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Neuromuscular Disorders 31 (2021) 968–977

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Review
A review of core myopathy: central core disease, multiminicore disease,
dusty core disease, and core-rod myopathy
Masashi Ogasawara a,b,c, Ichizo Nishino a,b,∗
a Department of Neuromuscular Research, National Center of Neurology and Psychiatry (NCNP), National Institute of Neuroscience, 4-1-1 Ogawahigashi,
Tokyo 187-8502, Japan
b Medical Genome Center, NCNP, Tokyo, Kodaira, Japan
c Department of Pediatrics, Showa General Hospital, Tokyo, Kodaira, Japan

Received 2 July 2021; received in revised form 13 August 2021; accepted 16 August 2021

Abstract
Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable.
Core myopathies are diagnosed by muscle biopsy showing focally reduced oxidative enzyme activity and can be pathologically divided into
central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Although RYR1-related myopathy is the most common
core myopathy, an increasing number of other causative genes have been reported, including SELENON, MYH2, MYH7, TTN, CCDC78,
UNC45B, ACTN2, MEGF10, CFL2, KBTBD13, and TRIP4. Furthermore, the genes originally reported to cause nemaline myopathy, namely
ACTA1, NEB, and TNNT1, have been recently associated with core-rod myopathy. Genetic analysis allows us to diagnose each core myopathy
more accurately. In this review, we aim to provide up-to-date information about core myopathies.
© 2021 Elsevier B.V. All rights reserved.

Keywords: Core myopathy; Central core disease; Multiminicore disease; Dusty core myopathy; Core-rod myopathy.

1. Introduction from a target fiber. Core myopathy is classified into CCD,

Core myopathies are clinically, pathologically, and
genetically heterogeneous muscle diseases. Areas of muscle
fibers that do not show oxidative enzyme staining, which
indicates lack of mitochondrial and oxidative enzyme activity,
are the characteristic pathological feature of the ‘cores’ [1].
Central core disease (CCD) which is the most frequent
and well-recognized subtype of core myopathy shows cores
running along the muscle fiber [1]. These cores also do not
stain with phosphorylase or other substances, but can be
rimmed with periodic acid-Schiff staining [2]. Neurogenic
disorders also show core structures that are characterized by
‘target fibers’ and ‘targetoid fibers’ [3]. Target fibers have
three distinct zones and are more focal than central cores;
however, it is sometimes difficult to differentiate a core
∗ Corresponding author at: Department of Neuromuscular Research,
National Center of Neurology and Psychiatry (NCNP), National Institute of
Neuroscience, 4-1-1 Ogawahigashi, Tokyo 187-8502, Japan.
E-mail address: nishino@ncnp.go.jp (I. Nishino).
multiminicore disease (MmD), dusty core disease (DuCD),
and core-rod myopathy, depending on histological findings on
muscle biopsy [4–7]. The core regions in CCD, MmD, DuCD,
and core-rod myopathy show a lack of NADH-TR enzymatic
activity, suggesting the absence of mitochondria and varying
degrees of myofibrillar disruption. There is considerable
pathological/genetic overlap in congenital myopathy; one
congenital myopathy is caused by various mutated genes,
and vice versa, one gene also causes various myopathies
[8,9]. The causative gene for CCD is RYR1 [10]. In contrast,
the causative genes for MmD vary widely, including RYR1,
SELENON, MYH2, MYH7, TTN, CCDC78, UNC45B, ACTN2,
and MEGF10 [11–20] (Table 1). DuCD is also caused by
biallelic mutations in RYR1 [7]. Core-rod myopathies are
caused by mutations in RYR1, NEB, ACTA1, KBTBD13,
CFL2, TRIP4, and TNNT1 [21–28] (Table 1). Here, we have
reviewed the different types and genetic causes of myopathies
(Table 2).

https://doi.org/10.1016/j.nmd.2021.08.015
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M. Ogasawara and I. Nishino Neuromuscular Disorders 31 (2021) 968–977

