL

 permits

    direct DNA-based diagnoses
    PARACLINICAL

 with high accuracy and in

    otherwise uninformative families
    NEG_FINDINGS

. In a single proband family,

    DNA marker analysis
    PARACLINICAL

 had determined that

    the Xp21 chromosomal region present in the affected male was also carried by a male fetus in a subsequent pregnancy
    FAMILY

.

    Analysis of this family's DNA with probes covering the entire 14 kb cDNA
    PARACLINICAL

 revealed a

    small deletion in the affected male that was not present in the fetus nor in the mother
    GENETICS

. In the second family the

    fetus was a female deletion carrier
    FAMILY

 identified by comparing intensities of restriction fragments. Since 1/3 of all

    DMD
    DIAGNOSIS

 patients are thought to result from new mutations and most families have only

    single affected males
    FAMILY

, the cloned cDNA probes now available are likely to revolutionize

    DNA-based
    PARACLINICAL

 diagnostic studies in this disorder. More reliable, more rapid and less expensive than

    linkage studies with DNA polymorphisms
    PARACLINICAL

, this method will be informative in the more than 50% of

    DMD
    DIAGNOSIS

/

    BMD
    DIAGNOSIS

 cases that have

    deletion mutations
    GENETICS

.


Deletion proximal to DXS68 locus (L1 probe site) in a boy with Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal hypoplasia.

We report a case of a boy with Duchenne muscular dystrophy (DMD) associated with GK deficiency (GK), congenital adrenal hypoplasia (AHC), and mental retardation. Cytogenetic analysis of prometaphasic chromosomes revealed an interstitial chromosome deletion at Xp21.2 possibly extending to Xp21.1 or Xp21.3. His phenotypically normal mother was heterozygous for this deletion. DNA probe analysis on Southern blots showed that the deletion affected the following probe sites: 754, pERT 84, 21A, XJ2.3, pERT 87, JBir, and J66-H1, whereas L1, C7, and CX5.4 probes gave a normal signal. Pulse field gel electrophoresis after SfiI digestion did not show abnormal fragments with L1. These data are consistent with a deletion of about 4 megabases and indicate that the GK and AHC loci are proximal to L1 and distal to J66-H1.

We report a case of a

    boy
    GENDER

 with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 associated with

    GK deficiency (GK)
    BIOCHEMICAL

,

    congenital adrenal hypoplasia (AHC)
    SYMPTOMS

, and

    mental retardation
    SYMPTOMS

.

    Cytogenetic analysis of prometaphasic chromosomes
    PARACLINICAL

 revealed an

    interstitial chromosome deletion at Xp21.2 possibly extending to Xp21.1 or Xp21.3
    GENETICS

.

    His
    GENDER

    phenotypically normal mother was heterozygous for this deletion
    FAMILY

.

    DNA probe analysis on Southern blots
    PARACLINICAL

 showed that the

    deletion affected the following probe sites: 754, pERT 84, 21A, XJ2.3, pERT 87, JBir, and J66-H1
    GENETICS

, whereas

    L1, C7, and CX5.4 probes gave a normal signal
    NEG_FINDINGS

.

    Pulse field gel electrophoresis after SfiI digestion
    PARACLINICAL

    did not show abnormal fragments with L1
    NEG_FINDINGS

. These data are consistent with a

    deletion of about 4 megabases
    GENETICS

 and indicate that the GK and AHC loci are proximal to L1 and distal to J66-H1.

congenital adrenal hypoplasia (AHC)
mental retardation


Fine mapping of glycerol kinase deficiency and congenital adrenal hypoplasia within Xp21 on the short arm of the human X chromosome.

We have studied patients with Duchenne muscular dystrophy (DMD), DMD together with glycerol kinase (GK) deficiency, or DMD together with both GK deficiency and congenital adrenal hypoplasia (AHC). Analysis of deletions in these patients allows the mapping of these mutations in Xp21. The following order is proposed: Xpter - L1 - AHC - GK - DMD - Xcen. One of the boys with DMD, GK, and AHC is shown by pulsed-field-gel electrophoresis to have a deletion which has a proximal endpoint at least 500 kb distal from the pERT87 (DXS164) locus.

We have studied patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

,

    DMD together with glycerol kinase (GK) deficiency
    DIAGNOSIS

, or

    DMD together with both GK deficiency
    DIAGNOSIS

 and

    congenital adrenal hypoplasia (AHC)
    DIAGNOSIS

.

    Analysis of deletions
    PARACLINICAL

 in these patients allows the mapping of these mutations in

    Xp21
    GENETICS

. The following order is proposed:

    Xpter - L1
    GENETICS

 -

    AHC
    DIAGNOSIS

 -

    GK
    DIAGNOSIS

 -

    DMD
    DIAGNOSIS

 -

    Xcen
    GENETICS

. One of the

    boys
    GENDER

 with

    DMD
    DIAGNOSIS

,

    GK
    DIAGNOSIS

    , and AHC
    DIAGNOSIS

 is shown by

    pulsed-field-gel electrophoresis
    PARACLINICAL

 to have a

    deletion which has a proximal endpoint at least 500 kb distal from the pERT87 (DXS164) locus
    GENETICS

.


