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Neuromuscular Disorders xxx (2014) xxx–xxx
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Case report

Congenital muscular dystrophy with dropped head phenotype
and cognitive impairment due to a novel mutation in the LMNA gene
Ulrike Bonati a,f,⇑, Nina Bechtel a, Karl Heinimann b, Erich Rutz c, Jacques Schneider d,
Stephan Frank e, Peter Weber a, Dirk Fischer a,f
a

Division of Neuropaediatrics, University Children’s Hospital Basel, Switzerland
b
Division of Medical Genetics, University Hospital Basel, Switzerland
c
Paediatric Orthopaedic Department, University Children’s Hospital Basel, Switzerland
d
Division of Neuroradiology, University Children’s Hospital Basel, Switzerland
e
Institute of Pathology, Department of Neuropathology, Basel University Hospital, Switzerland
f
Department of Neurology, University Hospital Basel, Switzerland
Received 22 November 2013; received in revised form 10 January 2014; accepted 7 February 2014

Abstract
Mutations in A-type nuclear lamins are known to cause a variety of diseases, which can affect almost all organs of the human body
including striated muscle. For lamin-related congenital muscular dystrophy two different phenotypes are known to date. Here, we
describe a 3-year-old, white Caucasian girl with a novel de novo mutation in the LMNA gene with marked hypotonia of neck and
trunk muscles with dropped head posture, loss of cervical lordosis and marked joint laxity. In addition to this novel mutation, the
patient also had cerebral white matter lesions on MRI and cognitive impairment on developmental testing. This is only the second
A-type lamin-related congenital muscular dystrophy patient in which white matter lesions are described. Thus, white matter
involvement might be a feature in A-type lamin-related congenital muscular dystrophy, warranting screening of these patients for
both white matter lesions and cognitive impairment.
Ó 2014 Elsevier B.V. All rights reserved.

Keywords: Congenital muscular dystrophy; L-CMD; LMNA gene mutation; White matter lesions; Dropped head phenotype

1. Introduction
A-type lamin-related congenital muscular dystrophy
(L-CMD) is caused by mutations in the LMNA gene on
chromosome 1q22. Lamins are nuclear envelope proteins.
A variety of human diseases, affecting not only striated
muscle but almost all other organs, have been linked to
impaired type-A lamin function due to mutations in the
LMNA gene. Two different phenotypes of muscle
⇑ Corresponding author at: Division of Child Neurology, University

Children’s Hospital, Spitalstrasse 33, Postfach, 4031 Basel, Switzerland.
Tel.: +41 61 704 19 07; fax: +41 61 704 12 53.
E-mail address: ulrike.bonati@ukbb.ch (U. Bonati).

impairment in L-CMD have been described, but brain
involvement, in contrast to other forms of CMD [1], has
not yet been considered to be a common feature in
L-CMD. Here, we describe a novel heterozygous
mutation in exon 1 (c.93G>C) of the LMNA gene
leading to CMD with dropped head sign, white matter
lesions, and cognitive impairment in a 3-year-old girl.

2. Case report
The patient is a 3-year-old white Caucasian girl. She is
the second daughter of a family with no previous history

http://dx.doi.org/10.1016/j.nmd.2014.02.004
0960-8966/Ó 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Bonati U et al., Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel
mutation in the LMNA gene, Neuromuscul Disord (2014), http://dx.doi.org/10.1016/j.nmd.2014.02.004

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U. Bonati et al. / Neuromuscular Disorders xxx (2014) xxx–xxx

of any muscular disorders. No consanguinity is known. She
has a 6 year old healthy sister.
At the age of 14 months she was referred to our
outpatient department due to failure to thrive and
difficulties swallowing. Past medical history revealed that
she had already been found to be small for gestational
age in prenatal screening. A chorionic villus sampling
was therefore done in the first trimester which showed
normal results. Because her perinatal weight was below
P3, an elective Caesarean section at 38 weeks of gestation
was performed. After weaning she never started to chew
nor tried to eat solid food. She repeatedly choked on dry
food but never had an aspiration or a pulmonary
infection. From the age of 8 months motor development
delay was noticed by her paediatrician. Due to failure to
thrive with poor weight gain and delayed growth she was
referred to our outpatient department at the age of
14 months. Elevated CK levels were discovered and a
muscular dystrophy was suspected.

A

Neurological examination at first presentation showed
marked hypotonia of neck and trunk muscles with
dropped head posture, loss of cervical lordosis (as a first
sign of rigid spine syndrome), and lumbar hyperlordosis.
While lying on her tummy, she could not lift her head or
upper body from the ground. She was able to sit
unsupported and moved in shuffle-position but was
unable to crawl. She pulled herself up to a stand while
holding onto furniture and walked with support. Fine
motor skills were not impaired. No ataxia was found.
She had no contractures but marked joint laxity,
especially in her ankle and foot joints. Deep tendon
reflexes were symmetrical in the upper limbs, but absent
in the lower limbs. Free ambulation was reached with
delay at 24 months of age, when she was able to walk
10 m without support. Due to marked joint laxity of her
foot and ankle joints, which impaired her walking ability
(see Fig. 1A and B), orthotics to support ankle joint
stability were tried but were scarcely beneficial. Free

