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An unusual variant of Becker muscular dystrophy.

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References
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PJ, Bruyn GW, eds. Handbook of clinical neurology, vol 8.
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pain, but varieties of hereditary sensory and automatic neuropathy. Brain 1983;106:373-390
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An Unusual Variant
of Becker Muscular
Dystrophy
Marianne de Visser, MD,* Egbert Bakker, PhDJ
Joep C. Defesche, MSc,t Piet A. Bolhuis, PhD,’?
and Gert Jan van Ommen, PhD3
We report on 5 brothers with slowly progressive limbgirdle weakness. Calf hypertrophy was absent. The
levels of creatine kinase, electromyography, and
findings from a muscle biopsy specimen were compatible with muscular dystrophy. The propositus’s biopsy
specimen also showed numerous rimmed vacuoles. DNA
analysis revealed a deletion in the dystrophin gene, establishing a diagnosis of Becker muscular dystrophy.
Both the absence of calf hypertrophy and the presence
of rimmed vacuoles are unusual features in this disorder.
de Visser M, Bakker E, Defesche JC, Bolhuis PA,
van Ommen GJ. An unusual variant
of Becker muscular dystrophy.
Ann Neurol 1990;27: 5 78-58 1
Becker muscular dystrophy (BMD) is an X-linked recessive muscular dystrophy. The genes for BMD and
Duchenne muscular dystrophy (DMD) are allelic, the
so-called dystrophin gene, and assigned to band p21
on the short arm of the X chromosome 11, 2).
The clinical criteria for the diagnosis of BMD are:
X-linked recessive inheritance; slow progressive muscle weakness, greater proximally than distally; ambulation maintained at least until the age of 16 years; and
hypertrophy of the calf. Laboratory features include
significantly elevated activities of serum creatine kinase
(CK), and electromyographical (EMG) and histopathological changes indicating mostly acute and/or chronic
From the Departments of *Neurology and ?Experimental Medicine,
University of Amsterdam, Amsterdam, and the Department of
$Human Genetics, State University Leiden, Leiden, The Netherlands.
Received Aug 9, 1989, and in revised form Oct 13. Accepted for
publication Nov 6, 1989.
Address correspondence to D r de Visser, Department of Neurology, Academic Medical Center, Meibergdreef 9, 1105 A 2 Amsterdam, The Netherlands.
578 Copyright 0 1990 by the American Neurological Association
I
I1
Ill
ma
1
2
3
4
years
5
~
Fig 1. Pedigree. The propositus is indicated by the a w w . Open
square = male; open circle = f m l e ; hatched square = afected;
x = subject was examined.
myopathy but sometimes also chronic denervation
f3-51.
A kinship is described in which 5 of 7 brothers were
found to have a myopathy manifesting as mild limbgirdle weakness with early onset. DNA analysis using
complementary DNA (cDNA) and genomic probes of
the short arm of the X chromosome was carried out
and showed a deletion in all 5 affected family members. However, the absence of hypertrophy of the calf
in all patients and the presence of rimmed vacuoles in
the propositus’s muscle biopsy specimen are highly unusual features in BMD.
Case Reports
Propositus
The propositus (11-3, Fig l), a 22-year-old man, had never
been able to run properly. Difficulty in climbing stairs and
rising from a chair prompted him to seek medical advice. On
clinical examination, he had a waddling gait and a positive
Gowers’ sign. He showed slight atrophy of the proximal
muscles of the leg and no hypertrophy of the calves. There
was minimal to moderate symmetrical weakness of the prox-
imal limb muscles. Knee jerks were absent. There were
no sensory deficits or fasciculations. Contractures were not
noted. Serum CK activity was markedly raised (3,600 units/
liter; normal upper value in our laboratory, 130 unitdliter).
EMG of the left rectus femoris muscle showed fibrillation
potentials and positive sharp waves at rest. In addition, myopathic changes were found in various leg muscles. Motor and
sensory nerve conduction velocities were normal. Electrocardiography (ECG) showed no abnormalities. Computed tomographic (CT) examination of the skeletal muscles at the
midportion of the thighs revealed a decrease in attenuation
of the quadriceps femoris, the long head of the biceps
femoris, the semimembranosus, and the adductor magnus
muscles. The gracilis and semitendinosus muscles were
round and slightly hypertrophic.
