American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 166C:198210 (2014)

A R T I C L E

The Genetics of Lissencephaly

ANDREW E. FRY,* THOMAS D. CUSHION, AND DANIELA T. PILZ

Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach
optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been
characterized in recent years. Identication of the genetic basis of these disorders has brought fascinating insights
into the mechanisms of brain development, as well as benets to patients through improved molecular diagnosis
and genetic counseling. This review explores the clinical presentation, radiological features, histological ndings
and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in
patients with smooth brain phenotypes. 2014 Wiley Periodicals, Inc.

KEY WORDS: lissencephaly; genetics; agyria; pachygyria; subcortical band heterotopia; PAFAH1B1; LIS1; DCX; TUBA1A

How to cite this article: Fry AE, Cushion TD, Pilz DT. 2014. The genetics of lissencephaly. Am J Med Genet
Part C Semin Med Genet 166C:198210.

INTRODUCTION
The term lissencephaly, derived from
the Ancient Greek for smooth (lissos)
and brain (enkephalos), was first coined
in a zoological context to differentiate
the normally smoothsurfaced brains of
reptiles from the more convoluted
(gyrencephalic) brain surfaces of
higher animals [Owen, 1868]. The
first pathological descriptions of human
brains with an abnormally smooth
cerebral cortex came in 1914 [Stratton
et al., 1984], and the term lissencephaly
was subsequently used in clinical reports
to describe this range of brain malfor-
mations. In severe lissencephaly the
cortex lacks surface folds (agyria) while
milder manifestations include abnor-
mally broad folds (pachygyria) or a
heterotopic layer of gray matter embed-
ded in the white matter below the cortex
(subcortical band heterotopia, SBH)
[Barkovich et al., 1991; Barkovich
et al., 2012]. The precise prevalence of
lissencephaly is uncertain but estimates
range from 11.7 to 40 cases per million
births [de Rijkvan Andel et al., 1991;
Dobyns and Das, 2009].
The pathogenesis of lissencephaly is
best understood in the context of normal
cortical development. In humans primi-
tive neurons (neuroblasts) are generated
through mitosis of neural stem cells in the
ventricular zone (VZ, a region close to
the lateral ventricles) of the fetal brain
between 5 and 22 weeks of gestation
[WynshawBoris et al., 2010]. Post
mitotic neuroblasts undergo radial mi-
gration outward from the VZ, guided by
radial glial fibers, to populate the cortical
plate (CP, the embryonic cerebral cortex)
[Ayala et al., 2007]. Slow or arrested
migration leads to a thickened cortex
with reduced folding (pachygyria or
agyria) or the stranded neurons of
SBH.
Over the last three decades the
identification of a growing number of
causative genes for lissencephaly pheno-
types has meant that many patients now
Studies of the genes mutated
in patients and the
corresponding animal models
have given us valuable insights
into the molecules and
pathways involved in brain
development.
receive a genetic diagnosis. Making a
genetic diagnosis can clarify the recur-
rence risk in a family, provide prognostic
information, avoid unnecessary investi-
gation and make prenatal genetic diag-
nosis possible. Studies of the genes
mutated in patients and the correspond-
ing animal models have given us valuable

Dr. Andrew E. Fry is a Clinical Lecturer in Medical Genetics. He is currently working at the Institute of Medical Genetics in Cardiff where his research
focuses on the clinical and molecular characterization of cortical brain malformations.
Dr. Thomas D. Cushion is a molecular geneticist currently working as a postdoctoral research scientist at the Institute of Life Science of Swansea
University. His research interests lie in the role of microtubule polymers and associated proteins in neuronal migration and the development of the
mammalian cerebral cortex.
Prof. Daniela T. Pilz is a Consultant and Honorary Professor in Clinical Genetics whose research interests are focused on the discovery of the nature and
molecular causes of human developmental disorders especially malformations of cortical development.
*Correspondence to: Andrew E. Fry, Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, United Kingdom.
Email: fryae@cardiff.ac.uk
DOI 10.1002/ajmg.c.31402
Article rst published online in Wiley Online Library (wileyonlinelibrary.com): 23 May 2014

