Characteristic findings of skeletal muscle MRI in

caveolinopathies

メタデータ 言語: jpn

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公開日: 2020-01-20
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キーワード (En):
作成者: 石黒, 久美子
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URL https://doi.org/10.20780/00032432
 Available online at www.sciencedirect.com

Neuromuscular Disorders 28 (2018) 857–862

www.elsevier.com/locate/nmd

Characteristic findings of skeletal muscle MRI in caveolinopathies

Kumiko Ishiguro a, Takahiro Nakayama b, Masaru Yoshioka c, Terumi Murakami a,
Sachiko Kajino a, Minobu Shichiji a, Takatoshi Sato a, Naomi Hino-Fukuyo d, Satoshi Kuru e,
Makiko Osawa a, Satoru Nagata a, Mariko Okubo f, Nobuyuki Murakami g, Yukiko K Hayashi f,h,
Ichizo Nishino f, Keiko Ishigaki a,∗
a Department of Pediatrics, School of Medicine, Tokyo Women’s Medical University, 8–1 Kawada-cho, Shinjuku-ku, Tokyo, Japan
b Departmentof Neurology, Japan Organization of Occupational Health and Safety, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan
c Department of Neurology, National Hospital Organization Sendai Nishitaga Hospital, Sendai, Miyagi, Japan
d Department of Pediatrics, Tohoku University School of Medicine, Sendai, Miyagi, Japan
e Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Mie, Japan
f Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan
g Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama, Japan
h Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan

Received 30 January 2018; received in revised form 16 May 2018; accepted 25 July 2018

Abstract
Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular
dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic
skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one
patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF)
mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus
muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and
observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps
femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal
muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due
to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific
findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.
© 2018 Elsevier B.V. All rights reserved.

Keywords: Caveolinopathy; Caveolin-3; Rippling muscle disease; Limb-girdle muscular dystrophy 1C; Skeletal muscle magnetic resonance imaging;
Polymerase I and transcript release factor.

1. Introduction cle disease (RMD), limb-girdle muscular dystrophy type 1C

(LGMD1C), distal myopathy, familial hypertrophic cardiomy-
Caveolins are important components of uncoated plasma opathy, and idiopathic hyper creatine kinasemia (hyperCK-
membrane invaginations that regulate both signal transduc- emia) [2,3]. The clinical phenotypes may overlap each other
tion and vesicular trafficking [1]. Mutations in the CAV3 within the same individual or in individuals within the same
gene encoding caveolin-3 that maps to chromosome 3p25 family and present with the same mutations in CAV3; thus,
can produce several phenotypes, including Rippling mus- the genotype-phenotype correlation remains unclear [4].
RMD is a rare autosomal dominant disorder, characterized
by signs of increased muscle irritability. These signs, which
∗ Corresponding author.
give RMD its name include percussion-induced rapid contrac-
E-mail addresses: ishigaki.keiko@twmu.ac.jp, keishi@ped.twmu.ac.jp (K.
Ishigaki). tion, percussion-induced localized muscle mounding, and/or

https://doi.org/10.1016/j.nmd.2018.07.010
0960-8966/© 2018 Elsevier B.V. All rights reserved.
858 K. Ishiguro et al. / Neuromuscular Disorders 28 (2018) 857–862

