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Review
Fetal akinesia: review of the genetics of the
neuromuscular causes
Gianina Ravenscroft,1 Elliot Sollis,1 Adrian K Charles,2 Kathryn N North,3
Gareth Baynam,4,5 Nigel G Laing1
1
Centre for Medical Research,
University of Western Australia;
Western Australian Institute for
Medical Research, Nedlands,
Western Australia, Australia
2
Department of Pediatric
Pathology, Princess Margaret
Hospital, Perth, Western
Australia, Australia
3
Discipline of Paediatrics and
Child Health, Faculty of
Medicine, University of Sydney,
Institute for Neuroscience and
Muscle Research, The
Children’s Hospital at
Westmead, New South Wales,
Australia
4
Genetic Services of Western
Australia, King Edward
Memorial Hospital, Western
Australia, Australia
5
School of Paediatrics and Child
Health, University of Western
Australia, Western Australia,
Australia
Correspondence to
Professor Nigel G Laing,
Western Australian Institute for
Medical Research, Ground Floor,
B Block, QEII Medical Centre,
Nedlands, Western Australia,
6009, Australia;
[email protected]
Gianina Ravenscroft and Elliot
Sollis contributed equally.
Received 23 May 2011
Revised 31 July 2011
Accepted 16 August 2011
Published Online First
7 October 2011
ABSTRACT
Fetal akinesia refers to a broad spectrum of disorders in
which the unifying feature is a reduction or lack of fetal
movement. Fetal akinesias may be caused by defects at
any point along the motor system pathway including the
central and peripheral nervous system, the
neuromuscular junction and the muscle, as well as by
restrictive dermopathy or external restriction of the fetus
in utero. The fetal akinesias are clinically and genetically
heterogeneous, with causative mutations identified to
date in a large number of genes encoding disparate parts
of the motor system. However, for most patients, the
molecular cause remains unidentified. One reason for this
is because the tools are only now becoming available to
efficiently and affordably identify mutations in a large
panel of disease genes. Next-generation sequencing
offers the promise, if sufficient cohorts of patients can be
assembled, to identify the majority of the remaining
genes on a research basis and facilitate efficient clinical
molecular diagnosis. The benefits of identifying the
causative mutation(s) for each individual patient or family
include accurate genetic counselling and the options of
prenatal diagnosis or preimplantation genetic diagnosis.
In this review, we summarise known single-gene
disorders affecting the spinal cord, peripheral nerves,
neuromuscular junction or skeletal muscles that result in
fetal akinesia. This audit of these known molecular and
pathophysiological mechanisms involved in fetal akinesia
provides a basis for improved molecular diagnosis and
completing disease gene discovery.
Fetal akinesia refers to a broad spectrum of disorders in which the unifying feature is reduced or
absent fetal movement. Various labels are given to
these disorders, including fetal akinesia deformation
sequence (FADS), fetal hypokinesia sequence,
PenaeShokeir syndrome, arthrogryposis multiplex
congenita (AMC) and multiple pterygia syndrome
(MPS). Associated abnormalities can include
arthrogryposis, pterygia, subcutaneous oedema,
fetal hydrops, lung hypoplasia, rocker-bottom feet,
craniofacial anomalies (particularly cleft palate,
retromicrognathia), intrauterine growth retardation
and poor muscle bulk. These disorders are clinically
and genetically heterogeneous. A recent review has
elegantly described the clinical features of the fetal
akinesias and their differential diagnoses.1 Despite
recent studies identifying novel disease genes
and/or mutations (table 1), the majority of fetal
akinesia cases do not have a genetic diagnosis.
Fetal akinesias can result from primary defects
involving any point along the motor system: the
central nervous system including the brain and
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spinal cord, the peripheral nerve, the neuromuscular junction (NMJ) and the skeletal musculature,
and also the connective tissue (restrictive dermopathy).1 In this review, we cover the known genetics
and pathobiology of monogenic disorders affecting
the spinal cord, peripheral nerves, NMJ or skeletal
muscles that result in reduced or absent fetal
movement. Brain abnormalities resulting in reduced
fetal movement are not discussed since that is too
large a topic to include within the scope of this
review. Smigiel and colleagues have recently
reviewed the genetics of restrictive dermopathy2;
thus, this group of fetal akinesias will also not be
further discussed. In addition, we have excluded
from this review environmental causes of reduced
fetal movement including circulating maternal
antibodies to neurotransmitters, myelin and muscle
proteins; multiple births; restricted intrauterine
space; drug use; maternal illness and ischaemia.1
It is becoming increasingly clear that many of
the neuromuscular causes of fetal akinesia represent the severe end of the spectra of other recognised disease entities, such as spinal muscular
atrophy (SMA), congenital myasthenic syndromes
(CMSs), congenital muscular dystrophies and
myopathies.3e7 These cases of fetal akinesia may
be recessive disorders compared with milder
(although often still severe) later-onset dominant
diseases caused by mutations in the same gene.