The Family
Subjects 1-1, 1-2, 11-2, 11-5, and 11-9 (see Fig 1) had no
objective neuromuscular signs. Serum CK activities were
normal in all these individuals. Subjects 11-6, 11-7, and 11-8
were asymptomatic but, according to their parents, had always had a “stiff” gait. On examination, they were found to
have limb-girdle weakness, similar to that of the propositus.
However, muscle weakness in the sibs was only mild. Serum
CK activities were markedly elevated in all 3 (2,700-3,500
unitdliter). ECGs showed no abnormalities. EMG, performed in 11-6 and 11-7, showed myopathic changes. Subject
11-4 was also asymptomatic, but on clinical examination,
there was pelvifemoral weakness. In addition, slight bilateral
ptosis, pectus excavatum, moderate thoracic kyphoscoliosis,
and bilateral pes cavus were found. Serum CK activity was
6,490 unitdliter.
Results
Muscle Pathological Findings
Muscle biopsy specimens were taken from the left
quadriceps femoris muscle in 4 of the patients.
In the muscle specimen from
Subject 11-3 (the propositus), the fiber diameters
ranged from 4 to 120 pm (Table). The atrophic fibers
LIGHT MICROSCOPY.
Summaiy of Histopathological Findings in Muscle
Subject No.
Diameter (range) (pm)
Type I fibers
Type I1 fibers
Fibers with internal nuclei
Fiber splitting
Regenerating fibers
Necrotic fibers
Rimmed vacuoles
Angular atrophic fibers
Endomysial fibrosis
+
= mild;
++
=
moderate;
11-3
11-6
11-7
11-8
4-110
4-120
22%
6- 130
12-120
40%
8-100
12-100
20%
12-90
12-110
10%
-
-
-
+++
+
+
+
+
+++
+
+
++
+++
++
+++
+
++
+
+
++
+
-
++
+
+
= marked; - = absent.
Brief Communication: de Visser et al: An Unusual Variant of BMD 579
the type described in inclusion body myositis were
seen.
Electron microscopy yielded no additional information to the light microscopic examination in the 3 sibs.
Biochemical Analysis
In the propositus, the activity of a-1,4 glucosidase was
within the normal range.
Fig 2. Transverse section of Propositus’s quadriceps muscle.
(A)Atrophicfibers are clustered together and stained dark(y
with oxidative enzyme activity. (NADH-TR; x 350 before
3J% reduction.) (B) Marked variation in the diameter of muscle
fibers and numerous rimmed vacuoles are shown. (Modzfied
Gomori trichrome stain; x 350 before 35% reduction.)
were round or angular and accompanied by pycnotic
nuclear clumps, tended to cluster together and stained
darkly with the NADH-TR (tetrazolium reductase)
reaction (Fig 2A) and the nonspecific esterase. Type
grouping was not observed. However, the most conspicuous feature was the presence of numerous
rimmed vacuoles (see Fig 2B). Approximately 10% of
the fibers, mostly of type 11, showed this feature. The
vacuoles were negative with periodic acid-Schiff and
oil red 0 stains.
The histopathological findings in the 3 sibs (Subjects
11-6, 11-7, and 11-8) are summarized in the Table.
ELECTRON MICROSCOPY. In Subject 11-3 (the propositus), numerous autophagic vacuoles containing
myelin figures were observed. They were located
under the sarcolemma and centrally in otherwise wellpreserved muscle fibers. N o filamentous inclusions of
580 Annals of Neurology
Vol 2 7
No 5
May I990
Molecular Genetic Analysis
Restriction fragment length polymorphisms (RFLPs)
and DNA deletions were investigated in DNA from
peripheral blood of the parents, the 5 patients, and one
of the 2 healthy brothers. Southern blots were hybridized previously {b] with RC8, D2, 99.6, B24, C7,
PERT 87-15, PERT 87-8,PERT 87-1, XJ2.3, XJ1.l,
754, 754-11, OTC, and L1.28 for RFLP analysis and
with cDNA probes 9-7, 30-1, 30-2,47-4, and 63-1 for
detection of deletions. N o definite deletions were detected, using five of the six available cDNA probes.