2014 Wiley Periodicals, Inc.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 199

insights into the molecules and pathways
involved in brain development.
This review surveys the genetic basis
of lissencephaly phenotypes, focusing on
the etiology of the common classical
form of lissencephaly, as well as its rarer
variants.
CLASSICAL
LISSENCEPHALY
Classical lissencephaly is distinguished
from other forms of lissencephaly by the
presence of an abnormally thick, 4layer
cortex and, typically, by the absence of
other major brain abnormalities (e.g.,
severe congenital microcephaly, agenesis
of the corpus callosum, or cerebellar
hypoplasia) [Barkovich et al., 2012].
Classical lissencephaly is sometimes
referred to as type 1 lissencephaly to
differentiate it from cobblestone cortical
malformation [Forman et al., 2005].
Classical lissencephaly is caused by
mutations in three genes: PAFAH1B1
[Dobyns et al., 1993], DCX [des Portes
et al., 1998b; Gleeson et al., 1998]
and TUBA1A [Kumar et al., 2010].
The neuroradiological appearance of
lissencephaly and SBH is often graded
using a 6point grading system based on
the severity and anteriorposterior gra-
dient of the abnormalities, from severe
grade 1 (complete agyria) to mild
grade 6 (SBH only) [Dobyns and
Truwit, 1995; Dobyns et al., 1999b]
(Table I, Fig. 1).
PAFAH1B1 (also often called LIS1)
was the first gene associated with
lissencephaly [Dobyns et al., 1993;
Reiner et al., 1993]. In the 1960s Miller
The deletions found in MDS
patients were frequently de
novo and consistently
encompassed PAFAH1B1
along with several nearby
genes including the YWHAE
(1433e) gene
[1963] and Dieker et al. [1969] reported
sib pairs with multiple congenital abnor-
malities including lissencephaly. Patients
with MillerDieker syndrome (MDS)
have severe lissencephaly (grade 1 or 2)
associated with dysmorphic facial fea-
tures consisting of a high forehead, small
jaw, short upturned nose, protruberant
upper lip and bitemporal narrowing.
Developmental delay and intellectual
disability are usually severe [Dobyns
et al., 1991; Cardoso et al., 2003].
Additional structural abnormalities oc-
casionally reported in MDS include heart
defects, omphalocele, cleft palate and
genital anomalies in males. The observa-
tion of sib pairs initially led to the
suggestion that MDS was an autosomal
recessive disorder [Dobyns et al., 1991].
However, cytogenetic testing revealed
that MDS patients had subtle chromo-
somal deletions at band 17p13.3 [Dobyns
et al., 1983]. The deletions found in
MDS patients were frequently de novo
and consistently encompassed PA-
FAH1B1 along with several nearby
genes including the YWHAE (1433e)
gene [Dobyns et al., 1991; Cardoso
et al., 2003]. The observed familial
recurrences had been due to rare
chromosomal translocations resulting in
unbalanced arrangements involving
17p13.3 in the affected children [Stratton
et al., 1984].
Subsequent studies have found that
around 65% of patients with isolated
lissencephaly sequence (ILS, lissence-
phaly without other major congenital
anomalies or dysmorphic features) have
deletions (whole gene or partial) or
intragenic mutations of PAFAH1B1
[Lo Nigro et al., 1997; Cardoso
et al., 2000]. In ILS the lissencephaly
is usually less severe (grades 24) but the
majority of patients still experience
significant developmental delay and
intellectual disability [Dobyns et al.,
1992; Saillour et al., 2009]. Severe
motor impairment is common. Patients
often present with neonatal hypotonia,
which evolves into spastic quadriparesis
with truncal hypotonia. The facial
features of ILS patients are less dysmor-
phic than those of MDS, and ILS
patients usually lack malformations
outside the brain. The severity of the
neurological impairment broadly cor-
relates with the extent of the agyria and
cortical thickening [Barkovich et al.,
1991; Cardoso et al., 2000]. Around
83% of patients experience earlyonset
seizures, typically infantile spasms, and

TABLE I. Grading System for Classical Lissencephaly and SBH

Grade Description of cortical malformation

1 Diffuse agyria
2 Diffuse agyria with a few shallow undulations over the frontal and temporal (2a) or occipital (2b) poles.
3 Mixed agyria and pachygyria with either frontal pachygyria and parietooccipital agyria (3a) or parietooccipital pachygyria
and frontal agyria (3b).
4 Diffuse or partial pachygyria only, which is more severe posteriorly (4a) or frontally (4b).
5 Mixed pachygyria (posteriorly, 5a; frontally, 5b) and SBH
6 SBH only (posteriorly, 6a; frontally, 6b)

Modified from Dobyns and Truwit [1995]. Grades 16 denote the overall severity of the lissencephaly seen on neuroimaging, with grade 1
(generalized agyria) being the most severe and grade 6 (subcortical band heterotopia, SBH) the mildest form. Grades 1a6a are more severe
posteriorly while grades 1b6b are more severe anteriorly.
200 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Figure 1. The classical lissencephaly spectrum. Classical lissencephaly and SBH are graded according to severity (grades 16) and the
anteriorposterior gradient of cortical abnormalities (see also Table I). Axial brain scan images of five patients with PAFAH1B1related
lissencephaly are shown. They include: grade 1 (complete agyria, gradient being difficult to determine when the abnormality is severe and
diffuse), grade 2a (diffuse agyria with a few frontal undulations), grade 3a (posterior agyria and frontal pachygyria), grade 4a (posterior
predominant pachygyria) and grade 6a (SBH, thick posteriorly). Grade 5a (posterior pachygyria with frontal SBH is very rare and is not
shown). The 2a image is from a T1weighted MRI scan, the rest are T2weighted.