The increasing use of second-trimester ultrasound
has enabled earlier detection of these cases. Difficulties in differentiating pathologic changes from
developmental changes may arise. For example,
central nuclei are a normal part of muscle development but a pathological hallmark of congenital
myotonic dystrophy and centronuclear myopathy.
Thus, diagnosis of fetal akinesia must combine
assessment of clinical features and muscle
morphology and confirmation by genetic testing
where possible.
FETAL AKINESIA DUE TO MUTATIONS IN GENES
INVOLVED IN MOTOR NEURON DEVELOPMENT
AND SURVIVAL
Survival motor neuron 1 (SMN1)
Spinal muscular atrophy (Mendelian Inheritance in
Man (MIM) 253300) is an autosomal recessive
disorder due to mutations in the survival motor
neuron 1 gene (SMN1; MIM 600354) and typically
presents with weakness, respiratory insufficiency
and failure to gain motor milestones during the first
months of life. However, a more severe phenotype
with prenatal or neonatal onset and associated
contractures is increasingly recognised. A study of
12 cases diagnosed as having SMA and joint
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Table 1
Summary of disease genes associated with fetal akinesia
Gene symbol
MIM
Mode of inheritance
Disease entity
Genes involved in motor neuron development and survival
SMN1
600354
AR
SMA, FADS
ERBB3
190151
AR
LCCS2
GLE1
603371
AR
LCCS1, LAAHD
PIP5K1C
606102
AR
LCCS3
UBE1
314370
XL
XL-SMA
Genes encoding components of the neuromuscular junction
CHRNA1
100690
AR
FADS
CHRND
100720
AR
AMC/CMS with
fetal akinesia; FADS
CHRNG
100730
AR
Lethal and EV MPS
CNTN1
600016
AR
CM with fetal akinesia
DOK7
610285
AR
FADS
SYNE1
608441
AR
AMC with fetal akinesia
RAPSN
601592
AR
AMC, FADS
Genes encoding adult skeletal muscle proteins
ACTA1
102610
AD
FADS
BIN1
601248
AR
CNM with fetal akinesia
DMPK
605377
AD
FADS/DM
FKRP
606596
AR
WWS with fetal akinesia
LMNA
150330
AR
LGMD1B with fetal akinesia
MTM1
300415
XL
MTM with fetal akinesia
NEB
161650
AR
FADS
RYR1
180901
AR, AD
FADS, CRM with
fetal akinesia
TPM2
190990
AR, AD
EV MPS, DA1, DA2B
TNNI2
191043
AD
DA1, DA2B
TNNT3
600692
AD
DA1, DA2B
Genes encoding fetally-expressed myostructural proteins
MYH3
160270
AD
DA2A, DA2B
MYH8
160741
AD
CC-DA7, DA7
MYBPC1
160794
AD
DA1
UTRN
128240
Arthrogryposis with
fetal akinesia
Other genes
FGFR2
176943
AD
FADS
GBE1
607839
AR
GSD-IV/FADS
AD, autosomal dominant; AMC, arthrogryposis multiplex congenita; AR, autosomal
recessive; CC, Carney complex; CM, congenital myopathy; CMS, congenital myasthenic
syndrome; CNM, centronuclear myopathy; CRM, core-rod myopathy; DA, distal
arthrogryposis; DM, myotonic dystrophy; DMPK, dystrophia myotonica protein kinase; EV,
Escobar variant; FADS, fetal akinesia deformation sequence; GSD-IV, glycogen storage
disease type IV; LAAHD, lethal arthrogryposis with anterior horn cell disease; LCCS, lethal
congenital contracture syndrome; LGMD1B, limb-girdle muscular dystrophy type 1B; MPS,
multiple pterygia syndrome; MIM, Mendelian Inheritance in Man; MTM, myotubular
myopathy; SMA, spinal muscular atrophy; WWS, WalkereWarburg syndrome; XL, X
linked.
contractures in at least two regions of the body found that six
were homozygous for the common deletion of SMN1. These
infants died by postnatal day 25.8 In a report of 30 cases diagnosed in utero with FADS (MIM 208150), spinal cord pathology
was identified in only one case. Subsequent molecular analysis
revealed homozygous deletion of SMN1.9 Additional cases of
SMA with fetal akinesia have been reported. Devriendt et al
described a patient who presented with fetal akinesia from
32 weeks’ gestation. At birth, generalised oedema and flexion
contractures were present. The patient died at the age of
25 days. The patient had a homozygous deletion of SMN1 and
a single copy of SMN2.10 Another infant born with features of
FADS including micrognathia, high arched palate and multiple
joint contractures showed homozygous deletion of SMN1 with
only one copy of SMN2 (MIM 601627).11 Thus, homozygous
deletions of SMN1 can cause severe forms of SMA presenting as
FADS. The severe presentation in these cases may be attributed
to the concurrent low SMN2 copy number.10 11
794
Epidermal growth factor receptor 3 (ERBB3)
Atrophy of the anterior horn of the spinal cord is also seen in the
neonatally lethal congenital contracture syndrome type 2
(LCCS2; MIM 607598) identified in two IsraelieBedouin
kindreds.12 Affected cases had diminished intrauterine movement, polyhydramnios, multiple joint contractures, severe
muscle wasting, micrognathia and neurogenic bladders; fetal
hydrops was not a feature.12 All affected individuals were
homozygous for an ERBB3 mutation resulting in a frameshift and
premature stop codon.13 ERBB3 (MIM 190151) encodes the v-erbb2 avian erythroblastic leukaemia viral oncogene homolog 3 that is
a modulator of the phosphatidylinositol 3-kinase pathway. ErbB3null mice generally die in utero. Those that develop to term are
small, are immobile, fail to breathe and die shortly after birth.14
mRNA export mediator GLE1 (GLE1)
Loss of motor neurons also occurs in LCCS1 (MIM 253310).
