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Neuromuscular Disorders 21 (2011) 563–568
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Inﬂammatory changes in infantile-onset LMNA-associated myopathy
Hirofumi Komaki a, Yukiko K. Hayashi b,⇑, Rie Tsuburaya b, Kazuma Sugie c,
Mitsuhiro Kato d, Toshiro Nagai e, George Imataka f, Shuhei Suzuki g, Shinji Saitoh h,Naoko Asahina h, Kazuya Honke i, Yoshihisa Higuchi j, Hiroshi Sakuma a, Yoshiaki Saito a,
Eiji Nakagawa a, Kenji Sugai a, Masayuki Sasaki a, Ikuya Nonaka a,b, Ichizo Nishino ba

Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP),
4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8551, Japanb
Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japanc
Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japand
Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iidanishi, Yamagata, Yamagata 990-9585, Japane
Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Koshigaya, Saitama 343-8555, Japanf
Department of Pediatrics, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japang
Department of Pediatrics, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japanh
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido 060-8648, Japani
Department of Pediatrics, National Hospital Organization Iou Hospital, 73-1 Iwademachi Ni, Kanazawa, Ishikawa 920-0192, Japanj
Department of Pediatrics, Kinki University School of Medicine, Nara Hospital, 1248-1 Otodacho, Ikoma, Nara 630-0293, Japan
Received 15 July 2010; received in revised form 12 April 2011; accepted 20 April 2011

Abstract
Mutations in LMNA cause wide variety of disorders including Emery–Dreifuss muscular dystrophy, limb girdle muscular dystrophy,
and congenital muscular dystrophy. We recently found a LMNA mutation in a patient who was previously diagnosed as infantile onset
inﬂammatory myopathy. In this study, we screened for LMNA mutations in 20 patients suspected to have inﬂammatory myopathy withonset at 2 years or younger. The diagnosis of inﬂammatory myopathy was based on muscle pathology with presence of perivascular
cuﬃng and/or endomysial/perimysial lymphocyte inﬁltration. We identiﬁed heterozygous LMNA mutations in 11 patients (55%),
who eventually developed joint contractures and/or cardiac involvement after the infantile period. Our ﬁndings suggest that LMNA
mutation should be considered in myopathy patients with inﬂammatory changes during infancy, and that this may help avoid
life-threatening events associated with laminopathy.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords: Inﬂammatory myopathy; Laminopathy; Emery–Dreifuss muscular dystrophy; Limb girdle muscular dystrophy; Congenital muscular
dystrophy; LMNA; Infantile; Pathology; Steroid therapy; Muscle image

1. Introduction
Laminopathy is a group of disorders caused by mutations in the LMNA gene encoding A-type lamins that
⇑ Corresponding author. Address: Department of Neuromuscular
Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo
187-8502, Japan. Tel.: +81 42 346 1712; fax: +81 42 346 1742.
E-mail address: hayasi_y@ncnp.go.jp (Y.K. Hayashi).

0960-8966/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.nmd.2011.04.010

includes autosomal forms of Emery–Dreifuss muscular
dystrophy (AD- and AR-EDMD) and limb girdle muscular dystrophy type 1B (LGMD1B). EDMD is characterized
by the triad of: (1) early contractures of the elbows, Achilles tendons, and posterior cervical muscles; (2) slowly progressive muscle weakness and atrophy that begins in a
humeroperoneal distribution; and (3) cardiomyopathy with
conduction defects which culminates in complete heart
block and atrial paralysis [1]. LGMD1B patients show
progressive proximal dominant muscle involvement andAuthor's personal copy

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H. Komaki et al. / Neuromuscular Disorders 21 (2011) 563–568

cardiomyopathy with conduction defects, but joint contracture is not prominent. The onset of these diseases isusually 2 years or later. Recently, LMNA-related congenital muscular dystrophy (L-CMD) was reported as a noveland severe form of laminopathy [2]. L-CMD has variable
severity and can be divided in two main groups: a severegroup with absent motor development and patients withdropped-head syndrome.
We recently came across an infantile-onset laminopathy
patient with marked mononuclear cell inﬁltrations in his
muscle mimicking inﬂammatory myopathy (Patient 1 inTable 1, Fig. 1A). This patient showed hypotonia anddelayed motor milestones with elevation of serum CK levels from 3 months of age. Although, he became ambulant
at 15 months of age, he presented proximal dominant muscle weakness and atrophy with no dropped-head at 2 yearsof age. Corticosteroid therapy was started based on themuscle pathological ﬁndings that had beneﬁcial eﬀects on
his motor development. LMNA gene analysis was done

