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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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DCX-Related Disorders

Includes: DCX-Related Lissencephaly, DCX-Related Subcortical Band Heterotopia

, MD, , MD, , PhD, , PhD, and , MD.

Author Information
, MD
Center for Human Genetics and Department of Human Genetics
University of Regensburg
Regensburg, Germany
, MD
Department of Human Genetics
University of Hamburg
Hamburg, Germany
, PhD
Institute of Molecular Regenerative Medicine
Paracelsus Medical University Salzburg
Salzburg, Austria
, PhD
Institute of Molecular Regenerative Medicine
Paracelsus Medical University Salzburg
Salzburg, Austria
, MD
Division of Molecular Neurology
University Hospital Erlangen
Erlangen, Germany

Initial Posting: ; Last Update: March 24, 2011.

Summary

Disease characteristics. DCX-related disorders include the neuronal migration disorders classic lissencephaly (formerly also known as lissencephaly type 1), usually in males; and subcortical band heterotopia (SBH, also called double cortex), primarily in females. Males with classic DCX-related lissencephaly typically have severe and global developmental delay, infantile-onset seizures (infantile spasms, West syndrome, focal and generalized seizures), and severe intellectual disability. In individuals with SBH, cognitive abilities range from normal to learning disabilities and/or severe intellectual disability. The majority of individuals with SBH present with focal or generalized seizures. Behavior problems may also be observed. In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates with the degree of the underlying brain malformation.

Diagnosis/testing. The diagnosis of a DCX-related disorder is considered in the presence of characteristic MRI findings (frontally pronounced or generalized classic lissencephaly and/or SBH) in combination with neurologic features (in particular developmental delay, epileptic seizures, cognitive impairment) and/or a family history compatible with X-linked inheritance. The diagnosis is confirmed by molecular genetic testing. The DCX-related lissencephaly presents as classic lissencephaly and is characterized by absent gyri (agyria) or reduced gyration (pachygyria) with thickened cortex. Molecular genetic testing of DCX should include sequence analysis including all coding exons and exon-intron boundaries in combination with a specific method (e.g., MLPA) to identify exonic deletions or duplications.

Management. Treatment of manifestations: Antiepileptic drugs (AEDs) for epileptic seizures; special feeding strategies in newborns with poor suck; physical therapy to promote mobility and prevent contractures; special adaptive chairs or positioners as needed; occupational therapy to improve fine motor skills and oral-motor control; participation in educational training and enrichment programs.

Surveillance: Regular neurologic examination and EEG to monitor seizures; measurement of height, weight, and head circumference during routine health maintenance examinations; monitoring for orthopedic complications such as foot deformity or scoliosis.

Genetic counseling. DCX-related disorders are inherited in an X-linked dominant manner. About 25% of males with DCX-related lissencephaly have a de novo DCX mutation. Approximately 10% of unaffected mothers of children with a DCX mutation were reported to have somatic mosaicism or germline mosaicism. A woman who is heterozygous for a DCX mutation has a 50% chance of transmitting the mutation in each pregnancy. Hemizygous male offspring usually manifest DCX-related classic lissencephaly; while heterozygous female offspring may be asymptomatic mutation carriers or more frequently manifest a wide phenotypic spectrum of SBH. If the disease-causing mutation has been identified in the family, carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible.

Diagnosis

Clinical Diagnosis

DCX-related conditions include the neuronal migration disorders:

  • Classic lissencephaly, usually in males
  • Subcortical band heterotopia (SBH), primarily in females

The diagnosis of DCX-related disorders relies on characteristic findings in cerebral MR imaging in combination with associated clinical features and may include a family history consistent with X-linked inheritance.

Family history. A detailed family history should be obtained. Special attention should be paid to epilepsy, miscarriages, stillbirths, children who died at a young age without obvious birth defects, and cognitive impairment or developmental delay.

Cerebral MR imaging. Ultrasound examination of the head or CT scan can help establish the diagnosis of classic lissencephaly in small children, but cerebral MR imaging is necessary to visualize minimal or subtle pathologic changes. If necessary, imaging should be performed under anesthesia.