This rare autosomal recessive disorder is characterised by
absence of fetal movements from w13 weeks’ gestation,
accompanied by hydrops, facial abnormalities, lung hypoplasia,
pterygia, multiple joint contractures and almost absent skeletal
muscle.15 16 A slightly milder phenotype designated as lethal
arthrogryposis with anterior horn cell disease (LAAHD; MIM
611890) is characterised by fetal akinesia, arthrogryposis and
motor neuron loss.17 The LCCS1 locus was mapped in Finnish
families to chromosome 9q3415 and mutations identified in
mRNA export mediator GLE1 (MIM 603371).18 All except one
of 52 patients with LCCS1 were homozygous for a substitution
in intron 3 (LCCS1 FinMajor) that creates a cryptic splice acceptor
site. The remaining individual was a compound heterozygote
for the FinMajor mutation and a point mutation (p.R569H).
All 12 patients with the slightly milder LAAHD were compound
heterozygous for GLE1 mutations. Another individual
affected with arthrogryposis but with prolonged survival and
originally diagnosed as having severe SMA was also found to be
compound heterozygous for GLE1 mutations.18 Thus, LCCS1
and LAAHD are allelic disorders with homozygosity for the
FinMajor mutation that results in a more severe phenotype.
Inositol hexakisphosphate has been shown to bind directly to
the yeast homologue of GLE1 (Gle1). The inositol hexakisphosphateeGle1 complex stimulates activity of a DExD/H-box
protein to mediate mRNA export.19
Phosphatidylinositol-4-phosphate 5-kinase, type I, gamma
(PIP5K1C)
LCCS3 (MIM 611369), also identified in IsraelieBedouin
kindreds, is a variant of LCCS2 lacking the bladder defect.
Affected newborns were small with multiple contractures and
severe muscle atrophy. All died of respiratory insufficiency
within hours of birth.20 A homozygous missense mutation was
identified in PIP5K1C (MIM 606102) in all affected individuals.20
This enzyme is involved in the production of phosphatidylinositol-4,5-bisphosphate. Thus, LCCS2 and LCCS3 are associated
with defects in the phosphatidylinositol 3-kinase pathway, and
all LCCS genes are involved in inositol pathways. PIP5K1C
null mice die on the day of birth due to immobility and an
inability to feed; their neurons show defects in synaptic vesicle
trafficking.21
Trisomy 1q
Motor neuron loss was seen in a case that presented at 29 weeks’
gestation with absent fetal movements, camptodactyly and
hydrops; micro/retrognathism and posterior cleft palate
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diagnosed as Pierre Robin sequence (PRS). Cytogenetic analysis
revealed a rearrangement consisting of direct duplication of
chromosomal region 1q23.1-q31.1.22 Other partial 1q trisomies
have been reported in cases with PRS and camptodactyly. Taken
together, these studies suggest that one or more dosage-sensitive
genes in the 1q25 segment cause PRS and distal arthrogryposis.22
Ubiquitin activating enzyme 1 (UBE1)
The severe, lethal form of X linked SMA (MIM 301830) is
characterised by AMC, hypotonia, areflexia and infantile death
due to respiratory insufficiency, associated with loss of anterior
horn cells.23 Mutation analysis of 123 genes within the linkage
region identified mutations in the UBE1 (MIM 314370) in five of
the six affected families studied. Missense mutations, M539I
and S547G, were each identified in one family, while a synonymous C-to-T substitution, found to significantly reduce UBE1
expression, occurred in three families.24
FETAL AKINESIA DUE TO MUTATIONS IN GENES AFFECTING
THE PERIPHERAL NERVES
Severe cases of congenital hypomyelination neuropathy,
involving near-total amyelination of the peripheral nerves, have
been associated with AMC, respiratory distress and early infant
death.25 Congenital hypomyelination neuropathy can be caused
by mutations in the early growth response 2 gene (EGR2; MIM
129010)26 and the myelin protein zero gene (MPZ; MIM
159440)27 and thus may represent a severe form of DejerineeSottas syndrome (MIM 145900), which is an early-onset
motor and sensory neuropathy. None of the described hypomyelination cases with in utero presentation underwent genetic
testing; however, it is plausible that some may harbour EGR2
and MPZ mutations.