at 6 years of age when his ankle and elbow joint contractures appeared and a heterozygous p.Glu358Lys mutation
was identiﬁed.
From this result, we screened LMNA mutation in the 20
patients with the onset at 2 years or younger who were
pathologically suspected as inﬂammatory myopathy.
2. Patients and methods
2.1. Patients
All clinical materials used in this study were obtained for
diagnostic purposes and written informed consent was
obtained from guardians of all patients. This work wasapproved by the Ethical Committee of National Centerof Neurology and Psychiatry (NCNP). We retrospectively
recruited patients with onset at 2 years or younger who
were pathologically suspected to have inﬂammatory myopathy from a total of 10,874 muscle biopsies stored in the

Table 1
Clinical, radiological, and genetic ﬁndings of patients with LMNA mutations and inﬂammatory changes.
Patient#/gender/LMNA
mutations

Age at onset/age at biopsy/
age at lastconsultation

Initial signs/
CK at biopsy

Musclepathology

Steroid treatment:
responsiveness/
age at start ofadministration/
duration ofadministration

Age at acquired
ambulation/
maximummotorability

Cardiacinvolvement

Joint
contracture

Respiratory
dysfunction

CT/MRI(age)/imaging
at thigh

CT/MRI(age)/imaging
at calf

1/M/E358K*

3 m/2 y/11 yMotor delay/900

IC: marked, diﬀuse;
NR: moderate; Fib:
mild

Eﬀective/2 y/9 y

15 m/Ambulant

No

No

MRI (8 y)/selective
involvementof VL, VI, VM

MRI (8 y)/selective
involvementof SO, mGC

2/M/R249W*

Motor delay/1000

IC: marked, pathy;
NR: mild; Fib: mild

Eﬀective/10 m/11 y

Unknown/ambulant

9 y: Heart
failureND

Motor delay/1100

IC: marked, pathy;
NR: marked; Fib: mild

Eﬀective/1 y/15 y

18 m/Ambulant

CT (13 y)/DI
with relative
sparing of RF,
GR, SACT (13 y)/DI

4/F/R249Q*

2 y/2 y/15 yHigh CK/2000

IC: moderate, focal; NR:
moderate; Fib: moderateEﬀective/3 y/6 m

14 m/Ambulant

13 y: 200B0
A–V block,
15 y 3° A–V
block,
pacemaker
implantation
12 y: 1° A–V
block

9 y:
Nocturnal
NPPV
No

ND

3/M/N39D

10 m/10 m/12 y(Died byrespiratory failure)
11 m/1 y/16 y

6 y:
Ankles,elbows,
8 y: rigid
spine
4 y:
Ankles,knees
1 y:Ankles,knees, hips,
Rigid spinefromchildhood
3 y:Ankles,
8 y: elbows

5/M/R28Q

5 m/1 y/11 yMotor delay/800

IC: marked, pathy;
NR: moderate;
Fib: moderate

Ineﬀective/1 y/2 y

18 m/9 y: Inability to walkCT (6 y)/selective
involvementof SO, mGC
ND

6/M/R41S

9 m/1 y/13 yMotor delay/900

Ineﬀective/1 y/8 y

16 m/9 y: Inability to walk

MRI (10 y)/
DI/DI

7/F/K32del*

1 y/2 y/6 y

Unsteady gait/800

IC: moderate, diﬀuse,
NR: moderate Fib:
moderate
IC: mild, focal; NR:
mild; Fib: mild

CT (6 y)/DI
with relative
sparing of RF,
GR
CT (11 y)/DI
with relative
sparing of RF,
GR, SA
MRI (10 y)/
DI/DI

Ineﬀective/2 y/8 m

15 m/5 y: Inability to walkNo

8/M/R249W*

11 m/1 y/24 y(Died by arrhythmia)

Motor delay/600

IC: marked, pathy;
NR: mild; Fib:
moderate

Ineﬀective/1 y/unknown

2 y/12 y: Inability to walkCT (4 y)/DI
with relative
sparing of RF,
GR/Selective
involvementof SO, mGC
ND

9/F/L292P

1 y/8 y/10 yMotor delay/300

IC: mild, focal;
NR: moderate;
Fib: marked

Unadministered

16 m/4 y: Inability to walk

2 y/4 y/7 y (Died byheart failure)

Unsteady gait/1000

Unadministered

10 m/ambulant

11/F/N456H

2 y/5 y/10 y

Unsteady gait/3000

IC: moderate, focal;
NR: moderate; Fib:
moderate
IC: moderate, focal;
NR: moderate;
Fib: marked