B

D

C

E

Fig. 1. (A/B) Patient at age 2 years and 8 months. Note the dropped head phenotype, the missing cervical lordosis and the marked laxity seen in the ankle
joints. (C) Hematoxylin–eosin stained muscle tissue from the patient showed mild myopathic changes consisting of increased variability of fibre diameters,
few necrotic and regenerating fibres, and macrophages. (D/E) Coronal (D) and axial (E) T2 weighted MR-images of the brain showing point like
parasagittal disturbances of myelination (arrows).
Please cite this article in press as: Bonati U et al., Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel
mutation in the LMNA gene, Neuromuscul Disord (2014), http://dx.doi.org/10.1016/j.nmd.2014.02.004

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U. Bonati et al. / Neuromuscular Disorders xxx (2014) xxx–xxx

ambulation was lost at the age of 2 years and 8 months
after a minor fall.
At first presentation serum CK level was 2759 U/l
(normal <200 U/l), suggestive of a (congenital) muscular
dystrophy. Pulmonary and heart exams including
echocardiography and electrocardiogram, were normal.
Histology of tissue from the right vastus lateralis muscle
at the age of 15 months revealed nonspecific myopathic
changes (see Fig. 1C). Staining for merosin, spectrin and
glycosylated alpha-dystroglycan was normal on
immunohistochemical assessment. T2-weighted and T2weighted fluid attenuating inversion recovery (FLAIR)
MRI sequences of the brain showed few small dot-like
hyperintensities of the parasagittal deep white matter
bilaterally possibly reflecting gliosis or disturbed
myelination (Fig. 1D and E). To evaluate cognitive
development the Mental Scale of the Bayley Scales of
Infant Development Second Edition (BSID II) was
performed repeatedly [2]. Results indicated a delay in
task related actions such as building towers due to
impaired motor function but also a mild delay in other
cognitive domains such as language and higher-order
thinking skills. When tested last at the age of 2.9 years,
she had a scaled score below average of 75.
Due to dropped head CMD phenotype, a LMNA gene
mutation was considered and the LMNA coding region
sequenced. This revealed a novel – de novo – heterozygous
missense mutation c.93G>C, which leads to an exchange
of amino acids at codon 31 (p.Glu31Asp). In silico
analyses predicted the mutation to be disease causing
(MutationTaster score:0.9998) [3], probably damaging
(PolyPhen-2 score: 0.994) [4] and damaging (SIFT
score:0.0) [5]. This mutation has not yet been described
according to the Leiden Open (source) Variation
Database (LOVD) and the UMD-LMNA mutations
database. However, another codon 31 missense mutation
(GAG>AAG (Lys)) was recently described by Menesez
et al. [6] in a patient with a very similar phenotype.

3

Here, we describe a novel LMNA mutation presenting
as a L-CMD with dropped head phenotype and cognitive
impairment. Brain MRI at 1.4 years showed few dot-like
white matter lesions bilaterally that we interpreted as
gliosis. As a differential diagnosis, disturbed myelinisation
could be a possible cause. A higher risk for
developmental delay is known for children born small for
gestational age (SGA) [9]. However, several confounding
factors have to be taken into account and in most of the
cases no white matter lesions in MRI are found. Also, in
our patient the white matter changes are slightly
asymmetric and occur in an area where we expect
myelination to be completed at this age. In contrast to
the lesions found in our patient, Virchow Robin Spaces
are also found in this part of the brain, but are well
delineated and isointense to cerebrospinal fluid [10].
Therefore, the cognitive delay and brain MRI changes
seen in this patient are less likely to be a consequence of
SGA or motor dysfunction (less learning experiences) but
rather a cerebral manifestation of the LMNA mutation.
Interestingly, a recent case report described very similar
white matter lesions in a 22 months old Japanese girl
with L-CMD [11] which, in conjunction with our patient
suggests that white matter cerebral involvement can occur
in patients with LMNA mutations. Menezes et al. [6]
recently reported on a patient carrying a LMNA
mutation in the same codon as our patient, and
displaying a very similar clinical phenotype with dropped
head sign, hypotonia, axial weakness, and elevated CK
(1066 U/L). In contrast to our patient, early ankle joint
contractures were present. Unfortunately, no brain MRI
imaging or developmental testing results were provided.
Undoubtedly, further patients need to be studied to
answer the question of whether white matter lesions are a
common feature of L-CMD. We therefore suggest that
L-CMD patients should be screened for brain
involvement and cognitive impairment.
Acknowledgement

3. Discussion
L-CMD is a relatively new entity, first described in 2005
by D’Amico et al. [7]. Transmission can be autosomal
recessive or dominant. As in our patient, de novo
mutations appear to be frequent. So far, two L-CMD
subtypes have been distinguished: (a) an early-onset
severe phenotype with poor spontaneous movements and
limited motor achievements; (b) an initially milder
phenotype with the ability to stand and walk, but
inability to obtain free head control with dropped head
sign [8].
White matter changes and to a lesser degree structural
changes are frequently found in the brain in various
forms of CMD, in Emery-Dreifuss muscular dystrophy,
as well as in patients with B-type lamin mutations [1], but
has not been described in A-type lamin mutations so far.

We would like to thank the patient and her family for
supporting this report.
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Please cite this article in press as: Bonati U et al., Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel
mutation in the LMNA gene, Neuromuscul Disord (2014), http://dx.doi.org/10.1016/j.nmd.2014.02.004

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Please cite this article in press as: Bonati U et al., Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel
mutation in the LMNA gene, Neuromuscul Disord (2014), http://dx.doi.org/10.1016/j.nmd.2014.02.004