percussion/ stretching-induced rolling movements across a confluent areas of increased density with muscle still present
muscle group (muscle rippling) [5]. Patients with RMD may at the periphery; and Stage 4, end-stage appearance with mus-
begin to suffer from muscle cramps, pain, and stiffness during cle entirely replaced by areas of increased density. The pat-
the first or second decade of their lives. Despite normal mus- terns of each of the affected muscles were classified accord-
cle strength, patients with RMD are often unable to sit down ing to the Treat-NMD workshop report as follows: Stage 0–1,
on their heels, and toe walking is a common observation. Re- black; Stage 2a–2b, gray; and Stage 3–4, white (Figs. 1 and
cently, congenital generalized lipodystrophy type 4 with mus- 2; cross sections of thigh and calf) [7,8].
cular dystrophy (CGL4) due to polymerase I and transcript
release factor (PTRF) mutations, has been reported (OMIM 3. Case description
#613,327). Patients with PTRF deficiency present with loss
of subcutaneous adipose tissues from birth, manifestations of 3.1. Case 1
muscular dystrophy, arrhythmia, and several other symptoms
[6]. Secondary reduction of caveolin-3 may progress with Case 1 was a 28-year-old woman, who had an elder brother
age or disease progression, and percussion-induced muscle with epilepsy, but no skeletal muscle symptoms; her parents
mounding is a characteristic finding in patients with PTRF and an elder sister were also asymptomatic (Fig. 3(a)). His-
deficiency as well as in patients with RMD caused by CAV3 tory revealed that she would fall down very often at 5–6 years
mutations. of age. At 11 years of age, she started to complain of muscle
Several skeletal muscle-imaging studies have recently been pain in the thigh after exercise, which was followed by rapid
reported for differential diagnosis and assessment of the pro- progression of calf muscle hypertrophy. At the age of 12, she
gression of each distinct neuromuscular disorder. T1-weighted was found to have a high serum CK level (14,171 U/L). Neu-
(T1W) skeletal muscle magnetic resonance imaging (MRI) of rological evaluation revealed moderate muscle weakness of
the lower limbs in genetically distinct neuromuscular disor- the neck anteflexion (3/5) and mild muscle weakness (4/5) in
ders have identified specific patterns characteristic to these the proximal limb muscles. She showed symptoms like weak
neuromuscular diseases. To date, there have been a few re- grip and apparent percussion myotonia. Deep tendon reflexes
ports on specific muscle MRI patterns in patients with cave- were slightly hyperactive in all extremities. She was unable
olinopathies. Herein, we present characteristic skeletal MRI to sit down on her heels due to calf muscle hypertrophy.
findings in four patients with childhood-onset RMD, who Muscle CT revealed atrophic and moth-eaten changes in the
were identified with known CAV3 mutations, and in one pa- rectus femoris, hamstrings, and gastrocnemius, with hyper-
tient with CGL4, who developed secondary caveolin-3 de- trophy of the vastus lateralis and paraspinal muscles. Fig. 4
ficiency due to PTRF deficiency. In addition, we reviewed presents her skeletal muscle CT at 18 years of age. Muscle
skeletal muscle imaging examinations of previously reported biopsy revealed moderate muscle fiber size variation, a few
caveolinopathies. necrotic and regenerating fibers, and moderate endomysial
fibrosis. The number of internal nuclei was increased and
2. Material and methods immunohistochemistry revealed that the cells were negative
for caveolin-3. The subject continued to experience stiffness
Muscle MRI was performed using conventional T1 and cramps with gradual progression of limb-girdle muscle
weighted spin echo on a 1.5-tesla TOSHIBA or Philips MR weakness. At 28 years of age, she complained of difficulty
scanner. Non-contrast images of the thighs and legs were ob- in jumping and climbing upstairs, and thus, skeletal muscle
tained. The axial plane was selected with respect to the long MRI images were obtained (Figs 1 and 2). Genetic analy-
axis of the body. The thickness of the slices ranged from 5 sis revealed a CAV3 mutation: p. Glu47Asp, which has been
to 10 mm with a gap of 10–20 mm between each slice. A reported to cause RMD [2].
fast gradient echo was used for pilots, whereas a spin echo
pulse sequence was used for the images (repetition time [TR], 3.2. Cases 2 and 3
424–696 ms; echo time [TE], 10–18 ms; row matrix 320–512
points; column matrix, 219–512 points; and variable field of Cases 2 and 3 were siblings, an 8-year-old and a 6-year-
view [FOV], 25–40 cm). The average total examination time old boy, respectively. At 9 months of age, the proband case
was 30 min per patient. Skeletal muscle MRI was evaluated (Case 3) was evaluated for motor development delay. He was
by a radiologist, a neurologist, and two pediatric neurologists. unable to sit without support and mild muscle weakness was
Individual muscles of the patients were analyzed; the involve- noted. At 17 months, elevated serum CK levels (500–800 U/L)
ment of 19 muscles in the leg (12 in the thigh and 7 in the were observed. He had been unable to jump at 2 years and
lower leg) were assessed and categorized using the Mercuri 6 months of age, and experienced muscle pain after exercise
score [7] as follows: Stage 0, normal appearance; Stage 1, and upon awakening at the age of 4 years and 8 months. He
scattered small areas of increased density; Stage 2a, numer- lacked the strength to unscrew bottle caps. Neurological eval-
ous discrete areas of increased density less than 30% of the uation revealed isolated muscle weakness in the anteflexion
volume of the muscle; Stage 2b, numerous discrete areas of of the neck (3/5). He showed calf hypertrophy and difficulty
increased density with early confluence (30%–60% of the vol- bending the ankle joints. Symptoms similar to percussion my-
ume of the muscle); Stage 3, washed-out appearance due to otonia such as mounding of his leg muscles and rippling were
 K. Ishiguro et al. / Neuromuscular Disorders 28 (2018) 857–862 859