Table 1 conversion precedes core formation in disease development

Pathological features of core myopathy for each gene. (Fig. 1A–F) [32,33]. The cores are most likely formed at
Gene CCD MmD DuCD Core-rod myopathy the periphery of muscle fibers and then extend longitudinally
RYR1 +++ + + + toward the central region [7,34]. There is a correlation
SELENON – ++ – – between core position and disease stage; older patients
MYH2 – + – – with more advanced stage disease show more centralized
MYH7 – + – – cores [34]. Proteins such as desmin, αβ-crystallin, filamin
TTN – + – –
CCDC78 – + – –
C, small heat-shock proteins, myotilin, RYR1, triadin, and
UNC45B – + – – dihydropyridine receptor (DHPR) accumulate at the core and
ACTN2 – + – – can be visualized by immunohistochemistry [7,33–37]. As
MEGF10 – + – – mentioned earlier, some of patients with a dominant RYR1
NEB – – – + mutation in the C terminal region of the gene may show the
ACTA1 – – – +
KBTBD13 – – – +
CNMDU1 phenotype. Even in these patients, some of these
CFL2 – – – + proteins accumulate in the fibers despite the absence of a
TRIP4 – – – + core structure, suggesting that CNMDU1 due to a dominant
TNNT1 – – – + C-terminal RYR1 mutation is a de facto core myopathy
[33,34,36].

2. Central core disease 2.1. RYR1-related myopathy

In 1956, Shy and Magee first reported dominantly
inherited non-progressive congenital myopathy in a family
with anatomical changes observed in the central fibrils using
Gomori trichrome staining [4]. Later, Dubowitz and Pearse
found that enzyme histochemistry, including phosphorylase
and oxidative enzyme staining, can reveal muscle fiber type
as well as define central cores [1,29]. Typical CCD shows
extreme type 1 fiber predominance with only a few type
2 fibers or even none at all, which is sometimes termed
“uniform type 1 fiber.” When some type 2 fibers are observed,
cores have a predilection for type 1 fibers [2,30,31]. Typical
CCD presents single cores, often at the center but sometimes
at the periphery of a fiber. Occasionally, more than one
core can be observed within the same fiber [31]. The
cores in typical CCD are extended for more than several
millimeters longitudinally and are found throughout the length
of a myofiber. Further, dominantly inherited cases show
“structured” cores, characterized by a striated myofibrillar
pattern and myofibrillar adenosine triphosphatase (ATPase)
activity [2]. In contrast, “unstructured” cores, which are
often seen in recessive cases, are defined by a decrease
in myofibrillar ATPase activity. However, observation of
these “structured” and “unstructured” cores is not useful for
diagnosis [2]. Typical CCD is associated with RYR1 mutations
at the C terminus of the gene. In contrast, patients with non-C
terminal RYR1 mutations show atypical cores characterized by
indistinct borders, location at the periphery or subsarcolemmal
region of fibers, and an ovoid shape [30]. Further, patients
with non-C terminal RYR1 mutations tend to have multiple
cores compared to those with C terminal RYR1 mutations,
showing multiminicore disease [30]. Interestingly, young
patients in families with pathologically confirmed typical
CCD sometimes show extreme type 1 fiber predominance or
uniform type 1 fiber but no cores; therefore, these patients are
sometimes diagnosed with congenital neuromuscular disease
with uniform type 1 fiber (CNMDU1). The presence of
such patients in the same family suggests that fiber-type
Mutations in RYR1 lead to dominantly inherited CCD
and the malignant hyperthermia susceptibility trait, which
is a rare pharmacogenetic syndrome characterized by
muscle rigidity and an increase in body temperature after
exposure to anesthetics via inhalation [10,38]. RYR1-related
myopathy is known to be associated with a wide range of
diseases, including MmD, congenital fiber-type disproportion,
centronuclear myopathy (CNM), King Denborough syndrome,
CNMDU1, and DuCD [7,38–42].
Patients with CCD show non-progressive or slowly
progressive weakness in truncal and proximal muscles.
Patients often show orthopedic problems, including congenital
hip dislocation, scoliosis, and club foot deformities [43].
Some patients show severe muscle weakness from infancy
while others develop symptoms in late adulthood, indicating
a wide clinical diversity most likely depending on the severity
of the mutation. Nevertheless, patients within a family sharing
the same dominant RYR1 mutation sometimes develop widely
variable phenotypes in terms of muscle involvement, raising
the possibility that additional risk factors are present [44].
Typical CCD is characterized clinically by early onset,
pathologically by the presence of distinct cores in almost all
type 1 fibers, and genetically by a dominant mutation at the
C terminal region of RYR1 [30]. In contrast, patients with
an RYR1 mutation outside the C terminal region show milder
clinical phenotypes and atypical cores on muscle biopsy [30].
In addition, patients with recessive RYR1 mutations, which
are usually distributed throughout the entire coding sequence,
develop more severe phenotypes than those with dominant
RYR1 mutations, and sometimes show fetal akinesia syndrome
[39,45]. Extraocular and bulbar muscle involvement can also
be observed in patients with recessive RYR1 mutations [39].
Central nuclei are an important feature of RYR1-related
myopathy, especially in relation to recessive cases, which can
lead to misdiagnosis of centronuclear myopathy [46].
In most patients with RYR1 mutations, the rectus
femoris, adductor longus, sartorius, and soleus muscles are

