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Textbook Genetic Neuromuscular Disorders A Case Based Approach 2Nd Edition Corrado Angelini Auth Ebook All Chapter PDF
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Genetic
Neuromuscular
Disorders
A Case-Based
Approach
Second Edition
Corrado Angelini
123
Genetic Neuromuscular Disorders
Corrado Angelini
Genetic Neuromuscular
Disorders
A Case-Based Approach
Second Edition
Corrado Angelini
IRCCS Fondazione S.Camillo Hospital
Università di Padova,
Dipartimento di Neuroscienze Padova
Venice
Italy
v
Contents
vii
viii Contents
Index�������������������������������������������������������������������������������������������������������������������� 425
Part I
Muscular Dystrophies
Duchenne Muscular Dystrophy
1
Description
Case Report
Laboratory Exams
Conclusion
Duchenne dystrophy can be due to point mutation or intragenic deletion or dupli-
cation in the dystrophin gene. Usually, the analysis of dystrophin protein in the
muscle showed absent protein, but in about 30% of cases, occasional “revertant”
fibers can be detected [3, 4]. These partially dystrophin-positive fibers result
from spontaneously occurring reversion of the mutation in some nuclei, but their
presence does not significantly influence the age at loss of ambulation.
Treatment with corticosteroids (deflazacort) is the gold standard [5].
Corticosteroids should be introduced when the child’s motor skills plateau, usu-
ally between 5 and 7 years of age (Figs. 1.1 and 1.2). Complications of cortico-
steroid therapy must be managed and include body weight management, H2
antagonists for gastric protection, regular monitoring and treatment of osteopo-
rosis, and ophthalmic assessment for cataracts and glaucoma. Regular cardiac
monitoring is also required to allow early treatment with ACE inhibitors. Surgery
may be required for correction of the scoliosis, and nocturnal BIPAP is beneficial
for the treatment of restrictive respiratory failure. DMD has a severe prognosis,
and life expectancy is significantly reduced with death occurring in early adult-
hood. The use of steroids, particularly deflazacort, has given a considerable
result both in prolonging ambulation and antagonizing secondary phenomenon
such as respiratory insufficiency and/or cardiomyopathy.
Laboratory Exams 5
a b c d
e f g
h i
Fig. 1.1 Patients with Duchenne muscular dystrophy at different ages. Note calf hypertrophy (a)
and hypotrophy of the quadriceps muscles (b), gait on tiptoes and Achilles tendon retraction in a
steroid-treated patient with weight gain (c, d), and waddling gait in one long-walker patient (e).
Weakness and atrophy in the lower girdle muscles cause the Gowers’ maneuver (f–i): when the
patient rises from the floor, he needs to help himself with one or two hands
6 1 Duchenne Muscular Dystrophy
a b c d
e f g h
Fig. 1.2 Patients with Duchenne muscular dystrophy. Weakness and atrophy in the lower
girdle muscles cause difficulty rising from a chair (a–d) and climbing the stairs (e, f).
Weakness and atrophy in the upper girdle muscles cause difficulty dressing (g) and lifting
objects over the head (h)
Key Points
• Duchenne boys lose ambulation before 12 years; if treated with steroids, they
may prolong walking ability.
• Cardiomyopathy has to be monitored and treated.
References
1. Melacini P, Vianello A, Villanova C, Fanin M, Miorin M, Angelini C, et al. Cardiac and respi-
ratory involvement in advanced-stage Duchenne muscular dystrophy. Neuromuscul Disord.
1996;6:367–76.
2. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne
muscular dystrophy locus. Cell. 1987;51(6):919–28.
References 7
Description
Heterozygous mutations in the DMD gene (Table 2.1) may be observed in female
carriers of Duchenne muscular dystrophy. They are usually asymptomatic but may
present with enlargement of calf muscles and muscle cramps. Some cases have
overt muscle weakness or a severe myopathy, depending on the degree of random
X-chromosome inactivation pattern. CK level is an important marker of carrier sta-
tus, being elevated in about 70% of carriers. The use of antibodies to dystrophin in
muscle biopsy has improved the identification of carriers, showing single or clus-
tered fibers with negative dystrophin labeling. DMD carriers are susceptible to
develop a dilated cardiomyopathy, since cardiac muscle cells cannot regenerate and
an unfavorable X-chromosome inactivation pattern may result in large groups of
negative fibers. Conversely, the skeletal muscle is a syncytium where regeneration
is possible, and some nuclei can migrate and compensate for the lack of dystrophin.
In the DMD carrier here described, the most relevant sign was dilated cardiomyopa-
thy that required cardiac transplantation.