nearly all will eventually develop epi-
lepsy [Saillour et al., 2009]. The epilepsy
is often medically resistant with around
half of patients having daily seizures
despite treatment. Other common fea-
tures include delayed visual develop-
ment, postnatal microcephaly and
feeding difficulties [Dobyns et al.,
1992]. Rare individuals with mild
lissencephaly and normal intelligence
have been reported [Leventer et al.,
2001a]. PAFAH1B1 mutations, often
mosaic, are an infrequent cause of SBH
(grade 56) [Pilz et al., 1999; Sicca
et al., 2003].
PAFAH1B1related lissencephaly
has a number of distinctive neuroradio-
logical features. These include a smooth,
thickened cortex (typically 1220 mm
compared with a normal thickness of 3
4 mm [Barkovich et al., 1991]) with a
cellsparse zone and a posterior to
anterior (P >A) severity gradient with
more severe abnormalities at the back of
the brain. Other potential features
include enlarged lateral ventricles, mild
hypoplasia of the corpus callosum,
prominent perivascular spaces and mild
hypoplasia of the cerebellar vermis
[Dobyns et al., 1999b; Saillour et al.,
2009]. When SBH is present it is
characterized by a layer of heterotopic
grey matter below the cortex and
separated from the cortex by a thin
layer of white matter. The overlying
cortex is usually normal or may be
simplified.
The histopathology of PA-
FAH1B1related lissencephaly, as with
other forms of classical lissencephaly,
demonstrates replacement of the normal
sixlayer cortex with an abnormally
thick cortex of four poorly organized
layers. The four layers consist of: a
superficial molecular layer relatively
devoid of neurons (layer I), a relatively
thick layer of pyramidal cells (layer II), a
neuronsparse layer which is myelinated
in older patients (layer III), and a thick
layer of disorganized small to medium
sized neurons (layer IV) [Forman et al.,
2005].
PAFAH1B1 encodes a highlycon-
served 45kDa protein with an N
terminal homodimerization and
coiledcoil domain, and seven Ctermi-
nal WD40 (tryptophanaspartic acid40)
repeats [Moon and WynshawBoris,
2013]. The PAFAH1B1 protein plays
key roles in cell division and motility
mediated through participation in a
range of protein complexes. PAFAH1B1
binds to and regulates cytoplasmic
dynein, a microtubule minus enddi-
rected motor [Sapir et al., 1997; Lev-
enter et al., 2001b]. Work in mice
suggests that PAFAH1B1 is required
for nuclear movement during neuronal
migration by coupling the nucleus to the
centrosome [Tanaka et al., 2004]. PA-
FAH1B1 is also a noncatalytic subunit
in a complex regulating brain levels of
the intracellular signaling molecule
platelet activating factor (PAF). Mice
which are double mutants of the PAF
receptor and Pafah1b1 heterozygotes
show slower neuronal migration, impli-
cating PAF signaling in neuronal migra-
tion [Tokuoka et al., 2003].
Although mainly due to PA-
FAH1B1, loss of YWHAE also contrib-
utes to the MDS phenotype. Deletions
of YWHAE not including PAFAH1B1
lead to dysmorphic facial features,
growth restriction and neuroradiological
changes [Nagamani et al., 2009; Mi-
gnonRavix et al., 2010]. Ywhae is
required for optimal neuronal migration
in mice [Toyooka et al., 2003].
YWHAE has also been shown to
interact with NDEL1 (NUDEL) a
partner of PAFAH1B1 and dynein in
the regulation of microtubules [Toyo
oka et al., 2003].
There has been a debate for some
years as to what genotypephenotype
correlations can be drawn for PA-
FAH1B1related lissencephaly. The se-
vere phenotype of MDS is clearly
associated with large deletions encom-
passing YWHAE. In contrast, mosaic
intragenic mutations are associated with
milder phenotypes and the rare cases
of PAFAH1B1related SBH [Sicca
et al., 2003]. Early reports suggested a
trend towards greater severity for trun-
cating mutations at the start of the gene,
with missense mutations and later trun-
cating mutations causing less severe
disease [Cardoso et al., 2000; Leventer
et al., 2001a]. However, subsequent
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 201