Fig. 1. Muscle MRI findings and classification according to the Mercuri score of Thigh. T1W muscle MRI imaging (upper) and the schema (lower) of the
affected muscles of the thigh (a) of each of the four cases. The schema indicates the pattern of muscles affected based on the individual muscles assessed.
The finding was graded according to the Mercuri score as follows: Stage 0–1, presented as black color; Stage 2a–2b, gray; and Stage 3–4, white. The rectus
femoral, sartorius, and biceps femoral muscles appeared shrunken and irregular in shape with indentations between the muscles and the connective tissue
resulting in a wrinkled effect on the MR images.

detected. Deep tendon reflexes were normal. Gower’s sign months of age, elevated CK levels (1417 U/L) were observed
was negative. Muscle biopsy at the age of 3 years indicated when she underwent catheter treatment for the cardiac prob-
moderate muscle fiber size variation, few necrotic and regen- lem. She showed mild motor developmental delay, such as
erating fibers, and moderate endomysial fibrosis. The number gained head control at 5 months and walking at 21 months of
of internal nuclei was increased and the cells were negative age. The subject presented with hyperreflexia, which included
for caveolin-3. Family history revealed that both his mother, the biceps and triceps reflex, patellar reflex, and Achilles ten-
36 years old at presentation, and his elder brother (Case 2), don reflex. She showed symptoms similar to percussion my-
had muscle pain and stiffness (Fig. 3(b)). His mother had otonia and apparent mounding. Her father was also noticed
often experienced leg cramps since elementary school. to have mild mounding, rippling, and thigh and calf muscle
The 8-year-old boy (Case 2) presented with calf muscle hy- hypertrophy. He could not sit down on his heels, although
pertrophy and complained of muscle pain after school. Both his symptoms were much milder than that of his daughter.
he and his mother showed mounding of the lower legs. The Genetic analysis of the patient and her father revealed the
severity of increased muscle irritability in Case 2 was more presence of a mutation in CAV3: p. Arg27Gln, which was the
remarkable than that in Case 3. Skeletal muscle MRI was same as that seen in Cases 2 and 3. Skeletal muscle MRI was
performed for Cases 2 and 3 at 8 and 4 years of age, respec- performed for Case 4 at 2 years of age (Figs. 1 and 2).
tively (Figs. 1 and 2). Genetic analysis revealed the presence
of a mutation in CAV3: p. Arg27Gln in the two boys and
their mother. This mutation has previously been associated 3.4. Case 5
with RMD [9,10].
Case 5 was a 3-year-old boy with CLG4 caused by
PTRF mutations [11]. He showed delayed motor develop-
3.3. Case 4 ment (started walking at 2 years and 6 months of age) and
insulin resistance (at 3 years of age). He presented with a
Case 4 was a 2-year-old girl, who was born as a very low homozygous c.696_697insC mutation in PTRF. Muscle CT
birth weight infant with aortic coarctation (Fig. 3(c)). At 3 was evaluated at the age of 3 years (Fig. 5).
860 K. Ishiguro et al. / Neuromuscular Disorders 28 (2018) 857–862

Fig. 2. Muscle MRI findings and classification according to the Mercuri score of Calf. T1W muscle MRI imaging (upper) and the schema (lower) of the
affected muscles of the calf of each of the four cases, as Fig. 1. Only Case 1 showed mild changes in the gastrocnemius muscles.