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Table 2
Clinicopathological features of core myopathies for each genetic mutation.

Gene/ Reference Inheritance Onset Clinical features Pathological features Muscle imaging
RYR1 AD/AR Neonatal to External ophthalmoplegia, Central and peripheral core, Involvement; Sa,
[7,9,42,87] adult bulbar involvement, multiminicores, T1FP / AM, Vasti
scoliosis, dislocation of the uniform type 1, rods and Sparing; RF, Gra, AL
hips, malignant hyperthermia cores, fiber-type
disproportion, dusty core
SELENON AR Neonatal to Axial myopathy with Multiminicores in both fiber Involvement; Sa
[11,51] late adult scoliosis, respiratory failure, types, T1FP
spinal rigidity
MYH2 AR Neonatal to Facial weakness and Multiminicores, T1FP Involvement; QF, ST,
[12,54,55] adult dysmorphism, proximal AM
weakness, scoliosis, Sparing; BF, Sa
ophthalmoplegia
MYH7 AD Neonatal to Weakness of great toe/ankle T1FP, cores or Involvement; VM,
[13,88] late adult dorsiflexors, neck flexor, multiminicores, hyaline Sa, TA
finger extensor, and facial bodies
weakness
TTN AR Neonatal to Neonatal hypotonia, facial T1FP, core-like areas, Involvement;
[14,64] childhood muscle weakness, dilated multiple internal nuclei longhead of BF
cardiomyopathy
CCDC78 AD Neonatal to Neonatal hypotonia, distal Atypical cores, T1FP NA
[15] childhood weakness, excessive fatigue,
myalgias, cognitive
involvement
UNC45B AR Infancy to Axial and proximal T1FP / Uniform type 1, Involvement;
[17] childhood weakness, delayed motor unstructured cores, eccentric Generalized
milestones, calf hypertrophy cores Sparing; SM
ACTN2 AD Neonatal to Distal weakness, Subsarcolemmal cores, Sparing; ST, SM, BF
[18,19] adult ophthalmoplegia, ptosis, well-delimited cores, T1FP
cardiac abnormalities,
respiratory involvement
MEGF10 AR Neonatal to Axial, fascial, and proximal Multiminicores, eosinophilic Involvement; Sa, SM,
[20,68] adult weakness, scoliosis, aggregates AM
respiratory problems, Sparing; RF, AL, Gra
contractures, nasal speech
NEB AR Neonatal to Generalized hypotonia, Nemaline bodies and cores Involvement; TA,
[24,75,76] childhood bilateral foot-drop, Soleus
ACTA1 AD Infancy to Proximal or generalized T1FP, unstructured cores Involvement; QF, Ga
[72,80] childhood muscle weakness, delayed
motor milestones, facial
weakness
KBTBD13 AD Childhood Proximal and neck weakness Rods and cores Inside-to-outside,
[25,81] zebra pattern of GM,
central shadow of RF
CFL2 AR Neonatal Floppy infant, respiratory Nemaline bodies, minicores NA
[23,82] distress
TRIP4 AR Neonatal to Axial and proximal Multiminicores, nemaline Involvement;
[27] adult weakness, rigid spine, rods, cytoplasmic, bodies, Posterior thigh
dysmorphic facies, caps, rimmed fibers Sparing; ST
cutaneous involvement,
respiratory failure, dilated
cardiomyopathy
TNNT1 AR Neonatal to Proximal weakness, Multiminicores in type 1 Involvement; SM,
[28] infancy scoliosis, congenital hip fibers, nemaline rods in type AM
luxation, rhabdomyolysis, 1 fibers Sparing; AT, gracilis
rigid spine, respiratory
involvement