reports have not confirmed this relation- normally, whereas those with the wild lissencephaly have been reported to have
ship [Uyanik et al., 2007; Saillour type DCX allele inactivated under somatic or germline mosaicism [Gleeson
et al., 2009] and have highlighted that migrate, forming the heterotopic band. et al., 2000; Aigner et al., 2003].
missense and 30 truncating mutations can In hemizygous males only the defective Patients with DCXrelated lissen-
also cause severe lissencephaly (poten- DCX allele will be active, leading to the cephaly have clinical problems similar
tially through mechanisms such as more severe phenotype.
nonsensemediated decay and because DCX mutations explain around
different parts of the protein are impor- 10% of ILS (mostly males), 85% of
tant for different functions). females with sporadic SBH and 25% of Patients with DCXrelated
DCX (also known as XLIS) was the males with sporadic SBH [des Portes lissencephaly have clinical
second major gene to be associated with et al., 1998a; Pilz et al., 1998; Gleeson
classical lissencephaly [des Portes et al., 1999b; Matsumoto et al., 2001; problems similar to those
et al., 1998b; Gleeson et al., 1998]. DAgostino et al., 2002; BahiBuisson found in patients with
DCX mutations are capable of causing et al., 2013]. Almost all cases of familial
PAFAH1B1related
the full spectrum of classical lissence- SBH are due to DCX mutations. In
phaly in males (grades 16) while familial cases affected mothers may have lissencephaly. The clinical
females tend to have SBH [Gleeson SBH with mild learning difficulties and severity of SBH is dependent
et al., 1998] (Fig. 2A,B). The high rate of epilepsy while their affected male off-
DCXrelated SBH in females is ex- spring have a more severe grade of on the extent of cortical
plained by lyonization. Xchromosome lissencephaly. Somatic mosaicism can be abnormalities, band thickness
inactivation produces two populations of an explanation for sporadic SBH in both
cells in the developing brain of female males and females [Gleeson et al., 2000].
and ventricular enlargement
heterozygotes. Neuroblasts with the Of note, around 10% of unaffected
defective DCX allele inactivated migrate mothers of children with DCXrelated
to those found in patients with PA-
FAH1B1related lissencephaly. The clini-
cal severity of SBH is dependent on the
extent of cortical abnormalities, band
thickness and ventricular enlargement
[Palmini et al., 1991; Barkovich et al.,
1994]. Familial mutations are usually
missense mutations [Gleeson et al.,
1999b], whereas patients with de novo
mutations are more likely to have truncat-
ing mutations [BahiBuisson et al., 2013].
DCX mutations cause a classical
lissencephaly with an A > P gradient.
Other radiological features include ven-
tricular dilation of the anterior horns,
mild hypoplasia of the corpus callosum
and prominent perivascular spaces, but no
cerebellar or posterior fossa abnormalities
[Leger et al., 2008]. Histopathology of
DCXrelated lissencephaly shows a
vaguely fourlayered cortex similar to
that seen in PAFAH1B1related lissence-
Figure 2. Genetic heterogeneity in lissencephaly. Axial brain scan images of patients phaly but with a relatively thin layer II
with lissencephaly of various genetic causes. The genes mutated are listed under their
respective images. (A) anteriorpredominant (grade 4b) pachygyria in a male with a DCX (pyramidal cells). layers III (cellsparse)
mutation; (B) diffuse SBH (grade 6) in a female with a DCX mutation; (C) posterior and IV (thickened, small to medium
predominant classical lissencephaly (grade 3a) due to a p.Arg402Cys mutation in TUBA1A; neurons) are also comparable but contain
(D) an almost agyric brain with abnormal basal ganglia due to a p.Arg402His mutation in
TUBA1A; (E) modest cortical thickening, agenesis of the corpus callosum and abnormal more neurons [Forman et al., 2005].
basal ganglia in a male with an ARX nonsense mutation; (F) a BaraitserWinter syndrome The DCX gene encodes double-
patient with an ACTB mutation and anteriorpredominant pachygyria; (G) as (F) but with cortin a 40kDa protein which is ex-
an ACTG1 mutation; (H) modest cortical thickening and A > P gradient in a patient
with homozygous RELN mutations. (A) and (E) are from T1weighted MRIs, the rest are pressed as multiple splice variants in the
T2weighted. developing brain, particularly in the
migrating cells of the VZ and CP [des
202 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Portes et al., 1998b; Gleeson
et al., 1998]. DCX is found enriched
at the distal ends of neuronal processes
[Moores et al., 2006]. DCX is a
microtubuleassociated protein. Its
binding to microtubules leads to their
stabilization and assembly [Gleeson
et al., 1999a]. DCX specifically binds
to 13protofilament microtubules and
induces nucleation [Bechstedt and
Brouhard, 2012]. DCX interacts with
PAFAH1B1 [Caspi et al., 2000] and
together they regulate the operation of
dynein [Tanaka et al., 2004]. DCX has
two evolutionarilyconserved repeats.
Mutations responsible for DCXrelated
lissencephaly tend to cluster in these two
domains [Sapir et al., 2000]. The repeats
play a role in microtubule binding and
both are required for DCX to efficiently
regulate microtubule function during
neuronal migration [Taylor et al., 2000].
THE TUBULINOPATHIES
Microtubules play specialized mechani-
cal roles in neurons during multiple
stages of cerebral cortical development.
Microtubules are a major component of
spindle fibers, which provide the me-
chanical forces behind cell division.
Following neurogenesis, microtubules
provide the push and pull forces required
for neuronal migration and then, upon
neurons reaching their destination, mi-
crotubules generate and stabilize axonal
processes, which extend away from the
cell body to mediate cell communica-
tion and synaptogenesis. Given these
diverse roles in cortical development,
and that DCX and PAFAH1B1 are both
regulators of microtubule function, it is
perhaps little surprise that microtubule
subunits have been found mutated in
patients with lissencephaly and related
brain malformations.
Phenotypic similarities between a
mouse with a mutation in the atubulin
gene, Tuba1a, and existing lissencephaly
models led to the investigation of
TUBA1Arelated
lissencephaly typically
demonstrates a P > A gradient
and can be associated with
hypoplasia of the cerebellum
(mild to severe), dysmorphic
basal ganglia, thin or absent
corpus callosum, congenital
microcephaly, ventricular
dilation, and abnormalities of
the hippocampus and
brainstem.
TUBA1A in humans [Keays et al.,
2007]. Since that initial study, a large