MRI (8 y)/DI
with relative
sparing of RF,
GR, SAND

MRI (8 y)/DI

10/F/R377C*

17 y: 2° A–V
block, 23 ycomplete A–
V block
6 y: LV
dysfunction,
8 y: PAC,
PVC
7 y: DCM(EF:32%)CT (4 y)/DI
with relative
sparing of RF,
GR/Selective
involvementof SO, mGC
ND

Unadministered

12 m/ambulant

Atrialﬁbrillation,
A–V block,
PAC, PVC
11 y: PSVT
attack

No

No

No

No

6 y:
Ankles,elbows
2 y: Ankles

11 y:Nocturnal
NPPV
No

17 y:
Ankles,
knees

No

No

No

5 y: Ankles

No

6 y: Ankle,
knee, neck,
8 y: rigid
spine

No

MRI (10 y)/
DI withrelativesparing of RF,
GR, SAND

MRI (10 y)/
DI

A–V block = atrioventricular conduction block, CK = creatine kinase, CT = computed tomography, DI = diﬀuse involvement, EF = ejection fraction, Fib = endomysial ﬁbrosis, GR = gracilis, IC = inﬂammatory cellular inﬁltration, LV = left
ventricle, mGC = medial head of gastrocnemius, MRI = magnetic resonance imaging, NPPV = noninvasive positive-pressure ventilation, NR = necrotic and regenerating process, PAC = premature atrial contraction, PSVT = paroxysmal
supraventricular tachycardia, PVC = premature ventricular contraction, RF = rectus femoris, SA = Sartorius, SO = soleus, VI = vastus intermedius, VL = vastus lateralis, VM = vastus medialis.

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565

Fig. 1. Inﬂammatory cellular inﬁltration observed in the patients with LMNA mutations on hematoxilin and eosin staining (A: Patient 1, B: Patient 3, C:
Patient 9). Serial frozen sections of muscle from Patient 5 were immunostained with HLA-ABC (D), double immunostained with CD4 (green) anddystrophin (red) (E), and CD20 (green) and dysrophin (red) (F). HLA-ABC stain in control muscle is shown in (G).

National Center of Neurology and Psychiatry. The diagnosis of inﬂammatory myopathy was based upon the mononuclear cell inﬁltrations at perimysial, endomysial, andperivascular sites [3]. Patients suspected to have dermatomyositis with skin rash and/or perifascicular atrophy on
muscle pathology were excluded in this study. Then wegathered a total of 20 patients including one patient(Patient 2) who had previously been reported as infantile
polymyositis [4].
2.2. Histopathological studies
All biopsied samples were taken from biceps brachii.
Muscle specimens were frozen in isopentane chilled inliquid nitrogen. Serial frozen sections were stained withhematoxylin and eosin, modiﬁed Gomori trichrome, anda battery of histochemical methods. Immunohistochemical
analysis was performed as described previously [5]. Antibodies used in this study are: dystrophin (DMDP-II [6],DYS1, DYS2, and DYS3 from Novocastra, Newcastle
upon Tyne, UK); sarcoglycans (SGCA, SGCB, SGCG,
and SGCD: Novocastra); laminin-a2 chain (ALEXIS,
Farmingdale, NY); a-dystroglycan (Upstate Biotech, Lake
Placid, NY); caveolin-3 (BD Transduction Laboratories,
Franklin Lakes, NJ); dysferlin (Novocastra); emerin(Novocastra); collagen VI (Novocastra); CD4 and CD8(Nichirei, Tokyo, Japan); CD20, and HLA-ABC (DAKO,Glostrup, Denmark).
2.3. Mutational analysis of LMNA
Genomic DNA was extracted from either frozen muscles or peripheral lymphocytes using standard protocols[7]. All exons and their ﬂanking intronic regions of LMNA
were ampliﬁed by PCR and directly sequenced using