Abbreviations: AD, autosomal dominant; AL, adductor longus; AM, adductor magnus; AR, autosomal recessive; AT, anterior thigh; BF, biceps femoris; Ga,
gastrocnemius; GM, gluteus maximus; Gra, gracilis; NA, not available; QF, quadriceps femoris; RF, rectus femoris; Sa, sartorius; SM, semimembranosus; ST,
semitendinosus; T1FP, type 1 fiber predominance; TA, tibialis anterior; VM, vastus medialis.

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M. Ogasawara and I. Nishino Neuromuscular Disorders 31 (2021) 968–977

Fig. 1. Histology and electron microscopy of muscle biopsy samples from one family with a dominant RYR1 mutation.
The son with CNMDU1 had muscle biopsy at 1 year and 8 months of age (A, B). The father with CCD had muscle biopsy at 27 years of age (C-F). (A)
NADH staining did not reveal cores. (B) ATP 4.2 staining showed that almost all fibers were type 1. (C) NADH staining revealed cores in almost all fibers. (D)
ATP 4.2 staining showed that almost all fibers were type 1. (E, F) Myofibril derangement and zigzag z-lines devoid of mitochondria are observed throughout
the myofiber. (A–D) Black bars indicate 50 μm. (E) White bar indicates 5 μm. (F) White bar indicates 1 μm.

relatively spared compared to the vastus lateralis, adductor
magnus, gracilis, and gastrocnemius muscles, respectively
[47]. Interestingly, this pattern is observed in both dominant
and recessive RYR1-related myopathy, except those with
ophthalmoparesis [47,48].
3. Multiminicore disease
MmD is characterized histochemically by the presence of
multiple small areas devoid of oxidative enzymes, indicating
the absence of mitochondria, and ultrastructurally by the focal
disruption of myofibrils [2]. This condition was originally
described in two children in a family who both displayed
non-progressive myopathy. It was termed “multicore disease”
by Engel in 1971; however, the condition was not molecularly
resolved, and clinically and pathologically, it resembled
disease associated with recessive RYR1 [8]. Nevertheless,
multiminicores are a non-specific finding and can be observed
in various diseases, including other myopathies, tenotomy, and
even neuropathic conditions (“target fibers”) [2,31]. Further,
moth-eaten fibers in muscular dystrophies resemble fibers
with minicores [31]. Therefore, it is usually difficult to
diagnose MmD solely based on muscle biopsy findings.
In addition, MmD per se is not a single disease but
is associated with numerous genetic causes that result
in multiminicores or cores. In the next sections, we
review current information on each gene associated with
MmD.
3.1. SELENON-related myopathy
SELENON-related myopathy is caused by recessive
mutations in SELENON, which encodes selenoprotein N and
used to be designated SEPN1. SELENON-related myopathy
is clinically characterized by axial myopathy with scoliosis
and/or torticollis, as well as respiratory failure [11,49].