number of TUBA1A mutations have
been identified in patients with lissen-
cephaly [Poirier et al., 2007; Kumar
et al., 2010; Cushion et al., 2013].
TUBA1Arelated lissencephaly typically
demonstrates a P >A gradient and can
be associated with hypoplasia of the
cerebellum (mild to severe), dysmorphic
basal ganglia, thin or absent corpus
callosum, congenital microcephaly, ven-
tricular dilation, and abnormalities of the
hippocampus and brainstem.TUBA1A
mutations account for 30% of patients
with a lissencephaly with cerebellar
hypoplasia (LCH) phenotype and a
smaller proportion (1%) of individuals
with classical lissencephaly [Kumar
et al., 2010]. The subset of patients
with TUBA1Arelated classical lissence-
phaly have neuroimaging findings which
are largely indistinguishable from PA-
FAH1B1related lissencephaly, and all
have alterations at the same arginine
residue at codon 402 [Kumar
et al., 2010] (Fig. 2C,D). Neuropatho-
logical examination of one fetus with the
recurrent p.Arg402Cys mutation found
features reminiscent of those observed in
classical lissencephaly, and different
from the pathological findings in cases
with other TUBA1A mutations [Fallet
Bianco et al., 2008].
Following the identification of
TUBA1A mutations in lissencephaly
patients, heterozygous (and usually de
novo) mutations in a number of neuro-
nally expressed tubulin subunit genes
have been associated with a spectrum of
malformations of cortical development.
These include the btubulin genes
ARTICLE
TUBB2B and a subset of TUBB3
mutations, which are usually associated
with a polymicrogyrialike cortical dys-
plasia [Jaglin et al., 2009; Poirier
et al., 2010; Cushion et al., 2013], and
TUBB5, which is associated with poly-
microgyria and congenital microcephaly
[Breuss et al., 2012]. Homozygous
deletions in another atubulin gene,
TUBA8, have also been described in two
consanguineous families with extensive
polymicrogyria [Abdollahi et al., 2009].
Recently, three mutations in the g
tubulin gene TUBG1 (which is highly
expressed in fetal brain) were identified
in individuals with posteriorly predomi-
nant pachygyria (two with severe mi-
crocephaly; the third with a dysmorphic
corpus callosum) but no cerebellar
abnormalities [Poirier et al., 2013].
The range of cortical phenotypes
associated with tubulin gene defects (the
tubulinopathies) is broad but also
shows significant overlap between genes.
For example, a small number of TU-
BA1A mutations have been linked to
polymicrogyrialike brain malforma-
tions [Jansen et al., 2011]. Similarly,
there are reports of pachygyriaassociat-
ed TUBB2B mutations [Guerrini
et al., 2012; Cushion et al., 2013].
Extracortical features such as dysmor-
phic basal ganglia and abnormalities of
the corpus callosum and cerebellum are
commonly observed in tubulinopathy
patients, and are useful diagnostic in-
dicators of tubulin gene involvement.
COBBLESTONE CORTICAL
MALFORMATION
Cobblestone cortical malformation
(CCM, also known as cobblestone
cortex, cobblestone lissencephaly or
type 2 lissencephaly) is clinically,
genetically, histologically and neuro-
radiologically distinct from classical lis-
sencephaly. CCM can appear agyric or
pachygyric, although with higher quali-
ty brain imaging an irregular or pebbled
aspect to the cortex becomes visible.
The cortex in CCM is typically thinner
than in classical lissencephaly (1 cm).
Irregularity in the graywhite boundary
may also be present, similar to that seen in
polymicrogyria. Other MRI features
ARTICLE
include dilated ventricles, white matter
abnormalities, occasional mild brain stem
hypoplasia and cerebellar abnormalities
including cysts [Kato et al., 2010].
Histopathologically, CCM is due to
overmigration of neurons (in contrast
to the undermigration of classical
lissencephaly). Neurons migrate through
breaches in the glia limitans and accu-
mulate in the subarachnoid space giving
the cortex an uneven surface (although at
a scale which is often not resolved by
MRI). CCM is genetically heteroge-
neous but is mostly due to autosomal
recessive defects in adystroglycan
Oglycosylation. Around half of
patients have mutations in POMT1,
CCM is genetically
heterogeneous but is mostly
due to autosomal recessive
defects in adystroglycan
Oglycosylation. Around half
of patients have mutations in
POMT1, POMT2,
POMGNT1, FKTN,
FKRP, and LARGE
POMT2, POMGNT1, FKTN, FKRP,
and LARGE [Mercuri et al., 2009]. Three
major phenotypes are associated with
CCM: Fukuyama congenital muscular
dystrophy, WalkerWarberg syndrome
and muscleeyebrain disease. These dis-
orders demonstrate a combination of eye,
muscle and brain abnormalities.
XLINKED LISSENCEPHALY
WITH AMBIGUOUS
GENITALIA
Xlinked lissencephaly with ambiguous
genitalia (XLAG) is a second, rarer cause
of Xlinked lissencephaly. XLAG was first
described in 1994 in a family with five
affected males [BerryKravis and Israel,
1994]. Features in affected males include
severe developmental delay, small or
ambiguous genitalia, early hypotonia
leading to spasticity, and earlyonset
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
seizures. Other common features include
microcephaly, feeding difficulties, growth
failure, diarrhea, and temperature insta-
bility [Dobyns et al., 1999a; Kato et al.,
2004; Suri, 2005]. Mortality in the first
year is high in affected males, but survival
beyond one year has been reported
[Dobyns et al., 1999a]. XLAG can be
sporadic or familial. Carrier females may
be normal or have learning difficulties,
epilepsy and agenesis of the corpus
callosum [Bonneau et al., 2002; Kitamura
et al., 2002].
Phenotypic analysis of the Arx
knockout mouse was used to identify
ARX as the gene associated with XLAG
ARX encodes the
Aristalessrelated homeobox
protein (Aristaless referring to
the lost head structures in the
fly mutant)
[Kitamura et al., 2002]. ARX encodes
the Aristalessrelated homeobox protein
(Aristaless referring to the lost head
structures in the fly mutant) [Miura
et al., 1997].
The ARX protein is highlycon-
served in vertebrates and expressed in
fetal and adult brain
The ARX protein is
highlyconserved in vertebrates
and expressed in fetal and
adult brain
[Stromme et al., 2002]. ARX acts as a
homeodomain transcription factor,
which has key roles in cerebral develop-
ment [Bienvenu et al., 2002]. Genes
regulated by ARX include those in-
volved in cell migration, axonal guid-
ance, neurogenesis, and transcriptional
regulation. In addition to XLAG, muta-
tions in ARX are responsible for a wide
range of disease phenotypes including
nonsyndromic learning disability, Part-
203
ington syndrome (intellectual disability
with dystonia) and Xlinked infantile