As a general rule DCX-related cortical malformations are more severe anteriorly (referred to as an anterior to posterior [A>P] gradient) and include the two forms of classic lissencephaly and SBH [Pilz et al 1998, Dobyns et al 1999].

The more severe manifestation of DCX-related classic lissencephaly is characterized by absent gyri (agyria) or reduced gyration (pachygyria) with thickened cortex of about 10-20 mm (normal: ~4 mm) [Guerrini & Parrini 2010]. Using the classification scheme for neuronal migration disorders explained below, these findings correspond to grades 2-4 (part of the classic lissencephaly spectrum) and grade 5 (the overlap between classic lissencephaly and band heterotopia).

Abnormalities in neuronal migration can be classified further according to the following six-grade system, which evaluates both severity and anterior-posterior gradient [Dobyns & Truwit 1995, Dobyns et al 1999]:

Classic lissencephaly can be classified further according to the following six-grade system, which evaluates both severity and anterior-posterior gradient [Dobyns & Truwit 1995, Dobyns et al 1999]:

1.

Complete agyria

2.

Diffuse agyria with a few undulations at the occipital poles

3.

Mixed agyria and pachygyria

4.

Diffuse pachygyria, or mixed pachygyria and normal or simplified gyri

5.

Diffuse pachygyria or simplified gyri at the frontal regions with subcortical band heterotopia in the occipital poles

6.

Subcortical band heterotopia only

DCX-related SBH is characterized by symmetric bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles, which appears as an isointense second cortical structure beneath the cortex (double cortex). The cerebral cortex in SBH may appear normal and/or thickened with or without simplified gyration [Guerrini & Filippi 2005].

DCX-related SBH is predominantly located in the frontoparietal lobe and is grade 6 (complete band heterotopia). Grade 5, a more severe malformation that overlaps with classic lissencephaly and band heterotopia, is characterized by SBH in the occipital regions and pachygyria in the frontal regions [Dobyns et al 1999]. In some individuals with a DCX mutation, only focal SBH in the frontal lobes has been described.

Additional facultative cerebral features associated with DCX-related lissencephaly include prominent perivascular (Virchow Robin) spaces (in >60%), delayed myelination (>10%) as well as enlarged ventricles in the more severe cases, in particular affecting the anterior horns of the lateral ventricles. In almost 50% of males with DCX-related lissencephaly mild abnormalities or hypoplasia of the corpus callosum are observed. However, in contrast to other monogenic forms of classic lissencephaly, DCX-related lissencephaly appears not to be associated with agenesis of the corpus callosum or true cerebellar hypoplasia [Leger et al 2008].

Clinical features of DCX-related classic lissencephaly. Typically seen in persons with DCX-related classic lissencephaly [Leger et al 2008]:

  • Mandatory significant cognitive and language impairment as well as delay of psychomotor development. More than half of affected individuals will not be able to walk independently
  • Behavioral disturbances including autistic features, increased irritability, agitation and/or abnormal sleep pattern
  • Infantile-onset seizures (infantile spasms, West syndrome, focal and generalized seizures); more than one third of affected individuals are refractory to antiepileptic medication
  • Postnatal microcephaly in about 20%

Aside from these clinical manifestations, currently no further distinctive clinical findings have been observed.

Clinical features of DCX-related SBH. Overall, SBH is observed about ten times more frequently in females than in males [D'Agostino et al 2002]. A wide phenotypic variability is observed even among affected members of the same family [Aigner et al 2003, Martin et al 2004].

  • Individuals with SBH almost always present with focal or generalized seizures (~50% each). More severe SBH has been associated with earlier seizure onset and may be more likely progress to Lennox-Gastaut syndrome. The epilepsy in more than half of affected individuals is refractory to antiepileptic therapy [Guerrini & Filippi 2005, Dobyns 2010].
  • Cognitive performance ranges from normal to learning disabilities and/or severe intellectual disability.
  • Behavioral problems may be observed.