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Fig. 2. Histology and electron microscopy of muscle biopsy samples from patients with MmD, DuCD, or core-rod myopathy.
(A–D) SELENON-related myopathy, (E, F) CCDC78-related myopathy, (G, H) UNC45B-related myopathy, (I, J) MEGF10-related myopathy, (K, L) DuCD,
and (M-P) NEB-related myopathy. (A) NADH staining revealed multiminicores. (B) ATP 10.6 staining showed that fibers with cores were type 1. (C, D) Z-line
streaming was observed in a limited area. (E) NADH staining revealed atypical cores. (F) mGT showed irregular staining in some muscle fibers. (G) NADH
staining showed increased staining along subsarcolemma and decreased staining in the central regions. (H) HE staining showed increased internal nuclei. (I)
NADH staining showed multiple cores. (J) HE staining showed marked fiber size variation, perimysial fibrosis, and fiber size variation. (K) NADH staining
showed decreased or increased enzymatic activity, sometimes in the same core. (L) mGT detection showed irregular areas of reddish-purple granular material
deposition. (M) NADH staining revealed cores. (N) ATP 10.6 staining showed that fibers with cores were type 1. (O) mGT detection showed clustered fibers
with nemaline bodies. (P) Electron microscopy showed many nemaline bodies. (A, B, E–O) Black and white bars indicate 50 μm. (C, P) White bars indicates
2 μm. (D) White bar indicates 0.5 μm.

Disease onset is usually during the neonatal period or
early childhood, patients require ventilatory support before
adulthood [50], and muscle MRI shows selective high-level
sartorius muscle involvement [51].
In contrast to RYR1-related myopathy, with cores observed
virtually exclusively in type 1 fibers, multiminicores can be
observed in both type 1 and 2 fibers, albeit more often
in type 1 fibers (Fig. 2A, B) [2]. Ultrastructurally, focal
disruption of myofibrils in minicores encompass only a
few sarcomeres, which is different from the central cores
associated with a dominant RYR1 mutation, and they are
extended throughout the length of the myofiber (Fig. 2C, D)
[11]. Immunohistochemically, calsequestrin, triadin, SERCA,
and DHPR are absent in the cores associated with SELENON-
related myopathy, unlike those in RYR1-related myopathy
[36].
3.2. MYH2-related myopathy
MYH2-related myopathy is caused by autosomal dominant
or recessive mutations on the MYH2-encoding myosin heavy
chain 2 [12,52]. Initially, Darin et al. reported 19 patients
with an autosomal dominant MYH2 mutation who had joint
contractures and hip dislocation at birth [52,53]. Lossos