FETAL AKINESIA DUE TO MUTATIONS IN GENES ENCODING
COMPONENTS OF THE NMJ
The acetylcholine receptor (AChR)
During embryonic development, the AChR is comprised of two
a1, one b1, one g and one d subunit. After 33 weeks’ gestation,
the g subunit is replaced by the e subunit, and this configuration
of the AChR persists into adulthood (except in denervated
muscle).28
AChR: a and d subunits (CHRNA1 and CHRND)
In a study of 60 families with FADS, mutations in the genes
encoding the a (CHRNA1 (MIM 100690)) and d (CHRND)
subunits of the AChR were identified in two families each.29 In
these cases, prenatal ultrasound detected hypokinesia and
growth retardation. All affected fetuses did not survive to term.
Postmortem examinations revealed contractures, oedema and
pterygia. Affected fetuses from one family had a homozygous
missense mutation in a completely conserved residue of
CHRNA1. In the second family, the affected fetus carried
a homozygous duplication of 17 base pairs in CHRNA1 resulting
in a frameshift mutation and a subsequent premature stop
codon (H25RfsX19). A homozygous nonsense mutation in
CHRND in the third family introduced a premature stop codon
(W57X). Affected fetuses in the fourth family were compound
heterozygotes for a nonsense mutation encoding R443X and
a missense mutation F74L in CHRND.
In a further example, DNA analysis of two siblings with
reduced fetal movements diagnosed as having AMC (MIM
108110)30 and CMS (MIM 608931) identified compound
heterozygous mutations (E59K and S274del) in the d subunit of
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the AChR (CHRND; MIM 100720).31 Expression studies revealed
that the S274del mutation was a null mutation and that AChR
containing the E59K mutant had slower activation times.
AChR: g subunit (CHRNG)
Mutations in the gene encoding the g subunit of the AChR
(CHRNG; MIM 100730) are known to cause the recessively
inherited prenatal lethal (MIM 253290) and non-lethal (also
known as Escobar variant32; MIM 265000) forms of MPS.33 34
Mutations were identified in individuals from seven families
with Escobar syndrome; five families showed consanguinity, and
three of these also had a history of spontaneous abortions. In all
cases, the initial presentation was reduced fetal movement. At
birth, patients presented with joint contractures, multiple
pterygia and facial dysmorphism (high-arched palate, long face,
small mouth and retrognathia). Three nonsense mutations, one
putative splice-site and one frameshift mutation were identified.
These mutations are predicted to truncate major components of
the g subunit or to result in mRNA nonsense-mediated decay.33
In a separate study, mutations in CHRNG were identified in
affected individuals from 6 of 15 families with lethal or Escobar
variant MPS. In all cases, the mutations were homozygous; four
of the families were known to be consanguineous.34 CHRNG
mutations thus appear to account for w30% of lethal and
Escobar variants of MPS.35 Mutations in CHRNG have also been
identified in affected individuals from three families diagnosed as
having recessive FADS.29
Antibodies to the g subunit of the AChR
Approximately 20% of infants of women with myasthenia
gravis (MIM 254200) have transient neonatal myasthenia.
However, cases in which there are maternal antibodies specific
for CHRNG can have antenatal onset resulting in multiple joint
contractures and reduced fetal movement.36
Contactin-1 (CNTN1)
CNTN1 (MIM 600016) is a neural immunoglobin-family adhesion protein expressed in the central and peripheral nervous
system and at the NMJ.37 A consanguineous Egyptian family
was identified with four individuals affected by an autosomal
recessive lethal congenital myopathy, associated with fetal
akinesia and secondary loss of b2-syntrophin and a-dystrobrevin.38 All four affected infants were found to have a homozygous duplication (c.871dupT) in CNTN1, causing a frameshift
and premature stop codon (S291fsX296).37 Patient muscle
biopsies showed significantly reduced transcript levels and
abnormal contactin-1 localisation at the sarcolemma instead of
exclusively at the NMJ.
Downstream of kinase-7/muscle intrinsic activator of MUSK
(DOK7)
DOK7 (MIM 610285) binds with and phosphorylates muscle
skeletal tyrosine kinase (MUSK), a crucial step for AChR clustering in synaptogenesis.39 DOK7 mutations cause CMS with
limb girdle weakness40 and a recessive proximal myopathy.41
In a study of 14 families with lethal MPS or FADS and no
evidence of CHRNG, CHRNA1, CHRNB1, CHRND or RAPSN
mutations, a homozygous splice-site mutation in DOK7 was
identified in a consanguineous family with three children
affected with lethal FADS.35 This is consistent with the notion
that, whereas partial loss of DOK7 function will cause a CMS
phenotype, complete loss of function is lethal.35 A similar model
has been suggested for RAPSN mutations.42
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Nesprin-1/synaptic nuclear envelope protein-1 (SYNE1)
In a consanguineous family, two children presented with AMC
at birth, following decreased fetal movements, and showed
delayed motor milestones and progressive motor decline.4 An
unaffected brother of the two affected children married a firstdegree cousin, and they had two affected fetuses that at 28 and
16 weeks’ gestation showed bilateral clubfoot and reduced fetal
movement; these pregnancies were terminated. Linkage analysis
and fine mapping revealed a critical linkage region on 6q25.