Testing

Chromosome analysis. Structural chromosomal aberrations including X:autosome translocations have on occasion been associated with X-linked lissencephaly [Dobyns et al 1992, Gleeson et al 1998].

However, in females with two X chromosomes heterozygous microscopic or submicroscopic deletion or duplication including one copy of the entire DCX gene appear not to result in characteristic DCX-related SBH or classic lissencephaly. Likewise, gonosomal (i.e., sex chromosome) aneuploidies including the more frequent karyotypes 45,X and 47,XXX or 47,XXY have not been associated with disturbed neuronal migration.

Array-CGH may reveal rare microdeletions in Xq23 including only part of DCX [Hoischen et al 2009].

Molecular Genetic Testing

Gene. DCX-related disorders are defined as neuronal migration disorders (classic lissencephaly or SBH) resulting from DCX mutations. However, for practical purposes it is important to note that similar cerebral phenotypes may also result from mutations in other genes associated with disturbed neuronal migration (see Differential Diagnosis).

Clinical testing

Sequence analysis of the DCX coding exons and flanking exon-intron boundaries identifies intragenic hemizygous and heterozygous DCX sequence variants including frameshifts and missense, nonsense, and splice-site mutations in males and females as well as exon deletions in hemizygous males.

Intragenic DCX sequence variants appear to account for:

Notes: (1) In males with classic lissencephaly without a detectable DCX mutation, the non-coding first three DCX exons should also be analyzed. (2) Lack of amplification by PCR prior to sequence analysis in affected males can suggest a putative hemizygous DCX exonic deletion; confirmation may require additional testing by deletion/duplication analysis. (3) Sequence analysis of genomic DNA cannot detect heterozygous DCX exonic deletions in heterozygous females.

Deletion/duplication analysis by quantitative analysis for gene dosage detects deletion or duplication of one or several DCX exons in both hemizygous males and heterozygous females. Deletion/duplication analysis may be performed by multiplex ligation-dependent probe amplification (MLPA) among other methods. Alternatively, some high-resolution genomic CGH or SNP arrays may also have sufficient coverage for substantial parts of the DCX coding region, but may not allow exclusion of distinct deletions restricted to single exons.

Preliminary data obtained by MLPA indicate that exonic deletions or duplications explain another 4% of SBH in females, but are only rarely observed in classic lissencephaly and so far exclusively in females [Mei et al 2007, Haverfield et al 2009].

Table 1. Summary of Molecular Genetic Testing Used in DCX-Related Disorders

Gene SymbolTest MethodMutations DetectedFrequency of Mutations 1
Classic LissencephalySBH
DCXSequence analysis 2,3Sequence variants 4Total ~10% (~38% of males; rarely females); ~100% of families with X-linked lissencephaly/SBH~85% of females
~29% of males
Deletion / duplication analysis 5Deletion / duplication of one or more exons or the whole gene 1 male reported~4% of females

1. Data from D’Agostino et al [2002], Mei et al [2007], Haverfield et al [2009], Chou et al [2009], Dobyns [2010], Guerrini & Parrini [2010]

2. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons in a male; confirmation may require additional testing by deletion/duplication analysis.

3. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

When no DCX mutation is found in a proband of either sex, somatic mosaicism, a common finding in DCX-related conditions, needs to be considered [Demelas et al 2001, D'Agostino et al 2002, Poolos et al 2002, Aigner et al 2003]. (Somatic mosaicism for DCX mutations is the presence of a DCX mutation in some, but not all, cells of an individual.)

Findings on sequence analysis suggestive of somatic mosaicism include the following:

  • “Heterozygosity” for wild-type and mutant DCX sequences in males with SBH. These males should be evaluated for other causes of heterozygosity, such as a 47,XXY karyotype.
  • Marked unequal peak height of wild-type and mutant DCX sequences in females with mild clinical features (i.e., partial SBH/focal SBH)

Somatic mosaicism should, whenever possible, be further explored or confirmed by analysis of DNA from different tissues (e.g., hair roots, buccal swabs).