spasms [Suri, 2005].
The neuroradiological features of
ARXrelated lissencephaly are a modest
increase in the thickness of the cortex
(e.g., only 57 mm) with a P >A severity
gradient, agenesis of the corpus callosum,
moderate dilation of the lateral ventricles
and abnormal basal ganglia [Dobyns
et al., 1999a; Bonneau et al., 2002;
Kato et al., 2004] (Fig. 2E). The
neuropathology of ARXrelated lissence-
phaly shows only three cortical layers.
These are composed of a hypercellular
molecular layer (layer I), a pyramidal cell
layer with increased cells numbers (layer
II), and a thick layer of small and
mediumsized neurons (layer III). In
contrast to classical lissencephaly no cell
sparse layer is present [Forman
et al., 2005]. ARXrelated lissencephaly
is thought to be primarily due to aberrant
tangential migration of GABAergic in-
terneurons into the CP (in contrast to the
defects in radial migration of pyramidal
neurons seen in PAFAH1B1related
lissencephaly) [Kato and Dobyns, 2003;
Moon and WynshawBoris, 2013].
XLAG is caused by ARX mutations
which cause loss of function (e.g.,
frameshift or nonsense mutations which
prematurely truncate the protein). In
contrast, expansions of the second
polyalanine tract in ARX (the common
type of ARX mutation) are responsible
for other phenotypes without brain
malformations [Kato et al., 2004]. The
ARX protein has two key domains, a
homeobox domain for binding DNA
and a Cterminal aristaless domain.
Damaging missense mutations in either
of these conserved domains can also
cause XLAG [Kato et al., 2004].
BARAITSERWINTER
SYNDROME
BaraitserWinter syndrome (BWS) is
a rare malformation syndrome first
described in 1988 [Baraitser and
Winter, 1988]. Patients with BWS
have characteristic facial features, which
include hypertelorism, broad nose with
large tip and prominent root, congenital
nonmyopathic ptosis, ridged metopic
204 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
suture, and arched eyebrows. Iris or retinal
coloboma is frequently present, as is
sensorineural deafness. Postnatal micro-
cephaly and moderate short stature are
common. Polyhydramnios, increased nu-
chal translucency, pectus deformities,
congenital heart defects, and renal tract
anomalies are seen in some cases [Baraitser
and Winter, 1988; Verloes, 1993; Ramer
et al., 1995; Fryns and Aftimos, 2000;
Rossi et al., 2003; Riviere et al., 2012].
The majority of patients have a degree of
anteriorpredominant pachygyria. Intel-
lectual disability and epilepsy are common
and their severity correlates with the
extent of the brain malformations.
Recently, gainoffunction mis-
sense mutations in two genes, ACTB
and ACTG1 have been described in
patients with BWS as well as a range of
overlapping actinopathy phenotypes
Recently, gainoffunction
missense mutations in two
genes, ACTB and ACTG1
have been described in patients
with BWS as well as a range
of overlapping actinopathy
phenotypes including
FrynsAftimos syndrome and
cerebrofrontofacial syndrome
type 3
including FrynsAftimos syndrome and
cerebrofrontofacial syndrome type 3
[Riviere et al., 2012; Eker et al., 2014].
ACTB and ACTG1 encode b and g
actin respectively, two of the six mammali-
an isoforms of actin. b and gactin are
widely expressed nonmuscle cytoplasmic
actins which are critical to processes such as
cell growth, cell migration, and mainte-
nance of the cell cytoskeleton structure
[Perrin and Ervasti, 2010].
The typical brain abnormality asso-
ciated with BWS is pachygyria with an
A > P severity gradient [Rossi et al., 2003]
(Fig. 2F,G). The MRI brain scan can be
normal [Johnston et al., 2013]. However,
nearly all patients with ACTG1 mutations
and around 60% of those with ACTB
mutations have some degree of pachy-
gyria (manuscript under review). SBH or
a few periventricular heterotopia may also
be present [Rossi et al., 2003; Shiihara
et al., 2010]. The lateral ventricles may be
mildly enlarged. The cerebellum and
brainstem are usually normal. The corpus
callosum may be absent or appear short
and thick.
LISSENCEPHALY WITH
CEREBELLAR HYPOPLASIA
Around a third of LCH is due to
mutations in TUBA1A [Kumar
et al., 2010]. Homozygous mutations
in the RELN gene have also been found
in a small number of consanguineous
families [Hong et al., 2000]. Patients
homozygous for a balanced reciprocal
translocation [Zaki et al., 2007] and a
pericentric inversion [Chang
et al., 2007] disrupting RELN have
also been shown to develop LCH
phenotypes. RELNrelated LCH has
an A > P gradient and is associated
with severe abnormalities of the cere-
bellum, brainstem and hippocampus
(Fig. 2H). Reelin was initially implicated
in cortical development by the observa-
tion that homozygous mutations in the
mouse homolog Reln cause the reeler
phenotype: ataxia, tremors and impaired
coordination [DArcangelo et al., 1995].
Reeler mice have inverted cortical
layering (later born neurons are deeper
to earlyborn neurons) and cerebellar
hypoplasia [Caviness, 1982].
In humans RELN encodes a large
(400 kDa) extracellular glycoprotein
expressed in the fetal and adult brain, and
particularly in the cerebellum [DeSilva
et al., 1997]. In the fetal brain, reelin is
expressed by CajalRetzius cells in the
marginal zone of the brain (a superficial
layer of the fetal cortex) where it acts as a
stop signal for neurons migrating into
the CP [Frotscher, 1998]. The ligands of
RELN include the very lowdensity
lipoprotein receptor (VLDLR) and the
lowdensity lipoproteinrelated receptor
8 (LRP8/ApoER2). RELN binding to
VLDLR induces phosphorylation of
DAB1, which binds PAFAH1B1 in a
phosphorylationdependant manner
ARTICLE
[Assadi et al., 2003]. RELN is also linked
to regulation of microtubules through
DAB1 [GonzalezBillault et al., 2005].
Homozygous mutations in VLDLR are
also associated with a cerebellar hypo-
plasia phenotype, which is similar to but
milder than RELNrelated LCH. Clini-
cal features include cerebellar ataxia,
microcephaly, short stature, and intel-
lectual disability [Boycott et al., 2009;
Kolb et al., 2010]. In VLDLR related
cerebellar hypoplasia the cerebral cortex
is only mildly thickened and there is no
cellsparse zone [Kolb et al., 2010]. In
contrast, RELNrelated LCH is associ-
ated with a more severe lissencephaly
with an A > P gradient, more pro-
nounced cerebellar hypoplasia and a
malformed hippocampus.
MICROLISSENCEPHALY
Microlissencephaly is defined as lissen-
cephaly in association with a head
circumference at birth of less than 3
standard deviations below the mean.
Homozyogous mutations in the NDE1
(Nuclear distribution factor Ehomolog
1) gene have recently been shown to be a
cause of microlissencephaly. The clinical