Case Report
This woman was diagnosed at 25 years of age as a DMD carrier after DMD had
been diagnosed in her son (molecular analyses of the DNA revealed the presence of
an intragenic frameshift deletion involving exons 50–52 in the dystrophin gene and
the absence of dystrophin in his muscle biopsy). She showed an increased CK level
at rest (1187 U/L). She complained of limb weakness, myalgia, and precordial pain
and had an isolated monomorphic premature ventricular complex. On neurological
examination, she showed bilateral calf hypertrophy, difficulty in hopping, and mild
weakness in the proximal limb muscles. At 28 years, she had tested positively for
hepatitis B infection. At 30 years of age, she underwent vastus lateralis muscle
biopsy that confirmed her carrier status. One year later, she underwent bilateral
Laboratory Exams
a c e
d
f
Fig. 2.1 Dystrophin immunofluorescence analysis in skeletal muscle from control (a) and the
patient (b) showing some fibers (asterisk) with almost absent reaction. The explanted heart (c, d)
showed dilated left ventricle and fibrofatty replacement. Dystrophin immunofluorescence analysis
in explanted heart showed the typical “mosaic pattern” of dystrophin-positive and dystrophin-
negative cardiomyocytes (e, f)
Conclusion
Carriers of DMD have been known from studies conducted in families [4].
Manifesting carriers invariably show fibers or part of the fibers that lack dystro-
phin, giving rise to a somatic mosaic of X-chromosome inactivation pattern,
according to the classical Lyon’s hypothesis. CK levels are an important indica-
tor of carrier status and can be found also in sporadic females. The present case
exemplifies an extreme case of cardiomyopathy, while usually carriers present
12 2 Duchenne Muscular Dystrophy Carrier
with mild pathological muscle changes and both clinical and instrumental abnor-
malities in the cardiac tissue. This differentiates DMD carriers from most LGMD
female patients.
Key Points
• DMD carriers might have only high CK, but symptomatic carriers usually pres-
ent with myopathy and/or cardiomyopathy.
References
1. Melacini P, Fanin M, Angelini A, et al. Cardiac transplantation in a Duchenne muscular dystro-
phy carrier. Neuromuscul Disord. 1998;8:585–90.
2. Melacini P, Gambino A, Caforio A, et al. Heart transplantation in patients with inherited myop-
athies associated with end-stage cardiomyopathy: molecular and biochemical defects on car-
diac and skeletal muscle. Transplant Proc. 2001;33:1596–9.
3. Fanin M, Melacini P, Angelini C, Danieli GA. Could utrophin rescue the myocardium in
patients with dystrophin gene mutation? J Mol Cell Cardiol. 1999;31(8):1501.
4. Emery AEH. Duchenne muscular dystrophy: genetic aspects, carrier detection and antenatal
diagnosis. Br Med Bull. 1980;36:117–22.
Becker Muscular Dystrophy
3
Description
After the historical description by Becker and Kiener in 1955 in affected families,
the discovery of the dystrophin gene led to a drastic reconsideration of clinical phe-
notypes associated with deletion or duplication of the dystrophin gene (Table 3.1)
[1], and several different clinical entities were described with associated different
prognosis according to the localization of mutation and residual amount of dystro-
phin protein [2, 3].
Among these phenotypes there are cramps and myalgia, myoglobinuria, mild
myopathy, quadriceps myopathy, late-onset myopathy, and X-linked dilated cardio-
myopathy. It is not uncommon to find patients with deletion in the dystrophin gene
that have normal strength and endurance but high CK. Specific cases with early
cardiomyopathy are also a variant of BMD [4, 5] and may be susceptible to cardiac
transplantation [6].
Case Reports
This 7-year-old child was molecularly diagnosed at age 3 years because of asymp-
tomatic hyperCKemia. Unless for an occasional episode of malaise and hyperCK-
emia after dehydration, he is currently asymptomatic.
This boy presented with X-linked-positive family history for myoglobinuria and
suffered since age 9 years from recurrent myoglobinuric episodes and cramps
a b c d e
f g h
Fig. 3.1 Patients affected with BMD. Note hypotrophy of quadriceps muscles (b, d, e, g, h), broad
base posture (d, e), hypertrophy of the calves (a, e), and Gowers’ maneuver (f). Some patients
developed severe cardiomyopathy and required heart transplantation (g, h). Patient 1 (a), patient 2
(b), patient 3 (c, d), patient 4 (e), patient 5 (f), and patient 6 (g, h)
Laboratory Exam 15
associated with persistent high CK. At 21 years of age, he presented with frequent
muscle cramps, Gowers’ sign, calf hypertrophy, and lower girdle muscle
weakness.
This 10-year-old child presented with cramps and myalgia since age 7 years.
Elevated CK led to the diagnosis, following the identification of an enormous dys-
trophin (about 600 kDa) caused by the most large duplication so far reported in the
dystrophin gene [1]. The patient is now 35 years old, and he presents with waddling
gait (possible with the aid of a cane) and inability to rise from a chair and from the
floor and has developed a severe dilated cardiomyopathy.
At age 50 years, this man complained of muscle weakness and high CK levels. He
then developed a late-onset myopathy, leading at age 66 years to waddling gait, dif-
ficulty climbing stairs, and calf hypertrophy. His 9-year-old grandson complained
of myoglobinuria with high CK and was also diagnosed as affected with Becker
dystrophy.