Prenatal diagnosis in a female carrying a deletion close to the Duchenne locus.

Family studies including the proband are usually needed before a prenatal diagnosis may be performed for Duchenne muscular dystrophy. We report here on prenatal diagnosis in a family where the solitary index case was dead, and where the consultand and her mother were assumed to be carriers by independent evidence. DNA analysis revealed that both the consultand and her mother had an X chromosome deleted for DNA material in the Xp21 region. The female fetus also carried the deleted X chromosome.

    Family studies
    PARACLINICAL

 including the proband are usually needed before a

    prenatal diagnosis
    PARACLINICAL

 may be performed for

    Duchenne muscular dystrophy
    DIAGNOSIS

. We report here on

    prenatal diagnosis
    PARACLINICAL

 in a

    family where the solitary index case was dead
    FAMILY

, and where

    the consultand and her mother were assumed to be carriers by independent evidence
    FAMILY

.

    DNA analysis
    PARACLINICAL

 revealed that

    both the consultand and her mother had an X chromosome deleted for DNA material in the Xp21 region
    FAMILY

. The

    female
    GENDER

    fetus also carried the deleted X chromosome
    FAMILY

.


An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus.

Deletions giving rise to Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) occur in the same large gene on the short arm of the human X chromosome. We present a molecular mechanism to explain the clinical difference in severity between DMD and BMD patients who bear partial deletions of the same gene locus. The model is based on the breakpoints of intragenic deletions and their effect on the translation of triplet codons into amino acids of the protein product. Deletions identified in three DMD patients are shown to shift the translational open reading frame (ORF) of triplet codons for amino acids, and each deletion is predicted to result in a truncated, abnormal protein product. Deletions identified in three BMD patients are shown to maintain the translational ORF for amino acids and predict a shorter, lower molecular weight protein. The smaller protein product is presumed to be semifunctional and to result in a milder clinical phenotype. The same ORF mechanism is also applicable to potential 5' and 3' intron splice mutations and their effect on protein production and clinical phenotype.

    Deletions
    GENETICS

 giving rise to

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 and the less severe

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 occur

    in the same large gene on the short arm of the human X chromosome
    GENETICS

. We present a molecular mechanism to explain the clinical difference in severity between

    DMD
    DIAGNOSIS

 and

    BMD
    DIAGNOSIS

 patients who bear

    partial deletions of the same gene locus
    GENETICS

. The model is based on the breakpoints of

    intragenic deletions
    GENETICS

 and their effect on the

    translation of triplet codons into amino acids of the protein product
    GENETICS

. Deletions identified in three

    DMD
    DIAGNOSIS

 patients are shown to

    shift the translational open reading frame (ORF) of triplet codons for amino acids
    GENETICS

, and

    each deletion is predicted to result in a truncated, abnormal protein product
    GENETICS

.

    Deletions
    GENETICS

 identified in three

    BMD
    DIAGNOSIS

 patients are shown to

    maintain the translational ORF for amino acids and predict a shorter, lower molecular weight protein
    GENETICS

. The smaller protein product is presumed to be semifunctional and to result in a

    milder clinical phenotype
    SYMPTOMS

. The same ORF mechanism is also applicable to potential

    5' and 3' intron splice mutations
    GENETICS

 and their effect on protein production and clinical phenotype.

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


Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus.

In a patient suffering from X-linked chronic granulomatous disease (X-CGD)--a disorder of phagocytesuperoxide generation--and McLeod syndrome, characterized by the absence of the red cell Kell antigen, we identified a deletion of the entire X-CGD gene by means of DNA hybridization with a cDNA probe. Our findings suggest that the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus.

In a patient suffering from

    X-linked chronic granulomatous disease (X-CGD)--a disorder of phagocytesuperoxide generation
    GENETICS

--and

    McLeod syndrome
    DIAGNOSIS

, characterized by the

    absence of the red cell Kell antigen
    BIOCHEMICAL

, we identified a

    deletion of the entire X-CGD gene
    GENETICS

 by means of

    DNA hybridization with a cDNA probe
    PARACLINICAL

. Our findings suggest that

    the X-CGD and McLeod loci are physically close in the p21 region of the X chromosome proximal to the Duchenne muscular dystrophy locus
    GENETICS

.


[A combination of Duchenne's progressive muscular dystrophy with congenital ichthyosis--a deletion or 2 independent gene mutations at Xp21--Xp22?].