Testing Strategy

To confirm/establish the diagnosis of a DCX-related disorder in a proband. The diagnosis of classic lissencephaly or SBH is established by cerebral MR imaging.

Based on current mutation detection rates, the authors suggest the following molecular genetic workup, considering gender and cerebral MR imaging [modified according to Haverfield et al 2009]:

1.

Frontally pronounced classic lissencephaly or SBH: sequence analysis of DCX should be considered first.

2.

Generalized or occipitally pronounced classic lissencephaly:

a.

Deletion/duplication analysis in LIS1 and DCX; if no mutation is identified:

b.

Sequence analysis of LIS1; if no mutation is identified:

c.

Sequence analysis of DCX

3.

Frontally-pronounced classic lissencephaly in males:

a.

Sequence analysis of DCX; if no mutation is identified:

b.

Sequence analysis of LIS1; if no mutation is identified:

c.

Deletion/duplication analysis in LIS1 and DCX

4.

SBH in males or females:

a.

Sequence analysis of DCX; if no mutation is identified:

b.

Deletion/duplication analysis in LIS1 and DCX; if no mutation is identified:

c.

Sequence analysis of LIS1

Chromosome analysis and/or array CGH:

In rare males with SBH who do not have a mutation identified on molecular genetic testing of DCX and LIS1, somatic mosaicism should be considered (see Testing, Interpretation of test results) and may be further explored by sequence analysis of DNA extracted from tissues other than leukocytes.

Carrier testing for at-risk relatives

  • When the proband's DCX mutation is known
  • When the proband's DCX mutation is not known. Considering the genetic heterogeneity of both classic lissencephaly and SBH (see Differential Diagnosis), no specific molecular genetic test can be offered to clarify the potential carrier status of female relatives of index cases without a known mutation. In this situation we recommend:
    • Reevaluation of the proband’s cerebral MRI, if possible by a specialist familiar with neuronal migration disorders.
    • Based on the MRI findings, if applicable, initiate genetic testing of relevant genes for the index case.
    • If genetic testing of an index case with characteristic cortical malformation suggestive of a DCX-related disorder (i.e., symmetric frontally pronounced classic lissencephaly in males or SBH in females) is not possible, sequence analysis and deletion/duplication analysis of DCX may be offered for female at-risk relatives.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Males. DCX-related classic lissencephaly usually manifests with early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. Individuals with severe classic lissencephaly and survival into adulthood have been reported anecdotally; however, life span would be expected to be shortened. Severity of symptoms usually correlates with the degree of the underlying brain malformation.

Epileptic seizures occur in more than 90% of children and commonly start within the first year. The observed seizure pattern may include multiple seizure types, frequently with infantile spasms with or without characteristic hypsarrhythmia [Leger et al 2008, Dobyns 2010].

The rare male with the milder cerebral manifestations of subcortical band heterotopia (SBH) has findings similar to those of females with SBH [D'Agostino et al 2002, Poolos et al 2002, Aigner et al 2003].

Females. The SBH phenotype in heterozygous females, which is less pronounced than the classic lissencephaly phenotype in males, is very variable and correlates roughly with the extent and thickness of the subcortical band.

Penetrance is incomplete [des Portes et al 1998, Gleeson et al 1998]: females heterozygous for a DCX mutation may remain asymptomatic into adulthood and only be recognized after prenatal or postnatal diagnosis of a DCX-related disorder in an offspring or other family member.

Early cognitive and psychomotor development of females with SBH may be normal or delayed. At any time during childhood or during adult life psychomotor development may be complicated by the occurrence of epileptic seizures (which frequently are refractory to antiepileptic medication) and/or learning or behavioral problems [Barkovich et al 1994, Matsumoto et al 2001, Guerrini & Filippi 2005, Mei et al 2007]. Seizures may be either focal or generalized (~50% each) and in more severe cases eventually progress to Lennox-Gastaut syndrome [Dobyns 2010].