This 32-year-old man suffered from age 28 years of muscle weakness on both gir-
dles and had high CK levels, waddling gait, Gowers’ sign, marked hypotrophy of
quadriceps muscles, and slight calf hypertrophy.
This 15-year-old boy presented with muscle weakness, high CK levels, recurrent
myoglobinuric episodes, scoliosis, calf hypertrophy, waddling gait, and thigh hypot-
rophy. He developed an early and severe form of dilated cardiomyopathy, which
required cardiac transplantation at age 25 years.
Laboratory Exam
We showed that mutations in the proximal region of the DMD gene (exons 2–10) are
associated with severe phenotype, those in the proximal region of central rod domain
(exons 11–43) are associated with mild or asymptomatic phenotype, and those in the
distal region of central rod domain (exons 44–55) are associated with the classical
16 3 Becker Muscular Dystrophy
Conclusion
The clinical heterogeneity of BMD is extreme. Patients might present with
cramps/myalgia syndrome with high CK; others have recurrent myoglobinuric
episodes, while loss of strength is usually seen in the typical cases. A good term
to define this disorder is mild dystrophinopathy.
The heart involvement is crucial to determine prognosis in some cases. Some
cases have a predominant heart phenotype. The recommendation of ENMC in
BMD is to have every year an ECG and echocardiographic monitoring. The use
of multiple dystrophin antibodies in immunoblot is useful to give to individual
patients a prognosis.
Key Points
• There is a wide clinical variability for BMD, ranging from cramps/myalgia syn-
drome to proximal myopathy with cardiomyopathy.
• Western blot analysis is most useful for diagnosis, demonstrating abnormality of
dystrophin quantity, and molecular weight, usually due to in-frame deletion/
duplications in the dystrophin gene.
References
1. Angelini C, Beggs AH, Hoffman EP, Fanin M, Kunkel LM. Enormous dystrophin in a patient
with Becker muscular dystrophy. Neurology. 1990;40:808–12.
2. Angelini C, Fanin M, Pegoraro E, et al. Clinical-molecular correlation in 104 mild X-linked
muscular dystrophy patients: characterization of subclinical phenotypes. Neuromuscul Disord.
1994;4:349–58.
3. Angelini C, Fanin M, Freda MP, et al. Prognostic factors in mild dystrophinopathies. J Neurol
Sci. 1996;142:70–8.
4. Melacini P, Fanin M, Danieli GA, et al. Cardiac involvement in Becker muscular dystrophy.
J Am Coll Cardiol. 1993;22:1927–34.
5. Melacini P, Fanin M, Danieli GA, et al. Myocardial involvement is very frequent among
patients affected with subclinical Becker muscular dystrophy. Circulation. 1996;94:3168–75.
6. Melacini P, Gambino A, Caforio A, et al. Heart transplantation in patients with inherited myop-
athies associated with end-stage cardiomyopathy: molecular and biochemical defects on car-
diac and skeletal muscle. Transplant Proc. 2001;33:1596–9.
Emery-Dreifuss Muscular Dystrophy
Type 1 4
Description
Case Report
This boy had one maternal uncle affected with muscular dystrophy with an onset
of weakness at age 14 years, elbow contractures, tricuspid valve insufficiency,
and high CK levels. The proband’s mother has normal CK level. The patient
started walking at age 13 months with flexed knees. In the following years, he
presented with progressive muscle weakness. At age 7 years, he had waddling
gait, Gowers’ sign, diffuse muscle hypotrophy, and mild mental retardation. CK
was 1800 U/L.
Laboratory Exam
a b
Fig. 4.1 Muscle biopsy sections immunostained for emerin. Note that in comparison with the
control muscle (a) where the nuclear membrane is correctly stained, in the muscle from the patient
(b), the reaction is absent
Conclusion
Immunohistochemical studies of emerin easily detect its absence from all nuclei
in affected male patients with X-linked EDMD. In addition to the muscle,
emerin absence can be also detected in the skin and buccal cells requiring no
muscle biopsy when the diagnosis is suspected. Parallel studies of lamins are
useful controls. Furthermore, in carrier of the X-linked form, skin biopsies can
be used to demonstrate nuclei with and without emerin (X-chromosome inacti-
vation) [1, 2].
Key Points
References
1. Emery AE, Dreifuss FE. Unusual type of benign X-linked muscular dystrophy. J Neurol
Neurosurg Psychiatry. 1966;29:338–42.
2. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D. Identification
of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet.
1994;8:323–7.
Emery-Dreifuss Muscular Dystrophy
Type 2 5
Description
Case Report
Patient 1
This boy (Fig. 5.1) was born from nonconsanguineous parents but has one paternal
uncle and one paternal cousin affected with an unknown form of muscle disease. At
age 2 years, he presented with waddling gait, difficulty running and climbing stairs
(possible only with support of the rail), and Gowers’ sign. At age 4 years, he