The authors describe a combination of Duchenne muscular dystrophy and congenital ichthyosis in a 6.5-year-old boy. This is the first ever description appearing in the world literature. The authors discuss possible variants of mutation (either chromosomal aberration or two independent gene mutations in chromosome 21).

The authors describe a

    combination of Duchenne muscular dystrophy
    DIAGNOSIS

 and

    congenital ichthyosis
    SYMPTOMS

 in a

    6.5-year-old
    AGE

    boy
    GENDER

. This is the first ever description appearing in the world literature. The authors discuss possible variants of mutation (either

    chromosomal aberration or two independent gene mutations in chromosome 21)
    GENETICS

.


Familial deletion of Xp21.2 with glycerol kinase deficiency and congenital adrenal hypoplasia.

Congenital adrenal hypoplasia (CAH) and glycerol kinase deficiency (GKD) were diagnosed in a male during the neonatal period. On prometaphase chromosomes there was an interstitial deletion involving Xp21.2 and possibly Xp21.3 in the propositus and his mother. Duchenne muscular dystrophy (DMD) was excluded on the basis of normal serum creatine kinase and a muscle biopsy. Molecular hybridization of DNA from the propositus with 11 probes covering Xp21, including the DMD locus, was normal. In situ hybridization with the probe pERT87.15 showed a normal signal at the expected site indicating that the DMD locus was preserved and not translocated. This suggests that the DMD locus is located at the most proximal part of the sub-band Xp21.2 or in Xp21.1, and that the DXS68 (probe L1) is far from it on the distal flanking DNA.

    Congenital adrenal hypoplasia (CAH)
    DIAGNOSIS

 and

    glycerol kinase deficiency (GKD)
    DIAGNOSIS

 were diagnosed in a

    male
    GENDER

 during the

    neonatal
    AGE

    period
    AGE

. On

    prometaphase chromosomes
    PARACLINICAL

 there was an

    interstitial deletion involving Xp21.2 and possibly Xp21.3 in the propositus and his mother
    GENETICS

.

    Duchenne muscular dystrophy (DMD) was excluded
    DIAGNOSIS

 on the basis of

    normal serum creatine kinase
    NEG_FINDINGS

 and a

    muscle biopsy
    PARACLINICAL

.

    Molecular hybridization of DNA from the propositus with 11 probes covering Xp21, including the DMD locus, was normal
    PARACLINICAL

.

    In situ hybridization with the probe pERT87.15
    PARACLINICAL

 showed a normal signal at the expected site indicating that

    the DMD locus was preserved and not translocated
    GENETICS

. This suggests that

    the DMD locus is located at the most proximal part of the sub-band Xp21.2 or in Xp21.1
    GENETICS

, and that

    the DXS68 (probe L1) is far from it on the distal flanking DNA
    GENETICS

.


Infantile glycerol kinase deficiency--a condition requiring prompt identification. Clinical, biochemical, and morphological findings in two cases.

Infantile glycerol kinase deficiency (GKD) is an X-linked genetic disease characterized clinically by adrenal insufficiency and muscular dystrophy. The enzyme defect leads to increased levels of glycerol in blood and urine, which can be used for diagnosis. Without recognition of this condition, the chances for life-saving steroid treatment and for genetic counselling are missed. We report clinical, endocrinological, biochemical, and morphological findings in two non-related boys. One of them died in early infancy. The other is thriving at the age of 2 years although he is suffering from a myopathy not distinguishable from Duchenne muscular dystrophy. We discuss when to suspect and how to confirm the diagnosis of infantile GKD, and under what precautions the condition is detectable by commonly used screening procedures for inborn errors of metabolism.

    Infantile glycerol kinase deficiency (GKD)
    DIAGNOSIS

 is an

    X-linked genetic disease
    GENETICS

 characterized clinically by

    adrenal insufficiency
    SYMPTOMS

 and

    muscular dystrophy
    SYMPTOMS

. The

    enzyme defect
    BIOCHEMICAL

 leads to

    increased levels of glycerol in blood and urine
    BIOCHEMICAL

, which can be used for diagnosis. Without recognition of this condition, the chances for

    life-saving steroid treatment
    MEDICATION

 and for

    genetic counselling
    MEDICATION

 are missed. We report clinical,

    endocrinological
    SYMPTOMS

, biochemical, and morphological findings in two

    non-related
    FAMILY

    boys
    GENDER

. One of them

    died
    SYMPTOMS

    in early infancy
    AGE

. The other is

    thriving at the age of 2 years
    AGE

 although

    he
    GENDER

 is suffering from a

    myopathy not distinguishable from Duchenne muscular dystrophy
    NEG_FINDINGS

. We discuss when to suspect and how to confirm the diagnosis of

    infantile GKD
    DIAGNOSIS

, and under what precautions the condition is detectable by commonly used screening procedures for

    inborn errors of metabolism
    DIAGNOSIS

.

adrenal insufficiency
muscular dystrophy
endocrinological
died

life-saving steroid treatment
genetic counselling


A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male.