From the RFLP data, the probability of BMD was calculated as described previously [7], resulting in a posterior probability of 0.95 {6]. In the present study the
deletion analysis was extended with the dystrophin
cDNA probe 44-1 (also called probe 8) {8] and with
probe 7b8. The latter cDNA probe, which was constructed by Miss Petra Grootscholten in Leiden, contains part of probe 47-4 linked to probe 44-1. This
new probe detects the 10-kb HindIII band much better than the two separate probes. A deletion in all 5
patients was detected on a HindIII and on an EcoRI
digestion, using both 44-1 and 7b8. The following
genomic DNA bands were missing: for HindIII--0.5
kb, 1.5 kb, 10 kb, 1.25 kb, and 3.8 kb; and for
EcoRI-25 kb, 12 kb, 4.4 kb, and 6.6 kb, indicating a
deletion involving exons 45 to 48 of the dystrophin
gene. Sequence and clinical data {9, lo] show that this
type of deletion does not disturb the translational reading frame. In our own series of patients, 4 of 5 with a
similar deletion [I 11 were clinically diagnosed as having BMD, while the fifth had a new mutation and to
date was too young for a reliable differential diagnosis.
Discussion
The affected siblings in this family shared the following
features: (1) male involvement exclusively; (2) mild to
moderate pelvifemoral weakness with early and insidious onset; (3) absence of hypertrophy of the calves; (4)
absence of cardiac involvement; ( 5 ) markedly elevated
serum CK activity; and (6) deletion in the dystrophin
or DMDlBMD gene on the short arm of the X
chromosome. The markedly elevated serum CK activities, EMG findings, CT scan of the propositus’s thigh
muscles, and histopathological changes in three out of
four muscle biopsy samples are fully compatible with a
diagnosis of BMD [3, 4, 5, 12, 131. The presence of
the deletion in the X chromosomal dystrophin gene in
our patients unequivocally indicates that this deletion
is the cause of the disorder.
Our patients only partially met the clinical criteria
adopted for the diagnosis of BMD 131, since hypertrophy of the calf was absent. Most authors consider
muscle hypertrophy an obligatory feature in BMD.
However, calf enlargement was not found in 5 of
23 familial cases of BMD, examined by one of us
(M. d. V.) { 121. Only one of these patients had lost the
ability to walk.
The most prominent finding in the propositus’s muscle specimen (i.e., rimmed vacuoles) appears to be
atypical for BMD. Rimmed vacuoles or autophagic
vacuoles are secondary lysosomes. When lysosomal enzymes are delivered to membrane-bound spaces containing sequestered cytoplasmic material, these spaces become secondary lysosomes or autophagic vacuoles
[l4]. They most likely reflect a nonspecific active
process of the muscle fiber induced by sublethal cell
injury 1151. This is in accordance with the benign
course of the disease in our index patient. They have
been described in various neuromuscular disorders
[14-181 but have not been reported previously in
BMD. We have no explanation for the absence of
rimmed vacuoles in the sibs.
The absence of hypertrophy of the calf and the presence of rimmed vacuoles necessitate a differentiation
of the disorder in our family not only from other Xlinked neuromuscular diseases but also from disorders
that are histologically characterized by rimmed vacuoles. The limb-girdle distribution of muscle weakness
in our family and the absence of contractures or fasciculations make a diagnosis of one of the other wellknown X-linked neuromuscular diseases (X-linked recessive bulbospinal neuronopathy and Emery-Dreifuss
muscular dystrophy) highly unlikely. As for the disorders with autophagy, the recently reported family
with X-linked myopathy with excessive autophagy
El51 bears clinical resemblance to our kindred. However, in contrast with our findings, RFLP analysis performed in their family excluded the DMD/BMD locus
as the site of the genetic defect [19].
The Prinses Beatrix Fonds provided financial support (grant 872762).
We thank Ms. Petra Grootscholten and Mr. Sander Kneppers for
technical assistance, and Mrs. Joke van Gulik for typing the manuscript.
2. Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein
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51919-927
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References
1. Kunkel LM, et al. Analysis of deletions in DNA from patients
with Becker and Duchenne muscular dystrophy. Nature 1986;
322~73-77
Brief Communication: de Visser et al: An Unusual Variant of BMD
581
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