automated 3130 sequencer (PE Applied Biosystem, Foster
City, CA). Primer sequences are available upon request.
2.4. Clinical information
Clinical characteristics collected from attending physicians were demographic data, age of onset, initial signs,
motor functions, presence of cardiac involvement, presenceof joint contractures, respiratory function, eﬀectiveness ofsteroid, and pertinent laboratory examinations including
serum creatine kinase (CK), electrocardiogram, Holter
electrocardiogram, and echocardiogram.
2.5. Muscle imaging
Muscle computed tomography (CT) or magnetic resonance imaging (MRI) was done with some modiﬁcations
depending on the facilities in each hospital. Scans were performed at thigh (the largest diameter of thigh) and calf (thelargest diameter of lower leg) levels. Involvement of eachmuscle was evaluated at both scan levels.
3. Results
Ten types of heterozygous single nucleotide substitutionsin LMNA were identiﬁed in 11 of 20 patients. Four(p.Arg249Gln, p.Leu292Pro, p.Asn456His and p.Arg377
Cys) mutations were previously reported in patients with
AD-EDMD or LGMD1B, one (p.Arg249Trp) was foundonly in L-CMD patients, and two (p.Lys32del andp.Glu358Lys) were identiﬁed in AD-EDMD, LGMD1B,
or L-CMD patients [2,8–10]. Another three (p.Arg28Gln,
p.Asn39Asp, p.Arg41Ser,) were novel mutations and notdetected in 300 control chromosomes. All 11 patients had
neither consanguinity nor family history of myopathy orAuthor's personal copy

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H. Komaki et al. / Neuromuscular Disorders 21 (2011) 563–568

Fig. 2. Selective muscle involvement of thigh and calf muscles. Transverse sections of T1 weighted magnetic resonance imaging of thigh (A–C) and calf(D–F) in patients with LMNA mutations. Selective involvements of vastus lateralis (VL), vastus intermedius (VI), vastus medialis (VM), soleus (S), andmedial head of gastrocnemius (mGC, A, D: Patient 1), relatively mild and diﬀuse involvements with relative sparing of rectus femoris (RF), gracilis (G),sartorius (SA, B, E: patient 11), and diﬀuse and severe involvement with relative sparing of rectus femoris, gracilis, sartorius (C, F: patient 9) are observed.

cardiomyopathy. DNA samples from the parents of 11
patients were not available.
Table 1 shows clinical summary of the 11 patients with
LMNA mutations. Initial clinical signs were motor developmental delay or progressive muscle weakness. Head drop
was not observed in any patient. Serum CK levels weremildly to moderately elevated in all patients. Joint contractures, spinal rigidity, and cardiac involvement were notobserved at the time of the biopsy but became prominent
in some patients in later age. Importantly, Patient 6 had
an episodic paroxysmal supraventricular tachycardia during general anesthesia at age 11 years, and Patient 3
received pacemaker implantation due to complete atrioventricular conduction block at age 15 years. Patient 8 succumbed to sudden death due to arrhythmia at age
24 years and Patient 10 died by cardiac failure at age
7 years. Two patients developed chronic respiratory failure
requiring non-invasive positive-pressure ventilation.
Patient 2 died by respiratory failure at age 12 years. Steroid
was used in eight patients but beneﬁcial eﬀects such as
improvement of muscle power and reduction of serum
CK levels were seen only in four.
On muscle biopsy, the most striking inﬂammatorychange was observed in Patient 1 showing numerous
inﬂammatory cells predominantly located in the perimysialconnective tissue (Fig. 1A). This ﬁnding was diﬀusely seenin the whole muscle specimen. The other 10 patients also
showed variable degrees of mononuclear cellular inﬁltration with active necrosis and regenerating process(Fig. 1B, C, Table 1). Fiber size variation and endomysial
ﬁbrosis were also seen. Fiber type grouping, groups ofatrophic ﬁbers, and abnormal oxidative stains were notobserved. Immunohistochemically, sarcolemmal HLA
staining was increased in many ﬁbers in all patients examined (Fig. 1D). Inﬁltrated mononuclear cells were positive
for lymphocyte markers of CD4 (Fig. 1E), CD8 (data notshown), or CD20 (Fig. 1F). No abnormal immunostaining
was seen for the antibodies associated with muscular dystrophy (data not shown).
Muscle imaging was performed in relatively later stagesof the disease in eight out of 11 patients with LMNA mutations (Fig. 2). At the level of thigh, Patient 1 showed selective involvement of vastus lateralis, vastus intermedius andvastus medialis. Patient 6 showed diﬀuse involvement of allthigh muscles. The remaining six patients showed diﬀuse
involvement of thigh muscles with relative sparing of sartorius, gracilis and rectus femoris. At lower leg levels, threepatients (Patients 1, 4, and 7) showed selective involvementof soleus and medial head of gastrocnemius. The remaining
four patients showed diﬀuse involvement of calf muscles.
4. Discussion
In our series, surprisingly, more than half of the infantile
patients showing inﬂammatory changes are due to LMNA
mutations. Prominent mononuclear cell inﬁltrations cansometimes be evident in biopsies from muscular dystrophy
patients including CMD, LGMD, and facioscapulohumeral muscular dystrophy, leading to misdiagnosis ofinﬂammatory myopathy [11–16]. Apparently, however, frequency of inﬂammatory changes is much higher in infantile
striated muscle laminopathy patients, suggesting a possibil-