A gene of unknown function located in band Xp21 on the short arm of the human X chromosome gives rise to X-linked recessive muscular dystrophy, of either Duchenne or Becker type, when mutated. The gene encodes a large muscle-specific transcript of about 14 kilobases (kb) and its genomic size extends over more than 1,800 kb. The high mutation rate (about 10(-4) per generation) is likely to result from the large target size. Submicroscopic deletions, detectable with one or more of the dozen cloned DNA probes available for regions within the gene, constitute a significant proportion of the mutations. Because no such deletions have been found in normal individuals, it is assumed that intragenic deletions are the molecular basis of the mutations. The origin of deletions can be traced in families. With sufficient data collected, it will soon be possible to answer questions about the relative frequencies of mutations in male and female gametogenesis and about the timing of mutational events in mitotic or meiotic stages of germ cell development. We have studied a four generation family containing males who have Duchenne muscular dystrophy due to deletion of the sequence recognized by intragenic probe J-Bir. The deletion was present in two of five daughters of a woman who herself did not have the deletion. Haplotype analysis on 15 members of this family using nine informative restriction fragment length polymorphism (RFLP) markers indicated that the J-Bir deletion chromosome was transmitted from the unaffected father.

A

    gene of unknown function located in band Xp21 on the short arm of the human X chromosome
    GENETICS

 gives rise to

    X-linked
    GENETICS

    recessive muscular dystrophy, of either Duchenne or Becker type
    DIAGNOSIS

, when mutated. The gene encodes a

    large muscle-specific transcript of about 14 kilobases (kb)
    GENETICS

 and its genomic size extends over more than 1,800 kb. The high mutation rate (about 10(-4) per generation) is likely to result from the large target size.

    Submicroscopic deletions
    GENETICS

, detectable with one or more of the dozen cloned DNA probes available for regions within the gene, constitute a significant proportion of the mutations. Because no such deletions have been found in normal individuals, it is assumed that

    intragenic deletions
    GENETICS

 are the molecular basis of the mutations. The origin of deletions can be traced in families. With sufficient data collected, it will soon be possible to answer questions about the relative frequencies of mutations in male and

    female gametogenesis
    GENETICS

 and about the timing of mutational events in mitotic or meiotic stages of germ cell development. We have studied a

    four generation family containing males
    FAMILY

 who have

    Duchenne muscular dystrophy
    DIAGNOSIS

 due to

    deletion of the sequence recognized by intragenic probe J-Bir
    GENETICS

.

    The deletion was present in two of five daughters of a woman who herself did not have the deletion
    FAMILY

.

    Haplotype analysis
    PARACLINICAL

 on 15 members of this family using

    nine informative restriction fragment length polymorphism (RFLP) markers
    PARACLINICAL

 indicated that

    the J-Bir deletion chromosome was transmitted from the unaffected father
    GENETICS

.


Molecular analysis of a constitutional X-autosome translocation in a female with muscular dystrophy.

The gene responsible for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) maps to the X chromosome short arm, band Xp21. In a few females with DMD or BMD, the Xp21 region is disrupted by an X-autosome translocation. Accumulating evidence suggests that the exchange has physically disrupted the DMD/BMD locus to cause the disease. One affected female with a t(X;21)(p21;p12) translocation was studied in detail. The exchange points from both translocation chromosomes were cloned, restriction-mapped, and sequenced. The translocation is reciprocal, but not conservative. A small amount of DNA is missing from the translocated chromosomes; 71 to 72 base pairs from the X chromosome and 16 to 23 base pairs from the 28S ribosomal gene on chromosome 21.

The

    gene responsible for Duchenne muscular dystrophy (DMD)
    GENETICS

 and

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

    maps to the X chromosome short arm, band Xp21
    GENETICS

. In a few

    females
    GENDER

 with

    DMD
    DIAGNOSIS

 or

    BMD
    DIAGNOSIS

,

    the Xp21 region is disrupted by an X-autosome translocation
    GENETICS

. Accumulating evidence suggests that the

    exchange has physically disrupted the DMD/BMD locus
    GENETICS

 to cause the disease. One affected

    female
    GENDER

 with a

    t(X;21)(p21;p12) translocation
    GENETICS

 was studied in detail.

    The exchange points from both translocation chromosomes were cloned, restriction-mapped, and sequenced
    PARACLINICAL

.

    The translocation is reciprocal, but not conservative
    GENETICS

.

    A small amount of DNA is missing from the translocated chromosomes; 71 to 72 base pairs from the X chromosome and 16 to 23 base pairs from the 28S ribosomal gene on chromosome 21
    GENETICS

.


Hypokalemia complicating Duchenne muscular dystrophy.