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M. Ogasawara and I. Nishino
et al. later described 16 patients with recessive MYH2
mutations who had upper and lower proximal limbs, neck
flexors, shoulder girdle, and facial muscle weakness [12,54].
Those patients also show facial dysmorphism, scoliosis,
and external ophthalmoplegia without ptosis or aberrant eye
movements [12,54]. The onset of MYH2-related myopathy
with recessive mutations ranges from childhood to late adult
stage [12,54]. Muscle MRI shows prominent fat infiltration
in the quadriceps, adductors, and semitendinosus muscles, but
not in the biceps femoris and sartorius muscle [55].
In dominant MYH2-related myopathy, the predominant
and initial morphological change is the formation of
multiminicores in type 2A fibers, which is logical since the
mutations affect only type 2A fibers [52]. Recessive MYH2-
related myopathy, on the other hand, is usually caused by
truncating mutations and lack of type 2A fibers; therefore,
there are no true multiminicores but secondary alterations and
frequently type 1 fiber uniformity [56]. Some recessive cases
are due to missense mutations and, in a few of these cases,
type 2 fibers, typically without multimini cores, are present
[55].
3.3. MYH7-related myopathy
MYH7-related myopathies show clinically and
histopathologically variable phenotypes. Mutations in MYH7,
encoding the slow skeletal muscle fiber myosin heavy chain,
was initially reported in patients without skeletal muscle
weakness but with hypertrophic cardiomyopathy and cores
via muscle biopsy [57]. However, not all affected fibers
are type 1 and more cores are unstructured compared with
typical CCD due to dominant RYR1 mutations. Dominant
MYH7 mutations also cause Laing distal myopathy, which
is pathologically characterized by non-specific myopathic
changes, including excessive variation in fiber size, central
nucleation, fiber splitting, moth-eaten fibers, and ring fibers
[58]. However, multiminicores are also reported in some
patients with distal myopathy due to MYH7 dominant
mutations [13,59].
3.4. TTN-related myopathy
Mutations in the TTN gene encoding titin have been
associated with various skeletal and cardiac muscle diseases,
including dominantly inherited familial dilated cardiopathy
[60], autosomal recessive early-onset myopathy with fatal
cardiomyopathy (EOMFC) [14], tibial muscular dystrophy
[61], and hereditary myopathy with early respiratory failure
[62,63]. Minicores have also been reported in case of TTN-
related myopathy [14,64]. As for muscle MRI findings, one
report described symmetrical fatty infiltration of the long
head of the biceps femoris along with the semimembranosus
and semitendinosus muscles in TTN-related myopathy with
minicores [64].
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Neuromuscular Disorders 31 (2021) 968–977
3.5. CCDC78-related myopathy
Majczenko et al. reported five patients in one large
family who had dominantly inherited mutations in CCDC78,
which encodes coiled-coil domain-containing 78, and showed
congenital myopathy characterized by distal weakness and
atypical cores diagnosed via muscle biopsy (Fig. 2E, F) [15].
Clinical features of this myopathy are neonatal hypotonia,
effects predominantly in the distal muscle, excessive fatigue,
prominent myalgias, and mild cognitive involvement [15].
Muscle biopsy shows type 1 fiber predominance, prominent
central nuclei, and core-like areas [15].
3.6. UNC45B-related myopathy
In 2019, Dafsari et al. reported a patient with
congenital myopathy with a core-like structure diagnosed
via muscle biopsy that was caused by biallelic mutations
in uncoordinated mutant number-45 myosin chaperone B
(UNC45B) [16]. Subsequently, Donkervoort et al. reported ten
patients with biallelic mutations in UNC45B who exhibited
childhood-onset progressive muscle weakness [17]. Most of
them showed proximal muscle weakness and calf hypertrophy
[17]. Upon NADH staining, large irregular areas of oxidative
defects were observed in numerous muscle fibers that showed
eccentric cores (Fig. 2G, H) [17].
3.7. ACTN2-related myopathy
In 2019, Lornage et al. reported patients with congenital
myopathy caused by dominant mutations in ACTN2, which
encodes alpha-actinin-2 [18,19]. Lornage et al. reported
two patients who showed hypotonia from birth and muscle
weakness at the age of 7 years [18]. Savarese et al. reported
four families with adult-onset asymmetric distal muscle
weakness with initial ankle dorsiflexion involvement that later
progressed to proximal muscles [19]. Muscle biopsy showed