Nesprin-1 (SYNE1; MIM 608441) was the most plausible
candidate gene. Sequencing revealed a homozygous substitution
of the conserved AG splice-acceptor site at the junction of intron
136 and exon 137. This mutation resulted in retention of intron
136 leading to a premature stop codon.
Nesprin-1 is involved in anchoring the specialised nuclei underneath the NMJ; it is also involved in linking the nucleoskeleton to
the cytoskeleton. Mice that are homozygous null for the
C-terminus of nesprin-1 exhibit 50% perinatal lethality, progressive
muscle wasting, muscle weakness and kyphoscoliosis.43
Mutations in SYNE1 also cause autosomal recessive adultonset spinocerebellar ataxia 8 (MIM 610743) and Emerye
Dreifuss muscular dystrophy 4 (MIM 612998).
Rapsyn (RAPSN)
Rapsyn (receptor associated protein of the synapse) is involved
in assembly and localisation of the AChR to the muscle
membrane.44 Mutations in the rapsyn gene (RAPSN; MIM
601592) are a common cause of CMS (reviewed by Milone
et al45).
In a study of 16 patients with RAPSN-based myasthenic
syndromes, 10 had AMC. All 10 patients harboured a common
founder N88K substitution.46
In a study of 15 families with lethal MPS or FADS in which
CHRNG mutations were excluded, a homozygous RAPSN
c.1177-1178delAA frameshift mutation was detected in
a consanguineous family with three pregnancies affected with
lethal FADS. Akinesia was detected at 19 weeks’ (twin pregnancy) and 22 weeks’ gestation; both pregnancies were terminated. The fetuses had contractures, hydrops, absent respiratory
movement and craniofacial abnormalities; pterygia were
absent.42
RAPSN mutations were also identified in two isolated cases of
non-consanguineous infants born with contractures. The first
patient had distinctive facial features and repeated apnoeic
events. This infant was a compound heterozygote for a missense
L238P mutation and an intronic mutation. The second patient
presented with AMC, generalised hypotonia and similar
distinctive facial features. This patient had scoliosis, moderate
contractures, mild ptosis and exercise-induced weakness and
was found to be homozygous for a missense mutation (R164C)
in RAPSN.47 A third family has been reported in which one fetus
was aborted and two siblings were born at term with FADS,
associated with compound heterozygosity for missense mutations (F139S and A189V) in RAPSN. The symptoms included
severe respiratory insufficiency, contractures and craniofacial
abnormalities (tented lips, micrognathia, wide nasal bridge,
low-set ears and downslanting palpebral fissures).
FETAL AKINESIA DUE TO MUTATIONS IN GENES ENCODING
ADULT SKELETAL MUSCLE PROTEINS
Actin, skeletal muscle alpha (ACTA1)
Skeletal muscle a-actin is the principal protein of the skeletal
muscle thin filament. Mutations in the ACTA1 gene (MIM
796
102610) cause a wide spectrum of congenital myopathies characterised by muscle weakness (most often severe) and one or
more of the following pathological entities: actin accumulations,
caps, cores, core-like areas and rods, fibre-type disproportion,
intranuclear rods, nemaline bodies and zebra bodies.48e50
Mutations in ACTA1 have been shown to account for some
cases of FADS with pathological features usually associated with
the congenital myopathies. A patient diagnosed as having classic
PenaeShokeir syndrome/FADS presented with reduced fetal
movement, severe hypotonia at birth and respiratory insufficiency due to lung hypoplasia, requiring mechanical ventilation.