Although patients with Duchenne muscular dystrophy (DMD) have been shown to have decreased total body potassium levels, serum potassium levels have generally been though to be within normal limits. We report two siblings with DMD noted to be hypokalemic in conjunction with a respiratory illness. Hypokalemia may have exacerbated the pre-existing pulmonary insufficiency in these patients. The literature concerning hypokalemia and DMD is reviewed, and recommendations for the closer monitoring of serum potassium levels in patients with DMD are presented.

Although patients with

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

 have been shown to have

    decreased total body potassium levels
    BIOCHEMICAL

,

    serum potassium levels
    NEG_FINDINGS

 have generally been

    though to be within normal limits
    NEG_FINDINGS

. We report two

    siblings with DMD
    FAMILY

 noted to be

    hypokalemic
    BIOCHEMICAL

 in conjunction with a

    respiratory illness
    DIAGNOSIS

.

    Hypokalemia
    BIOCHEMICAL

 may have exacerbated the pre-existing

    pulmonary insufficiency
    SYMPTOMS

 in these patients. The literature concerning

    hypokalemia
    BIOCHEMICAL

 and

    DMD
    DIAGNOSIS

 is reviewed, and recommendations for the

    closer monitoring of serum potassium levels
    PARACLINICAL

 in patients with

    DMD
    DIAGNOSIS

 are presented.

Duchenne muscular dystrophy (DMD)
respiratory illness
DMD
DMD

decreased total body potassium levels
hypokalemic
Hypokalemia
hypokalemia

serum potassium levels
though to be within normal limits


Becker and limb-girdle muscular dystrophy associated with pituitary dwarfism.

In 1981 a report appeared of a patient with Duchenne muscular dystrophy associated with dwarfism caused by growth hormone deficiency, in whom the muscular disease was unusually benign. The authors suggested that the benign course might be related to the growth hormone deficiency and dwarfism. Other authors later supported this idea, having observed that in dystrophic mice and hamsters with congenital and experimentally induced pituitary dwarfism, respectively, pathological expressions of the dystrophy were markedly reduced. In this paper one case of Becker and one of limb-girdle dystrophy, each associated with short stature and growth hormone deficiency are described. In these cases the disease did not have a particularly benign course. It is concluded that caution is necessary, at least in certain cases, before an association between reduced muscular growth and the dystrophic process can be assumed.

In 1981 a report appeared of a patient with

    Duchenne muscular dystrophy
    DIAGNOSIS

 associated with

    dwarfism
    SYMPTOMS

 caused by

    growth hormone deficiency
    BIOCHEMICAL

, in whom the

    muscular disease was unusually benign
    NEG_FINDINGS

. The authors suggested that the benign course might be related to the

    growth hormone deficiency
    BIOCHEMICAL

 and

    dwarfism
    SYMPTOMS

. Other authors later supported this idea, having observed that in dystrophic mice and hamsters with congenital and

    experimentally induced pituitary dwarfism
    DIAGNOSIS

, respectively,

    pathological expressions of the dystrophy were markedly reduced
    SYMPTOMS

. In this paper one case of

    Becker
    DIAGNOSIS

 and one of

    limb-girdle dystrophy
    DIAGNOSIS

, each associated with

    short stature
    SYMPTOMS

 and

    growth hormone deficiency
    BIOCHEMICAL

 are described. In these cases the disease

    did not have a particularly benign course
    NEG_FINDINGS

. It is concluded that caution is necessary, at least in certain cases, before an association between

    reduced muscular growth
    SYMPTOMS

 and the

    dystrophic process
    DIAGNOSIS

 can be assumed.

growth hormone deficiency
growth hormone deficiency
growth hormone deficiency


The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins.

We have ascertained retrospectively a female patient, one of identical twins, who was diagnosed at age 23 years as having Duchenne muscular dystrophy (DMD). A muscle biopsy at that time showed a pattern in which large areas of destroyed muscle fibers replaced with adipose tissue were interspersed with normal-appearing muscle fascicles. The visualization of Barr bodies in the muscle biopsy, plus the patient's normal menstrual history served to rule out Turner's syndrome. The clinical expression of DMD in only one of monozygotic twins is strongly suggestive of uneven lyonization, with an excess of paternally derived X-chromosomes being inactivated in the patient. This view is supported by the appearance of the muscle biopsy. Twinning may conceivably predispose to uneven lyonization by reducing the size of the muscle cell anlage at the time of X-chromosome inactivation. Alternatively, lyonization may occur before the splitting of the embryonic mass, and by chance, the two embryonic centers could end up with a significantly different proportion of active maternal and paternal X-chromosomes.