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H. Komaki et al. / Neuromuscular Disorders 21 (2011) 563–568

ity that LMNA mutations may cause active inﬂammationin skeletal muscle during infancy by a certain mechanism.
In support of this notion, three of 15 L-CMD patients
report by Quijano-Roy et al. had inﬂammatory cell inﬁltration [2]. In Patients 4, 7, 9, 10 and 11, muscle biopsies weredone at the age of 2 years or later and inﬂammatorychanges were relatively milder compared to the otherearlier biopsies. These ﬁndings suggest that severities ofinﬂammation may be related to the age of biopsies.
Inﬂammatory myopathy manifesting with muscle weakness starting during infancy is a poorly deﬁned muscle disorder and limited number of patients were described in theliterature [4,17–20]. Thompson emphasized that responsiveness to corticosteroid is one of the crucial ﬁndings thatdeﬁne the infantile myositis [17]. However, this is unlikely
to be always the case as some of our laminopathy patients,
who were initially diagnosed as infantile-onset inﬂammatory myopathy also showed some clinical improvementby corticosteroid therapy. Good response to steroids is
not only a feature of myositis but can also be seen in othermuscular dystrophies including Duchenne muscular dystrophy. Therefore, the possibility of laminopathy should
not be excluded solely based upon steroid responsiveness.
Interestingly, all steroid-responsive patients were ambulant
whereas non-responsive patients could not walk, whichmight imply some genotype–phenotype correlation. Nonetheless, the correlation between genotype and steroid
responsiveness cannot be discussed at this moment as all
patients for whom steroid was used had distinct mutations.
In any case, corticosteroid therapy could be considered for
infantile striated muscle laminopathy patients as somepatients respond, although its long-term eﬃcacy is still
unknown.
The p.Arg249Trp mutation found in this study was previously reported in L-CMD patients [2], but not in ADEDMD or LGMD1B. In contrast, p.Glu358Lys mutation
has also been reported with extremely variability of phenotypes, including AD-EDMD, LGMD1B, or L-CMD [10].
Thus, the same mutation can result in diﬀerent phenotypes
and severities. These ﬁndings raise a possibility that otherunknown factor(s) may play a role in the development oflaminopathy phenotype.
Muscle imaging demonstrated selective muscle involvement in all eight patients examined. Vastus lateralis andintermedius were markedly aﬀected, while involvement ofadductor magnus was minimal. In addition, medial headof the gastrocnemius was remarkably involved while lateralhead was relatively spared in most patients. This selective
muscle involvement is basically identical to that observedin AD-EDMD/LGMD1B patients [21] and may be helpful
for the diagnosis of laminopathy in children.
Cardiomyopathy with conduction defects is a common
serious clinical problem in patients with EDMD and
LGMD1B [1]. In the present study, 8 of 11 patients developed cardiac complications such as arrhythmia and heart
failure in their childhood and two died due to arrhythmia
and heart failure, respectively. These ﬁndings clearly

567

demonstrate that accurate diagnosis followed by periodic
examination of cardiac function including electrocardiogram, holter electrocardiogram and echocardiogram, andappropriate implantation of deﬁbrillators is necessary to
avoid unexpected sudden death [22,23].
Our results expand clinical and pathological variation of
striated muscle laminopathy and the inﬂammatory histology is an important diagnostic clue to the LMNA related
myopathy patients. Further analysis is needed to elucidate
the role of mutant A-type lamins in inducing inﬂammatory
process during infancy.
Acknowledgements
We thank Ms. K. Goto and Ms. M. Ohnishi (National
Institute of Neuroscience, NCNP) for technical assistanceand Dr. M.C.V. Malicdan (National Institute of Neuroscience, NCNP) for reviewing the manuscript. This study was
supported by: KAKENHI (21591104) from Japan Society
for the Promotion of Science; by Research on Psychiatricand Neurological Diseases and Mental Health of Health
Labour Sciences Research Grant and the Research Grant(20B-12, 20B-13) for Nervous and Mental Disorders from
the Ministry of Health, Labour, and Welfare; by Researchon Health Sciences focusing on Drug Innovation from theJapanese Health Sciences Foundation; and by the Programfor Promotion of Fundamental Studies in Health Sciences of
the National Institute of Biomedical Innovation (NIBIO).
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