“unique multiple subsarcolemmal cores,” which are different
from typical minicores and are structured with type 1 fiber
predominance [18]. Recently, Chen et al. reported small well-
delimited cores in patients with a novel frameshift ACTN2
variant [65]. MRI findings in ACTN2-related myopathy show
selective muscle involvement in tibialis anterior muscles,
extensor digitorum longus, soleus, gastrocnemius medialis,
semimembranosus, and quadriceps femoris except for rectus
femoris [19].
3.8. MEGF10-related myopathy
Biallelic truncating mutations on MEGF10, encoding a
transmembrane protein of the multiple epidermal growth
factor family, was first described as early-onset myopathy
with areflexia, respiratory distress, and dysphagia (EMARDD)
[66]. Subsequently, Boyden et al. reported three patients
with compound heterozygous missense MEGF10 mutations
who developed infantile-onset myopathy with neck flexor
weakness, neck contracture, and multiminicores on muscle
M. Ogasawara and I. Nishino
biopsy [20]. Liewluck et al. reported that two patients with
compound heterozygous missense mutations in MEGF10
showed adult-onset respiratory insufficiency, scoliosis, distal
joint hyperlaxity, high-arched feet, and multiminicores
diagnosed via muscle biopsy (Fig. 2I, J) [67]. Although a
few reports describe muscle MRI results from patients with
MEGF10-related myopathy, gracilis muscles appear relatively
preserved compared to the severely involved sartorius muscle
[68,69].
4. Dusty core disease
Recently, Garibaldi et al. proposed “DuCD,” which is
defined by irregular areas of myofibrillar disorganization
with reddish-purple granular material depositions that show
uneven oxidative staining and are devoid of ATPase activity
(Fig. 2K, L) [7]. Dusty cores have peculiar histological
and ultrastructural characteristics compared with other core
myopathies; dusty cores have no clear borders, are not
round/ovoidal in shape, and have no regular size, in contrast
to typical CCD cores, which appear as clear ovoidal areas
devoid of oxidative enzymatic staining [7]. DuCD is a new
category of core myopathy; it was previously diagnosed as
CCD, centronuclear myopathy, MmD, or core-rod myopathy
[7]. DuCD is also caused by recessive RYR1 mutations and
is the most common pathological consequence of biallelic
mutations in RYR1 [7]. No other genes that cause MmD or
core-rod myopathy have been reported to cause DuCD (Table
1). In addition, a dominant RYR1 mutation has never been
shown to cause DuCD. Clinically, patients with DuCD show
earlier disease onset and a more severe clinical phenotype
than those with other types [7,70].
5. Core-rod myopathy
Core-rod myopathy is defined by a combination of distinct
cores and rods in the same patients [21,71]. Rods and cores
are often in separate fibers but can be seen in the same fibers.
The fact that areas with rods may appear as cores because
of loss of mitochondria should be considered for diagnosis.
Initially, Monnier et al. reported that an autosomal dominant
RYR1 mutation at the C terminal region of the gene causes
congenital myopathy with cores and rods in muscle fibers
[21,71]. ACTA1, NEB, and TNNT1 were originally reported
to cause nemaline myopathy. Subsequently, ACTA1, NEB,
and TNNT1 were also associated with core-rod myopathy
[22,24,28,72], followed by KBTBD13, CFL2, and TRIP4
[23,25,27,73]. Of note, actin accumulation in patients with
CFL2 or ACTA1 mutations appears as pale zones by ATPase
and NADH staining, mimicking cores [8].
5.1. NEB-related myopathy
Autosomal recessive mutations in NEB encoding nebulin
were reported to cause nemaline myopathy in 1999 [74].
Romero et al. first reported a case with core-rod myopathy
that showed generalized hypotonia and required immediate
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Neuromuscular Disorders 31 (2021) 968–977
intubation and resuscitation at birth [24]. However, clinical
phenotypes of core-rod myopathy caused by NEB mutations
are variable [75–77]. Some patients have shown mild
symptoms and began walking in the normal milestone range
or up to 3 years of age [75–77]. Pathologically, the cores
in NEB-related myopathy do not seem to be significantly
different from those observed in CCD (Fig. 2M) [24].
Nemaline bodies and z-line streaming are observed in the
same fibers (Fig. 2M–P). MRI findings of core-rod myopathy
caused by NEB mutations may be consistent with nemaline
myopathy, showing selective involvement of the tibialis
anterior and soleus [24,75,78].
5.2. ACTA1-related myopathy
In 1999, Nowak et al. reported that ACTA1 mutations
in the skeletal muscle cause dominantly inherited actin