The muscle biopsy showed actin accumulations and cytoplasmic and intranuclear rods. A heterozygous missense
mutation was identified in ACTA1 (D154N).51
Another patient with a heterozygous missense mutation
(G15N) in ACTA1 presented with fetal akinesia, lung hypoplasia,
reduced intrauterine growth and polyhydramnios and died 1 h
postdelivery. Postmortem analysis revealed low-set ears, bilateral
pes equinovarus, dysplastic thumbs, marked hirsutism, scoliosis,
fractures, hyperextended feet and flexed fingers. The muscle
biopsy showed accumulations of actin filaments.52 Other cases
of ACTA1-based nemaline myopathy with fetal akinesia have
also been reported.53 54
Amphiphysin 2 (BIN1)
Mutations in BIN1 (MIM 601248) cause autosomal recessive
centronuclear myopathy (MIM 255200), a congenital myopathy
characterised by centrally nucleated myofibres. In one consanguineous family, three affected fetuses presented with reduced
fetal movement and oligohydramnios, lung hypoplasia, intrauterine growth retardation, contractures and centronuclear
myopathy.55
Dystrophia myotonica protein kinase (DMPK)
Myotonic dystrophy is caused by a trinucleotide (CTG) repeat
expansion (MIM 160900). The congenital form of the disorder is
associated with maternal transmission of a markedly expanded
repeat, and the clinical presentation can overlap with FADS. For
example, two siblings presented with polyhydramnios, intrauterine growth retardation, pulmonary hypoplasia and short
umbilical cord, and died of respiratory insufficiency at 29 and
12 h of age. Reduced fetal movements were noted in the last
week of both pregnancies. Muscle biopsies revealed myopathic
features with small immature fibres and an excess of central
nuclei, consistent with a diagnosis of congenital myotonic
dystrophy. In addition, the maternal grandmother had displayed
symptoms of myotonic dystrophy.56 Although DNA was not
available for the siblings, molecular genetic analysis of the
mother revealed her to be a subclinical carrier of the disease.56
A study of the incidence of FADS in Denmark identified two
children with characteristic symptoms of FADS and underlying
congenital myotonic dystrophy. Both children died within the
first 72 h of life.57
Fukutin-related protein (FKRP)
FKRP (MIM 606596) is a glycosyltransferase that glycosylates
the membrane protein a-dystroglycan. Mutations in FKRP cause
a spectrum of muscular dystrophyedystroglycanopathies
(MDDG): the milder, later-onset limb-girdle muscular dystrophy
type 2I (LGMD2I or MDDGC5; MIM 607155); a congenital
form with or without mental retardation (MDDGB5; MIM
606612); and a more severe congenital form with brain and
eye anomalies (WalkereWarburg syndrome, muscleeeyee
brain disease or MDDGA5; MIM 613153). Severe cases of
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FKRP-related dystroglycanopathies may be associated with fetal
akinesia.
Two siblings, of consanguineous parents, diagnosed as having
WalkereWarburg syndrome due to a homozygous start codon
mutation (Met1Val), predicted to result in a null allele in FKRP,
have been reported.58 Reduced fetal movements were identified
in the first child at 34 weeks’ gestation. After birth, he exhibited
severe hydrocephalus, limited spontaneous movement, and
severe eye and brain abnormalities, and died at the age of 6 days
due to respiratory failure. Muscle biopsy demonstrated dystrophic features. The second affected fetus was found to have
severe hydrocephalus at 17 weeks’ gestation, and the pregnancy
was terminated.
(S2279dup) and a large in-frame deletion resulting in a loss of 54
of 106 exons in RYR1.
The I4898T mutation in RYR1 has been identified in several
unrelated families with central core disease. Recently, this
mutation, also in the heterozygous state, was identified in
monozygotic twins presenting with polyhydramnios and loss of
fetal movement from 27 weeks’ gestation. Both infants required
intubation and ventilator support from birth; death occurred at
27 and 40 days of life. Muscle biopsies were consistent with
core-rod myopathy (MIM 180901).66 In a cohort study of 24
patients with centronuclear myopathy, 17 harboured RYR1
mutations; of these, 11 had reduced in utero movement.67
Tropomyosin, slow beta (TPM2)
Lamin A/C (LMNA)
While the vast majority of fetal akinesia cases due to LMNA
mutations arise due to a restrictive dermopathy,2 an autosomal
recessive case of myopathic fetal akinesia due to a homozygous
mutation in LMNA occurred in a consanguineous family.3 The
mutation in the heterozygous form resulted in limb-girdle
muscular dystrophy type 1B (MIM 159001).3
Myotubularin (MTM1)
Mutations in MTM1 (300415) cause X linked myotubular
myopathy (MIM 310400). Some of these cases present with
reduced in utero movements and polyhydramnios,59 60 including
a manifesting carrier.61
Nebulin (NEB)
Mutations in the gene for the thin filament protein nebulin
(NEB; MIM 161650) cause nemaline myopathy,62 core-rod
myopathy63 and distal myopathy.64
In a study of severe cases of nemaline myopathy due to
recessive NEB mutations, affected infants displayed features
characteristic of fetal akinesia including reduced fetal movement, polyhydramnios, arthrogryposis, rocker-bottom feet,
talipes, cleft palate, low-set ears and a lack of spontaneous
breathing.48 Of the six infants that survived to term, death
occurred between 30 min and 19 months postbirth.
Ryanodine receptor-1 (RYR1)
The RYR1 (MIM 180901) is the voltage-gated Ca2+-release
channel of the sarcoplasmic reticulum. Mutations in RYR1 have
been classically associated with dominant central core disease
and malignant hyperthermia; however, recent studies have
shown that recessive RYR1 mutations result in a much more
severe clinical phenotype associated with multi-minicore
disease, centronuclear myopathy, congenital fibre-type
disproportion and congenital muscular dystrophy.65
In a study of seven patients from six families that presented
with fetal akinesia syndrome and polyhydramnios during pregnancy with central core disease (MIM 117000), mutations in
RYR1 were identified in four cases.5 Two cases from one family
(R614C/G215E) and a separate isolated case (L4650P/K4724Q)
were compound heterozygotes, while the fourth case harboured
a dominant mutation (G4899E).5
An isolated case born at 39 weeks’ gestation, after an
uneventful pregnancy, presented with an atypical form of lethal
neonatal hypotonia. The patient showed global hypotonia and
immobility, feeding difficulties and mild distal arthrogryposis,
without polyhydramnios or craniofacial abnormalities6; the
muscle biopsy demonstrated multi-minicores (MIM 180901).