Somatic mosaicism. Somatic mosaicism for DCX mutations has been reported in several females and in males with milder manifestations, in particular SBH [Demelas et al 2001, D'Agostino et al 2002, Poolos et al 2002, Aigner et al 2003].

Pathophysiology. In hemizygous males all neurons express the mutated allele and are disturbed in their migratory properties leading to the smoothened and disorganized cortex observed in classic lissencephaly

In females heterozygous for a DCX mutation inactivation of one of the two X chromosomes in neural/somatic cells is thought to result in two neuronal populations: (1) cells expressing the wild-type allele that form the normal cortex; (2) cells expressing the mutant allele that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons [Forman et al 2005, Marcorelles et al 2010, Wynshaw-Boris et al 2010].

Genotype-Phenotype Correlations

In general, there is a direct correlation between the severity of the cortical malformation and the resulting phenotype. More importantly and consistent with X-linked dominant inheritance, DCX mutations in hemizygous males predominantly result in classic lissencephaly, while DCX mutations in heterozygous females predominantly result in SBH. In addition, a slight effect of the type and location of the DCX mutation on the resulting severity of the brain malformation for both SBH and classic lissencephaly has been suggested [Leventer 2005].

  • DCX missense mutations were preferentially observed in males and females who have a positive family history, while nonsense or other mutations that predict a truncated protein predominantly occur in females with DCX-related SBH or classic lissencephaly who are simplex cases (i.e., a single occurrence in a family) [Gleeson et al 1999, Leger et al 2008].
  • So far no males with lissencephaly resulting from a constitutional hemizygous DCX whole-gene deletion have been reported, suggesting that these mutations may not be compatible with peri- and postnatal viability [Haverfield et al 2009, Leger et al 2008].
  • In persons with SBH, truncating mutations were more frequently associated with generalized subcortical bands than missense mutations, which were more common in individuals with SBH with frontal band heterotopia only [Matsumoto et al 2001, Leventer 2005, Leger et al 2008, Haverfield et al 2009].
  • Hemizygous DCX missense mutations within the C-terminal C-DC tandem repeat domain more frequently resulted in less severe forms of lissencephaly (grades 4-5) when compared to missense mutations in the N-DC domain.
  • DCX-related SBH in males appears to result predominantly from either mosaicism for a DCX mutation or specific hemizygous missense mutations which may sustain sufficient residual doublecortin function [Leger et al 2008].

As in other X-linked disorders, X-chromosome inactivation may further significantly contribute to a wide inter- and intrafamilial phenotypic variability in females heterozygous for a DCX mutation; for example, as observed in monozygous female twins heterozygous for the DCX nonsense mutation p.Arg303* [Martin et al 2004]. Heterozygous females with normal cerebral MR imaging and average or only mildly impaired cognitive skills have been associated with favorable skewing of X-chromosome inactivation and/or hypomorphic alleles [Guerrini et al 2003]

Penetrance

No instances of asymptomatic males with a hemizygous intragenic DCX mutation have been reported.

Penetrance in females heterozygous for a DCX mutation is greater than 90%; however, heterozygous females with missense and nonsense mutations may have no obvious brain malformation or seizures [Aigner et al 2003, Guerrini et al 2003].

No data are available on the frequency of mosaicism for a DCX mutation in asymptomatic individuals, but family studies indicate that they may be present in about 10% of asymptomatic mothers of individuals with DCX-related disorders [Gleeson et al 2000].

Nomenclature

Classic lissencephaly may also be called lissencephaly type 1. In the absence of associated intra- or extracranial malformations it is also termed isolated lissencephaly sequence (ILS).

Classic lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia (LCH).

Classic lissencephaly is morphologically and etiologically distinct from lissencephaly type 2, which is also called cobblestone lissencephaly.