myopathy and nemaline myopathy [79]. Most cases show
severe myopathy, and nine out of 17 patients died before 1
year of age [79]. However, dominant mutations in ACTA1
were also reported to cause core-rod myopathy with a
clinically milder phenotype [22,72,80]. Most of the reported
patients with core-rod myopathy caused by ACTA1 mutations
displayed infantile-to-childhood onset and survived to 49 to
73 years of age [22,72].
5.3. KBTBD13-related myopathy
Gommans et al. reported two large families with autosomal
dominant nemaline myopathy with core-like lesions in 2003
[73]. Subsequently, Sambuughin et al. from the same group
identified the causative gene as KBTBD13, which encodes a
BTB/POZ domain and five Kelch repeats and is expressed
primarily in skeletal and cardiac muscle [25]. The onset
of KBTBD13-related myopathy is in childhood, and patients
are unable to run or jump. Muscle biopsy of patients with
KBTBD13-related myopathy showed core-rod myopathy; no
cardiac abnormalities were observed [25,26,73,81]. Garibaldi
et al. reported that muscle MRI of patients with KBTBD13-
related myopathy shows a characteristic inside-to-outside
involvement of the thighs, zebra pattern in the gluteus
maximus, and central shadow in the rectus femoris [81].
5.4. CFL2-related myopathy
Agrawal et al. reported two siblings with core-rod
myopathy caused by homozygous mutations in CFL2, which
encodes skeletal muscle actin-binding protein, cofilin-2 [23].
Both patients showed hypotonia from birth, delayed early
motor milestones, frequent falls, and inability to run [23].
Minicores are occasionally observed in muscle biopsies.
Sometimes cores are not observed and only nemaline rods
or abnormal sarcomere myofibrillar networks and numerous
areas with uneven oxidative reaction are present [23,82].
M. Ogasawara and I. Nishino
5.5. TRIP4-related myopathy
In 2016, Davignon et al. reported a large consanguineous
family with members who developed neonatal-onset muscle
weakness predominantly involving axial muscles, life-
threatening respiratory failure, skin abnormalities, and
joint hyperlaxity caused by a homozygous mutation in
TRIP4, which encodes activating signal cointegrator-1 [83].
Subsequently, in 2020, Villar-Quiles et al. from the same
group reported additional five families with members
presenting as lethal neonatal to mild ambulatory adult cases
and having biallelic mutations in TRIP4 [27]. Muscle biopsies
showed multiminicores, nemaline rods, cytoplasmic bodies,
and caps [27,83].
5.6. TNNT1-related myopathy
An autosomal recessive mutation on TNNT1 encoding
troponin T1 was originally reported to cause nemaline
myopathy in 2000 [84]. Johnston et al. reported that affected
infants with homozygous TNNT1 mutation had tremors with
hypotonia and mild contractures of the shoulders and hips
in the first months of life [84]. Then, rare homozygous
and heterozygous mutations in TNNT1 were reported as the
cause of nemaline myopathy [85,86]. However, in 2020,
Pellerin et al. reported congenital core-rod myopathy in
French Canadians due to novel recessive mutations in TNNT1
[28]. Muscle MRI of the patients with core-rod myopathy
showed selectively affected semimembranosus and adductor
muscles [28].
6. Conclusion
Except for RYR1-related myopathy, core myopathy is
relatively rare and related to a wide variety of genes. In
addition, except for RYR1-related myopathy, the nature of
cores has not been well characterized; thus, there is often
no specific marker to differentiate between multiminicores
caused by various genes. Furthermore, the pathogenicity of
most of the reported mutations has not been confirmed, and
the mechanism of core formation is still largely unknown.
These gaps indicate the need for detailed pathological analysis
of each case and a careful association between genotypes and
pathological phenotypes.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
We thank Ms. Kaoru Tatezawa, Ms. Naho Fushimi,
Ms. Kazu Iwasawa, Ms. Yoko Tsutsumi, and Ms. Kanae
Kanna, Mr. Hisayoshi Nakamura in NCNP for their technical
assistance.
975
Neuromuscular Disorders 31 (2021) 968–977
Funding
This study was supported partly by Intramural Research
Grant (2-5 and 29-4 to IN) for Neurological and Psychiatric
Disorders of NCNP and by AMED under Grant Numbers
20ek0109490h0001 and JP19ek0109285h0003 (to IN).
Ethics approval and consent to participate
All patients provided informed consent for using their
samples for research after the diagnosis. This study was
approved by the ethical committees of the NCNP (A2019-
123).
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