We have ascertained retrospectively a

    female
    GENDER

 patient,

    one of identical twins
    FAMILY

, who was diagnosed at

    age 23 years
    AGE

 as having

    Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. A

    muscle biopsy
    PARACLINICAL

 at that time showed a pattern in which

    large areas of destroyed muscle fibers replaced with adipose tissue were interspersed with normal-appearing muscle fascicles
    MICROSCOPIC

. The visualization of

    Barr bodies in the muscle biopsy
    MICROSCOPIC

, plus the patient's

    normal menstrual history
    NEG_FINDINGS

 served to rule out

    Turner's syndrome
    NEG_FINDINGS

. The

    clinical expression of DMD in only one of monozygotic twins
    FAMILY

 is strongly suggestive of

    uneven lyonization
    GENETICS

, with an

    excess of paternally derived X-chromosomes being inactivated in the patient
    GENETICS

. This view is supported by the appearance of the

    muscle biopsy
    PARACLINICAL

.

    Twinning
    MEDICATION

 may conceivably predispose to

    uneven lyonization
    SYMPTOMS

 by reducing the size of the

    muscle cell anlage
    MICROSCOPIC

 at the time of

    X-chromosome inactivation
    GENETICS

. Alternatively,

    lyonization
    DIAGNOSIS

 may occur before the

    splitting of the embryonic mass
    MEDICATION

, and by chance, the two embryonic centers could end up with a

    significantly different proportion of active maternal and paternal X-chromosomes
    GENETICS

.

Duchenne muscular dystrophy (DMD)
lyonization

normal menstrual history
Turner's syndrome

Twinning
splitting of the embryonic mass


Monozygotic female twin carriers discordant for the clinical manifestations of Duchenne muscular dystrophy.

We studied twin sisters, in their sixth decade, who were obligate carriers of Duchenne dystrophy. One had a slowly progressing limb-girdle myopathy since her mid-20s. The other sister showed no evidence of neuromuscular disease by history or on physical examination but had high serum CK values and degeneration and regeneration of fibers in a muscle biopsy. Otherwise, they were phenotypically identical, karyotypically normal females with cytogenetically normal X-chromosomes. Based on red cell and HLA loci antigen determinations, there was a 99.2% probability that they were monozygotic. The mutant gene segregating in the family is probably linked to the Xp21 DNA marker pERT87.

We studied

    twin sisters, in their sixth decade
    FAMILY

, who were

    obligate carriers of Duchenne dystrophy
    FAMILY

. One had a

    slowly progressing limb-girdle myopathy
    SYMPTOMS

    since her mid-20s
    AGE

. The other sister showed

    no evidence of neuromuscular disease by history or on physical examination
    NEG_FINDINGS

 but had

    high serum CK values
    BIOCHEMICAL

 and

    degeneration and regeneration of fibers in a muscle biopsy
    MICROSCOPIC

. Otherwise, they were phenotypically identical,

    karyotypically normal females
    NEG_FINDINGS

 with

    cytogenetically normal X-chromosomes
    NEG_FINDINGS

. Based on

    red cell and HLA loci antigen determinations
    PARACLINICAL

, there was a 99.2% probability that

    they were monozygotic
    FAMILY

. The mutant gene segregating in the family is probably linked to the Xp21 DNA marker pERT87.


Activation of the intramyofibral autophagic-lysosomal system in muscular dystrophy.

Skeletal muscles obtained from myopathies with myofiber necrosis, including mdx dystrophic mice, plasmocid-induced myopathy in rats, and patients with Duchenne muscular dystrophy, were examined immunohistochemically with anticathepsin-peroxidase conjugates. Strong reactions for lysosomal cysteine proteinases, which can degrade myofibrillar proteins, were demonstrated in macrophages invading and surrounding the necrotic areas and some degenerative myofibers and also in intramyofibral portions of atrophic fibers of dystrophic mice and humans. Apparently normal and regenerating myofibers did not stain for lysosomal cathepsins. Abnormal increases of cathepsins L and B were seen even in the early stage of plasmocid myopathy and in a 20-day-old young mdx mouse before infiltration of macrophages, suggesting that autodigestion by intramyofibral lysosomal proteinases is an important event before digestion of the necrotic fibers by macrophage proteinases. Activation of the intramyofibral lysosomal system, as in muscular dystrophy, was also observed in distal myopathy with rimmed vacuoles without macrophageal infiltration (Am J Pathol 1986, 122:193-198). Thus, this activation seems to be an important, early response to myocellular damage.

    Skeletal muscles
    PARACLINICAL

 obtained from

    myopathies
    DIAGNOSIS

 with

    myofiber necrosis
    MICROSCOPIC

, including

    mdx dystrophic mice
    DIAGNOSIS

,

    plasmocid-induced myopathy
    DIAGNOSIS

 in rats, and patients with

    Duchenne muscular dystrophy
    DIAGNOSIS

, were examined

    immunohistochemically
    PARACLINICAL

 with anticathepsin-peroxidase conjugates.