Microlissencephaly is defined
as lissencephaly in association
with a head circumference at
birth of less than 3 standard
deviations below the mean.
Homozyogous mutations in
the NDE1 (Nuclear
distribution factor Ehomolog
1) gene have recently been
shown to be a cause of
microlissencephaly.
features of patients with NDE1 muta-
tions include profound cognitive im-
pairment, brain atrophy and extreme
microcephaly (head circumference more
than 10 standard deviations below the
mean) [Alkuraya et al., 2011;
ARTICLE
Bakircioglu et al., 2011]. MRI brain
imaging abnormalities in patients with
NDE1 mutations include simplified
gyration of the cerebral cortex and a
small cerebellum. There is proportionate
reduction in the size of brain structures
including cerebellum and brain stem.
Other reported features include agenesis
of the corpus callosum, a large midline
fluidfilled structure, and dilatation of
the lateral ventricles. Patients also show
poor overall growth. Neuropathology
shows abnormal cortical layering with
layers mixed together and reduced
numbers of neurons. The protein prod-
uct of NDE1 is localized to the centro-
some and mitotic spindle poles.
The NDE1 mutations found in micro-
lissencephaly patients interfere with
Cterminal domains, which interact
with cytoplasmic dynein [Alkuraya
et al., 2011].
DISCUSSION
Genetic factors play a key role in the
etiology of lissencephaly syndromes.
The identification of causative genes
for these disorders has opened up
options for genetic testing in the clinical
setting. Choice of genetic tests will be
guided by features in the history and
examination (e.g., birth head circumfer-
ence, family history and dysmorphic
features) but detailed neuroradiology,
preferably by MRI, remains the key
investigation in the assessment of the
lissencephalic patient. Radiological fea-
tures (e.g., severity gradient, cortical
thickness, other structural abnormalities)
can help distinguishing between the
major causes of lissencephaly [Cardoso
et al., 2000]. Due to similarities in
appearance, differentiation of classical
lissencephaly from other cortical mal-
formations such as polymicrogyria and
CCM can be challenging. It is the
experience of ourselves and others that
a significant proportion of patients
considered to have pachygyria have
other cortical malformations [Dobyns
and Das, 2009]. Obtaining expert
review of brain imaging helps focus
genetic testing and prevents waste of
diagnostic resources. Measurement of
creatine kinase can help distinguish
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
lissencephaly from CCM (because of
the associated myopathy) while if
polymicrogyria is suspected additional
investigations may include TORCH
screen, very long chain fatty acids,
hearing test and brain CT looking for
calcification.
The first line genetic investigation
for patients with lissencephaly is high
resolution arrayCGH, or karyotype
with fluorescence in situ hybridization
(FISH) for the 17p13.3 region (particu-
larly in the setting of diffuse agyria or a
severe classical lissencephaly with a
P >A gradient). Subsequent gene test-
ing should be guided by clinical and
radiological features (Table II). For ILS
with a P >A gradient the priorities for
testing (sequencing and targeted copy
number detection) would be PA-
FAH1B1 then TUBA1A. In contrast,
in the setting of SBH or a male with ILS
and an A > P gradient testing should
start with DCX.
With the advent of nextgeneration
sequencing (NGS) clinical testing is
already beginning to switch from se-
quential single gene tests to parallel
multigene and exome sequencing ap-
proaches. This will have the advantage of
detecting mutations in known genes
causing atypical phenotypes. There is
also evidence that NGS sequencing may
be more sensitive to somatic mosaicism
[Pagnamenta et al., 2012]. However, the
disadvantages include increased rates of
variants of uncertain significance (VUSs)
and the risk of incidental findings.
Parental testing and bioinformatic anal-
ysis remain valuable for interpreting
VUSs, but functional assays are needed
to assess the significance of some novel
mutations. Intragenic deletions and
duplications in PAFAH1B1 and DCX
are responsible for a significant propor-
tion of lissencephaly cases (e.g., around
10% of ILS [Haverfield et al., 2009]).
Current versions of FISH, arrayCGH,
Sanger sequencing and NGS still have
low sensitivity to exonic and multi
exonic deletions. Therefore targeted
copy number detection (e.g., by multi-
plex ligationdependent probe amplifi-
cation) would still be recommended
when the clinical features are consistent
with DCX or PAFAH1B1related
205
disease. Sensitivity of NGS testing to
exonic deletions is likely to improve as
sequencing depth increases (a tool to
measure copy number) and more of the
genome is sequenced (by allowing
detection of intronic and intergenic
breakpoints).
Genetic testing can confirm a
diagnosis at an early stage avoiding
unnecessary investigations. A molecular
diagnosis provides information about
the recurrence risk and may facilitate
preimplantation or prenatal genetic
testing. The genetic status of parents is
important for genetic counseling but is
easily neglected. Asymptomatic (or
mildly affected) female carriers of an
ARX or DCX mutations have a 50%
chance of having an affected son or a
carrier daughter. PAFAH1B1 mutations
are usually de novo but around 20%
of parents carry a balanced chromosomal
rearrangement that can significantly
increase recurrence risk [Dobyns
and Das, 2009]. Similarly, recurrence
risk can be much higher than
expected when somatic or germline
mosaicism is present in a parent
(e.g., with DCXrelated lissencephaly)
[Gleeson et al., 2000].
There are currently no genespecif-
ic treatments for lissencephaly. However,
recent work in animal models has
suggested it may be possible to restart
neuronal migration by reexpression of
missing genes postnatally. In a rat model
of SBH generated by in utero RNA
interference of the Dcx gene, restarting
migration by postnatal reexpression
of Dcx led to reduced amounts of
SBH and improved lamination [Manent
et al., 2009]. Similarly, increasing PA-
FAH1B1 levels by inhibition of its
proteolysis in mice neurons led to
normalization of the distribution of
PAFAH1B1 in cells, improving migra-
tion and partially rescuing lamination
defects in the hippocampus of the
mutant mice [Yamada et al., 2009]. In
humans, even partial reduction in the
extent of the cortical malformation may
bring significant benefits through im-
proved seizure control and reduce clini-
cal severity.
Recent improvements in DNA
sequencing technology mean we are
 206