The patient was a compound heterozygote for a duplication
J Med Genet 2011;48:793e801. doi:10.1136/jmedgenet-2011-100211
Dominant mutations in b-tropomyosin (TPM2; MIM 190990)
cause two congenital myopathies: nemaline myopathy68 and
cap disease.49 50
Homozygosity for TPM2 null mutations has been identified in
affected consanguineous siblings with the Escobar variant of
MPS.7 The proband, born at term, presented with severe
hypotonia and arthrogryposis, scoliosis, pes varus, distal and
proximal joint contractures and multiple pterygia; the muscle
biopsy showed multiple nemaline bodies. Two affected cousins
had the same clinical picture.
Mutations in TPM2 can also cause distal arthogryposes (DAs),
a group of clinically and genetically heterogeneous disorders
characterised by multiple congenital contractures of the limbs.
Distal arthrogryposis is divided into 10 subgroups based on
clinical features.69 Mutations in TPM2 were first associated with
DA1 (MIM 108120), which is characterised by camptodactyly
and clubfoot, with occasional involvement of the shoulders and
hips.70 A TPM2 missense mutation (R133W) was identified in
a mother and daughter affected with DA2B/SheldoneHall/
variant FreemaneSheldon syndrome (MIM 601680), the
most common DA.71 Both were born with predominantly distal
contractures and showed proximal and distal muscle
weakness.72
Troponin I, fast skeletal muscle (TNNI2)
Studies of other families with dominant DA2B mapped the
disease to 11p15.5.73 Subsequently, two different mutations
(R156X and R174Q) in the gene encoding the fast skeletal
muscle isoform of troponin I (TNNI2; MIM 191043) were
identified in 4 of 32 kindreds diagnosed as having DA2B.74 A
large Chinese kindred was also identified in which some affected
individuals presented with DA1 and others with DA2B.70
Sequencing of TNNI2 revealed a 3 bp deletion in exon 8, deleting
lysine residue 175 (p.K175del).75 Two further studies identified
3 bp deletions in TNNI2 in two separate multi-generational
families, one presenting with DA1 (p.K176del76) and one
presenting with DA2B (p.E167del).77
Troponin T, fast skeletal muscle (TNNT3)
A study of 47 families with classical FreemaneSheldon
syndrome, characterised by striking contractures of the orofacial
muscles (DA2A, ‘whistling face syndrome’; MIM 193700) or
DA2B, revealed a missense mutation (R63H) in TNNT3 (MIM
600692) in a mother with DA2B and her two affected children.78
A subsequent study sequencing TNNT3 in 31 patients identified
the same R63H mutation in one individual with DA1.79
In vitro, TPM2, TNNI2 and TNNT3 DA mutations result in
increased Ca2+ sensitivity of the thin filament and hence
increased contractility,80 leading to the hypothesis that the
development of DA in these cases is due to increased tension in
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Review
developing muscles resulting in contractures and limb deformities. Thus, the development of DA, in some cases, may be an
active process80 rather than a passive one.30 The distal muscle
groups are predominantly fast-twitch, and thus, these are the
muscle groups most affected.78
FETAL AKINESIA DUE TO MUTATIONS IN GENES ENCODING
FETALLY EXPRESSED MYOSTRUCTURAL PROTEINS
Mutations in a number of genes encoding proteins that
predominate in fetal life cause disorders arising from reduced
fetal movement.
Myosin heavy chain, embryonic (MYH3)
In a study of 28 cases of DA2A and 38 cases of DA2B, mutations
in the gene encoding embryonic myosin heavy chain (MYH3;
MIM 160270) were found in 26 and 12 cases, respectively.81 In
20 of the DA2A cases, a missense mutation was found which
was predicted to cause substitution of Arg672 with either
cysteine or histidine. This residue is paralogous to the
Arg674 residue of MYH8 that is mutated in trismuse
pseudocamptodactyly syndrome (TPS). Subsequently, three
further MYH3 myosin head mutations were identified in two
unrelated families with DA2B and a de novo case of DA2A.82
Myosin heavy chain, perinatal (MYH8)
A dominant mutation (c.2021G>A, p.R674Q) in the gene
encoding perinatal myosin (MYH8; MIM 160741) was identified
in a large family with Carney complex (a multiple neoplasia
syndrome; MIM 160980) associated with TPS (MIM 158300)
and two unrelated families with TPS alone.83 TPS, also referred
to as DA7, DutcheKentucky or HechteBeals syndrome, is a rare
autosomal dominant disorder characterised by inability to fully
open the mouth (trismus) and an unusual camptodactyly of the
fingers that is only observed upon hyperextension of the wrists.