    Strong reactions for lysosomal cysteine proteinases, which can degrade myofibrillar proteins
    MICROSCOPIC

, were

    demonstrated in macrophages invading and surrounding the necrotic areas and some degenerative myofibers and also in intramyofibral portions of atrophic fibers
    MICROSCOPIC

 of dystrophic mice and

    humans
    GENDER

.

    Apparently normal and regenerating myofibers did not stain for lysosomal cathepsins
    NEG_FINDINGS

.

    Abnormal increases of cathepsins L and B
    BIOCHEMICAL

 were seen even in the early stage of

    plasmocid myopathy
    DIAGNOSIS

 and in a

    20-day-old
    AGE

    young mdx mouse
    AGE

 before

    infiltration of macrophages
    MICROSCOPIC

, suggesting that

    autodigestion by intramyofibral lysosomal proteinases
    MICROSCOPIC

 is an important event before

    digestion of the necrotic fibers
    MICROSCOPIC

    by macrophage proteinases
    BIOCHEMICAL

.

    Activation of the intramyofibral lysosomal system
    MICROSCOPIC

, as in

    muscular dystrophy
    DIAGNOSIS

, was also observed in

    distal myopathy
    DIAGNOSIS

 with

    rimmed vacuoles
    MICROSCOPIC

    without macrophageal infiltration
    NEG_FINDINGS

 (Am J Pathol 1986, 122:193-198). Thus, this activation seems to be an important, early response to

    myocellular damage
    SYMPTOMS

.

myopathies
mdx dystrophic mice
plasmocid-induced myopathy
Duchenne muscular dystrophy
plasmocid myopathy
muscular dystrophy
distal myopathy


Female carriers of Duchenne muscular dystrophy: a dilemma.

In this paper female non-identical twins of a known Duchenne carrier are presented; one has typical features and the anticipated progression of Duchenne dystrophy, the other appears to be normal. In addition, two female children with Duchenne-like dystrophy are discussed. These cases show no evidence of translocation or mosaicism and offer an opportunity to reappraise the genetics of Duchenne dystrophy with specific regard to females. The subjects have been fully investigated, and in Case 3 the glycolytic enzymes and mitochondrial energy-producing capacity were also studied.

In this paper

    female
    GENDER

    non-identical twins of a known Duchenne carrier
    FAMILY

 are presented; one has

    typical features and the anticipated progression of Duchenne dystrophy
    SYMPTOMS

, the other appears to be normal. In addition, two

    female
    GENDER

    children
    AGE

 with

    Duchenne-like dystrophy
    DIAGNOSIS

 are discussed. These cases show

    no evidence of translocation or mosaicism
    NEG_FINDINGS

 and offer an opportunity to reappraise the genetics of

    Duchenne dystrophy
    DIAGNOSIS

 with specific regard to

    females
    GENDER

. The subjects have been fully investigated, and in Case 3 the

    glycolytic enzymes
    BIOCHEMICAL

 and

    mitochondrial energy-producing capacity
    BIOCHEMICAL

 were also studied.

Duchenne-like dystrophy
Duchenne dystrophy

glycolytic enzymes
mitochondrial energy-producing capacity


Weaning from mechanical ventilation: successful use of modified inspiratory resistive training in muscular dystrophy.

An 18-yr-old man with Duchenne muscular dystrophy and ventilatory failure could not be weaned from mechanical ventilation using a T-piece method, despite repeated attempts over 3 months. Subsequently, we weaned the patient using inspiratory muscle resistive training (IRT), modified by the concurrent delivery of intermittent mandatory ventilation (IMV). During the training program, the sessions were gradually prolonged from 5 min to a maximum of 30 min, the IMV rate was gradually decreased, and the magnitude of the resistive load was gradually increased. After 45 days of training, his vital capacity had increased from 380 to 850 ml, his maximal inspiratory airway pressure from -28 to -50 cm H2O, and his tolerance of T-piece breathing, from less than 10 min to over 16 h. After an additional 2 wk of nocturnal mechanical ventilation, he was successfully weaned. We conclude that IRT with IMV can be an effective method of weaning patients who have severe ventilatory failure.

An

    18-yr-old
    AGE

    man
    GENDER

 with

    Duchenne muscular dystrophy
    DIAGNOSIS

 and

    ventilatory failure
    SYMPTOMS

    could not be weaned from mechanical ventilation using a T-piece method, despite repeated attempts over 3 months
    NEG_FINDINGS

. Subsequently, we

    weaned
    MEDICATION

 the patient using

    inspiratory muscle resistive training (IRT), modified by the concurrent delivery of intermittent mandatory ventilation (IMV)
    MEDICATION

. During the

    training program
    MEDICATION

,

    the sessions were gradually prolonged from 5 min to a maximum of 30 min
    MEDICATION

,

    the IMV rate was gradually decreased
    MEDICATION

, and the magnitude

    of the resistive load was gradually increased
    MEDICATION

. After

    45 days of training
    MEDICATION

, his

    vital capacity had increased from 380 to 850 ml
    SYMPTOMS

, his

    maximal inspiratory airway pressure from -28 to -50 cm H2O
    SYMPTOMS

, and his

    tolerance of T-piece breathing
    NEG_FINDINGS

, from less than 10 min to over 16 h.