TABLE II. Summary of the Genetic Causes, Phenotypes and Neuroradiological Findings in Lissencephaly

Gene Alternative Mode of Cortical Severity Corpus Lateral Other

namea nameb inheritance Phenotype thickness gradient Microcephaly callosumc Cerebellumc ventriclesc featuresc
PAFAH1B1 LIS1 AD (de novo) MDS, ILS, P >A Postnatal Mild hypoplasia Mild vermis hypoplasia Enlarged Prominent perivascular spaces
SBH (rare)
DCX XLIS XLR SBH, ILS A > P Postnatal/normal Mild hypoplasia Enlarged Prominent perivascular spaces
HC in SBH anterior
horns
TUBA1A LIS3 AD (de novo) LCH, P >A Congenital Hypoplasia or agenesis Mild to severe Enlarged Dysmorphic basal ganglia,
ILS (rare) hypoplasia abnormalities of
hippocampus and brainstem
ARX XLIS2 XLR XLAG P >A Congenital/ Agenesis Normal or (rarely) Moderately Dysmorphic basal ganglia
Postnatal mild hypoplasia enlarged
ACTB BRWS1 AD (de novo) BWS A > P Postnatal/ Agenesis or dysmorphic Mildly enlarged
normal HC
ACTG1 BRWS2 AD (de novo) BWS A > P Postnatal/ Agenesis or dysmorphic Mildly enlarged
normal HC
RELN LIS2 AR LCH A > P Postnatal Thin Severe hypoplasia Enlarged Dysmorphic brain stem and
hippocampus
VLDLR AR CH None Occasional Normal or dysmorphic Hypoplasia
NDE1 LIS4 AR MLIS ? Congenital Agenesis Hypoplasia Enlarged Fluidfilled midline structure
TUBB2B AD (de novo) PMG, rarely P >A Occasional Hypoplasia or agenesis Normal or mild Enlarged Dysmorphic basal ganglia
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

AGY/PGY hypoplasia
TUBG1 AD (de novo) PGY, SBH P >A Severe/ Dysmorphic Mildly enlarged
normal HC

A, anterior; AD, autosomal dominant; AGY, agyria; AR, autosomal recessive; BWS, BaraitserWinter syndrome; CH, cerebellar hypoplasia; HC, head circumference; HP, hippocampus;
ILS, isolated lissencephaly sequence; LCH, lissencephaly with cerebellar hypoplasia; MDS, MillerDieker syndrome; MLIS, microlissencephaly; P, posterior; PGY, pachygyria; PMG,
polymicrogyria; SBH, subcortical band heterotopia; XLAG, Xlinked lissencephaly with ambiguous genitalia; XLR, Xlinked recessive.
a
Genes causing cobblestone cortical malformation (CCM) are not included in this list.
b
Mutations in LAMB1 cause a CCM associated with SBH which has led to it being called LIS5 (OMIM 615191) [Radmanesh et al., 2013].
c
Additional brain findings noted in these columns are often variable and may not be present in all patients.
ARTICLE
ARTICLE
entering an exciting time for clinical
genetics. There have previously been a
proportion of lissencephaly patients for
whom no genetic explanation could be
found. Working with these families and
using approaches such as exome and
whole genome sequencing it is likely
that new genetic causes for lissencephaly
will be found. Not only will this be of
benefit to patients and their families, but
it will also give us further insights into
the molecular mechanisms of brain
development and potentially suggest
new opportunities for therapeutic
intervention.
ACKNOWLEDGMENTS
The authors would like to thank
Dr. William Dobyns (Seattle Childrens
Research Institute) for allowing them
to use some of his MRI images in
this publication, and Mr. Jonathan
Fry (Heritage College, Melbourne)
for his assistance in preparing the
manuscript.
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