A subsequent study of four unrelated families with TPS,
including the original TPS pedigree, found that all shared the
p.R674Q MYH8 mutation, but haplotype analysis showed that
the mutation arose separately in North American and European
families.84
Myosin binding protein C1, skeletal muscle slow type (MYBPC1)
A study of a family with 12 members affected with DA1
revealed linkage to a region of chromosome 12q23.2 containing
more than 60 genes. A candidate gene approach identified
a missense mutation, p.W236R, in MYBPC1 (MIM 160794)
encoding skeletal muscle myosin binding protein C1.85 This
variant was also present in the proband’s grandfather who had
bilateral clubfoot.85 Subsequent sequencing of MYBPC1 in 14
other patients with DA1 identified a p.Y856H substitution in
one patient.
Utrophin (UTRN)
A chromosome 6q duplication was identified in a patient with
hypertelorism, downslanting palpebral fissures, a tented upper
lip, short neck, mental retardation and joint contractures.86
Comparative genomic hybridisation showed that the proximal
breakpoint occurred within the gene encoding utrophin (UTRN;
MIM 128240) between exons 42 and 54.86 The authors
suggested that this should result in haploinsufficiency of UTRN
and that this underlies the joint contractures. Utrophin, the fetal
homologue of dystrophin, is expressed at the sarcolemma of
fetal skeletal muscle but becomes confined to the NMJ in mature
fibres.87 Another case showing a 6q23-q25.1 duplication that
798
would have involved either disruption or an increased copy
number of UTRN presented with severe arthrogryposis/FADS,88
while patients with 6q duplication syndrome with proximal
duplications not encompassing UTRN do not show arthrogryposis.89 90 Thus, alterations involving UTRN are likely to
underlie the arthrogryposis associated with some cases of 6q
duplication syndrome. However, it must be noted that SYNE1
also lies within the reported 6q duplicated region.86 Recessive
SYNE1 mutations cause arthrogryposis.4
FETAL AKINESIA ASSOCIATED WITH OTHER GENES
Fibroblast growth factor receptor 2 (FGFR2)
Fibroblast growth factors have multiple roles in human
morphogenesis acting via receptors including FGFR-2. FGFR-2 is
expressed in mesenchymal and epithelial cells and is important
in multiple phases of limb development.91 FGFR2 (MIM 176943)
gain of function mutations cause craniosynostosis syndromes,
which can manifest limb anomalies including pterygia.30 A fetus
with features consistent with fetal akinesia, including multiple
pterygia, with an FGFR2 c.1019A>G, p.Y340C mutation has
been reported.92 There were additional dysmorphic and skeletal
findings consistent with an FGFR-2 related craniosynostosis.
Prenatally detected pterygia have not been otherwise reported
with FGFR2 mutations; thus, ‘double trouble’ genetic and/or
environmental factors are likely to have been involved in the
described case.
Glycogen branching enzyme (GBE1)
Glycogen storage disease type IV (MIM 232500) is a clinically
heterogeneous autosomal recessive disorder arising from GBE
deficiency and results in the accumulation of amylopectin-like
polysaccharides. The typical form involves liver disease in
childhood that progresses to lethal cirrhosis.93 The neuromuscular form varies in age of onset and severity. The perinatal form
presents as FADS characterised by AMC, hydrops and perinatal
death.94 Compound heterozygous or homozygous mutations in
GBE1 (MIM 607839) underlie the FADS form of glycogen
storage disease type IV.95 96
CONCLUSIONS
Despite recent identification of multiple genes for fetal akinesia,
the vast majority of cases are without a molecular diagnosis.
Most cases of this heterogenous group of disorders are isolated or
from small families. Whole exome sequencing of cohorts of wellcharacterised patients is the most promising way forward to
improve diagnosis, through the identification of novel loci, and
to analyse the known genes in further patients.97 For example,
whole exome sequencing of DNA from only two isolated cases
recently lead to the identification of the causative gene for
Fowler syndrome (MIM 225790), a rare form of prenatally lethal
fetal akinesia.98 Clinicians and researchers should ideally collect
detailed data on all undiagnosed patients with FADSdincluding
prenatal scans, autopsy findings (including muscle and neuropathology) and DNAdto enable and facilitate diagnosis and
gene discovery for these conditions. Targeted capture and nextgeneration sequencing of known disease genes already offer the
possibility of affordable analysis of multiple disease genes in
clinical diagnosis.99 The potential of whole exome sequencing
will be crucial to identifying the unknown genetic bases of fetal
akinesia.
Funding This work was supported by the Australian National Health and Medical
Research Council Fellowships 403904 and APP1002147 and project grant 403941.
J Med Genet 2011;48:793e801. doi:10.1136/jmedgenet-2011-100211
Downloaded from jmg.bmj.com on November 21, 2011 - Published by group.bmj.com
Review
Competing interests None.
23.
Contributors All authors were involved in the synthesis of this review article. GR and
ES contributed equally to this manuscript.
Provenance and peer review Not commissioned; externally peer reviewed.
24.
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Fetal akinesia: review of the genetics of the
neuromuscular causes
Gianina Ravenscroft, Elliot Sollis, Adrian K Charles, et al.
J Med Genet 2011 48: 793-801 originally published online October 7,
2011
doi: 10.1136/jmedgenet-2011-100211
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