    After an additional 2 wk of nocturnal mechanical ventilation
    MEDICATION

,

    he
    GENDER

 was successfully

    weaned
    MEDICATION

. We conclude that

    IRT with IMV
    MEDICATION

 can be an effective method of

    weaning
    MEDICATION

 patients who have

    severe ventilatory failure
    SYMPTOMS

.


DNA deletions in mild and severe Becker muscular dystrophy.

The DNA of 33 patients diagnosed as suffering from Becker muscular dystrophy (BMD) has been probed with cloned DNA sequences from Xp21, known to reveal DNA deletions in patients suffering from the more severe Duchenne muscular dystrophy (DMD). Two BMD cases showed clear deletions. A third case gave aberrant band sizes, which further analysis showed to be caused by a small deletion. This suggests that deletions in DXS164 occur approximately as frequently in BMD as they do in DMD. Of the two cases showing large deletions, one is at the severe end of the Becker clinical spectrum, whilst the other is a classical Becker-type dystrophy. The fact that loci defined by probes commonly deleted in classical DMD patients are also deleted in BMD patients of varying severity is strong additional evidence that these disorders are allelic, and further justifies the use of probes with defined linkage relationships to DMD also being used for counselling in BMD families.

    The DNA
    PARACLINICAL

 of 33 patients diagnosed as suffering from

    Becker muscular dystrophy (BMD)
    DIAGNOSIS

 has been

    probed with cloned DNA sequences from Xp21
    PARACLINICAL

, known to reveal

    DNA deletions
    GENETICS

 in patients suffering from the more

    severe Duchenne muscular dystrophy (DMD)
    DIAGNOSIS

. Two

    BMD
    DIAGNOSIS

 cases showed

    clear deletions
    GENETICS

. A third case gave

    aberrant band sizes
    SYMPTOMS

, which further analysis showed to be caused by a

    small deletion
    GENETICS

. This suggests that

    deletions in DXS164
    GENETICS

 occur approximately as frequently in

    BMD
    DIAGNOSIS

 as they do in

    DMD
    DIAGNOSIS

. Of the two cases showing

    large deletions
    SYMPTOMS

, one is at the

    severe end of the Becker clinical spectrum
    SYMPTOMS

, whilst the other is a

    classical Becker-type dystrophy
    DIAGNOSIS

. The fact that

    loci defined by probes commonly deleted in classical DMD patients
    GENETICS

    are also deleted
    GENETICS

 in

    BMD
    DIAGNOSIS

 patients of varying severity is strong additional evidence that these disorders are allelic, and further justifies the use of probes with defined linkage relationships to

    DMD
    GENETICS

 also being used for counselling in

    BMD
    DIAGNOSIS

 families.


A linkage study of Emery-Dreifuss muscular dystrophy.

We have searched for linkage between polymorphic loci defined by DNA markers on the X chromosome and X-linked Emery-Dreifuss muscular dystrophy (EDMD). There are high recombination rates between EDMD and the Xp loci known to be linked to Becker and Duchenne muscular dystrophy. There is a suggestion of linkage between EDMD and the loci DXS52 and DXS15, defined by probes St14 and DX13 respectively, located at Xq28. Z for DXS15 = 1.14 at theta = 0.15. This is in agreement with the previously reported linkage between a disorder strongly resembling EDMD and colour-blindness (Thomas et al. 1972), suggesting that there is a second locus on the X chromosome concerned with muscle integrity.

We have searched for linkage between

    polymorphic loci defined by DNA markers on the X chromosome
    GENETICS

 and

    X-linked Emery-Dreifuss muscular dystrophy (EDMD)
    DIAGNOSIS

. There are

    high recombination rates
    GENETICS

 between

    EDMD
    DIAGNOSIS

    and the Xp loci known to be linked to Becker and Duchenne muscular dystrophy
    GENETICS

. There is a suggestion of linkage between

    EDMD
    DIAGNOSIS

    and the loci DXS52 and DXS15, defined by probes St14 and DX13 respectively, located at Xq28. Z for DXS15 = 1.14 at theta = 0.15
    GENETICS

. This is in agreement with the previously reported linkage between a

    disorder strongly resembling EDMD
    SYMPTOMS

 and

    colour-blindness
    SYMPTOMS

 (Thomas et al. 1972), suggesting that there is a

    second locus on the X chromosome
    GENETICS

 concerned with

    muscle integrity
    SYMPTOMS

.

disorder strongly resembling EDMD
colour-blindness
muscle integrity