4. Results mius muscles. The rectus femoris and semitendinosus muscles

were also affected in Case 2. The vastus medialis, but not the
Skeletal Muscle MRI (Figs. 1 and 2) and CT scans (Figs. 3 calf muscles, were also involved. The most marked changes
and 4) in Case 3 included peripheral changes in the rectus femoris
Muscle CT scans of Case 1 at 18 years of age revealed and atrophy of the semitendinosus muscles, whereas the bi-
atrophic and moth-eaten changes in the rectus femoris, ham- ceps femoris was very mildly affected. The youngest patient
strings, and gastrocnemius (Fig. 4). in the current study (Case 4) had already demonstrated appar-
Changes in T1-weighed skeletal muscle MRI scans of the ent peripheral changes in the rectus femoris. In fact, changes
thigh and calf muscles were evaluated. In Case 1, MRI scans in rectus femoris were commonly noticed in all four cases in
of the skeletal muscles of the calves were obtained a few this study. The changes were more diffuse in Case 1, whereas
years after those of the thighs. The pattern of changes was in the other three cases, atrophic or peripheral changes form-
found to be similar in all four cases (Fig. 1). Case 1 showed ing ring-like patterns were noted in the rectus femoris.
diffuse changes mainly in the rectus femoris, sartorius, bi- Muscle CT images from Case 5 revealed peripheral in-
ceps femoris, and semitendinosus muscles. In addition, mild volvement of the rectus femoris and marked reduction in sub-
changes were noted in the semimembranosus and gastrocne- cutaneous adipose tissue (Fig. 5).

Fig. 3. Family trees of the four patients. (a) Case 1, (b) Case 2, (c) Case 4. ND: mutations were not detected. NA: patients were not analyzed.
 K. Ishiguro et al. / Neuromuscular Disorders 28 (2018) 857–862 861

Fig. 5. Muscle CT image of the patient with PTRF deficiency. Muscle CT

image of the 3-year-old boy with PTRF deficiency. Atrophic or peripheral
fatty changes were observed in the rectus femoris only.

ring-like pattern, which appears to be specific for this dis-

ease. Careful review of previous case reports revealed that
peripheral changes in the shape of the rectus femoris mus-
cle and diffuse changes in the semitendinosus muscle were
common in patients with RMD [13,14]. Scalco et al. reported
that only one (a 12-year-old boy) of the eight patients in
their study had presented with abnormal MRI findings (mild
involvement of the rectus femoris, sartorius, biceps femoris,
gastrocnemius, and semitendinosus muscles); the remaining
patients had demonstrated normal muscle images or not been
Fig. 4. Muscle CT scan images of Case 1 aged 18 years old. Muscle CT scan tested. In another case report on a family with RMD, a 28-
revealed atrophic and moth-eaten changes in the rectus femoris, hamstrings, year-old male presented with striking symmetric lipomatous
and gastrocnemius. degeneration of the distal parts of the rectus femoris, and
mild changes in the semitendinosus muscles, similar to Case
1 in the current study. In another report involving a 39-year-
5. Discussion old Japanese male with RMD and extraocular muscle paresis,
peripheral changes in the rectus femoris and mild changes
In recent years, the importance of clinical muscular imag- in the semitendinosus muscles were clearly noticeable in the
ing in patients with suspected or proven inherited muscle figure, although the authors had not commented on them in
diseases has increasingly been recognized [12]. The specific the original report [14].
patterns of skeletal muscle imaging facilitate differential diag- We evaluated muscle involvement changes specific to var-
nosis in some muscular dystrophies. To date, there have been ious stages ranging from early infancy to adulthood in RMD
a few reports on skeletal muscle imaging in patients with and identified a correlation between the degree of muscle in-
caveolinopathies; most patients with RMD demonstrated nor- volvement and the age or stage. The rectus femoris and semi-
mal skeletal muscle imaging [13]. In the present study, we tendinosus muscles were most affected in all four cases, al-
reported four patients, including young children from three though the range of involvement increased as the disease pro-
families, with childhood-onset RMD. The striking findings of gressed with age (Case 1). Furthermore, the pattern of muscle
this study using skeletal muscle MRI were that the peripheral MRI involvement was detectable even in a toddler (Case 4),
rectus femoris and semitendinosus muscles were affected in where the change was detected only in the rectus femoris,
the four childhood-onset RMD patients. The rectus femoris, whereas in school-aged children, the muscle involvement had
in particular, showed atrophic or peripheral involvement in a expanded from the rectus femoris to the semitendinosus and
862 K. Ishiguro et al. / Neuromuscular Disorders 28 (2018) 857–862

sartorius muscles. Interestingly, Case 1, the most severely af- Acknowledgment

fected adult patient with muscle weakness, showed high T1W
signal intensities extending to the semimembranosus, biceps This work was supported by Intramural Research Grant
femoris, gracilis, adductor longus, and gastrocnemius muscles. (29–3) for Neurological and Psychiatric Disorders of NCNP.
In previous reports, adult patients with RMD showed abnor-
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