To emphasize their X-linked inheritance, DCX-related lissencephaly and SBH have variably been termed and abbreviated:

  • X-linked lissencephaly (XLIS)
  • Lissencephaly, X-linked (LISX)
  • Isolated lissencephaly, X-linked (ILSX)
  • Subcortical laminar heterotopia, X-linked (SCLH)
  • Subcortical band heterotopia, X-linked (SBHX)
  • Double cortex syndrome

Prevalence

A Dutch study reported a prevalence of 1:85,000 for lissencephaly type 1 [de Rijk-van Andel et al 1991]. However, the study presumably included individuals with non-DCX-related lissencephaly.

Differential Diagnosis

LIS1-associated lissencephaly/subcortical band heterotopia. Mutations in DCX together with mutations in LIS1 (also termed PAFAH1B1) are the major genetic cause of nonsyndromic classic lissencephaly in males and of SBH in females [Kato & Dobyns 2003]. LIS1-associated lissencephaly is more prominent in the posterior regions of the brain, showing a posterior to anterior (P>A) gradient. In contrast, DCX-related lissencephaly presents with an A>P gradient.

The following are LIS1-associated disorders (see LIS1-Associated Lissencephaly/Subcortical Band Heterotopia):

Miller-Dieker syndrome (MDS), the syndrome most frequently associated with classic lissencephaly, is caused by a microdeletion of chromosome region 17p13.3 that includes LIS1, the modifying gene 14-3-3-ε, and additional genes [Cardoso et al 2003]. In the past the diagnosis was established by FISH analysis using a LIS1-specific probe (PAC95H6), but currently the diagnosis is established by more sensitive gene-specific molecular genetic deletion/duplication analysis, (e.g. MLPA, which in addition can detect intragenic heterozygous LIS1 exon deletions or duplications).

Miller-Dieker syndrome is characterized by distinctive facial features (i.e., prominent forehead, bitemporal hollowing, short nose with upturned tip and anteverted nostrils, and protuberant upper lip with thin vermillion border) and severe classic lissencephaly that is classified as grade 1-2 according to the classification scheme of Dobyns et al [1999]. Cardiac malformations and omphalocele were also reported as rare associated extracerebral manifestations [Chitayat et al 1997].

  • LIS1-associated isolated lissencephaly sequence (ILS), in which classic lissencephaly is associated with microdeletions of the entire gene LIS1, microdeletions within the gene, or intragenic mutations together account for about 75% of persons with isolated lissencephaly and usually result in lissencephaly grades 2-4.
  • LIS1-associated subcortical band heterotopia (SBH) has in rare instances been associated with germline or somatic intragenic LIS1 mutations and, in contrast to DCX-related SBH, typically presents with occipitally pronounced SBH [Lo Nigro et al 1997, Pilz et al 1999, D'Agostino et al 2002, Sicca et al 2003, Uyanik et al 2007].

TUBA1A-related lissencephaly. Heterozygous de novo mutations in TUBA1A, the gene encoding tubulin alpha1A, account for about 1% of individuals with classic lissencephaly and about 30% of individuals with the rare phenotype of lissencephaly with cerebellar hypoplasia (LCH). In particular, recurrent mutations affecting arginine at codon 402 result in a cerebral phenotype with occipitally pronounced (P>A) classic lissencephaly (similar to that seen with heterozygous LIS1 mutations) in combination with rounded hippocampi and intact but dysmorphic corpus callosum. In addition the cerebellar vermis may be slightly hypoplastic. In contrast, other missense TUBA1A mutations were associated with generalized, mostly asymmetric pachygyria, most pronounced in the posterior frontal, perisylvian, and parietal regions; malformation of the hippocampus; absent or severely hypoplastic corpus callosum; severe cerebellar hypoplasia; and a thin brain stem [Kumar et al 2010].

X-linked lissencephaly with ambiguous genitalia (XLAG) results from hemizygous loss-of-function mutations in ARX [Kitamura et al 2002, Uyanik et al 2003, Kato et al 2004]. Individuals with a 46,XY karyotype who have a hemizygous ARX mutation present with a specific form of lissencephaly with an intermediate thickening of the cortex, showing more pachygyria than agyria (lissencephaly grade 3-4). In contrast to the isolated lissencephaly of DCX-related ILS, the pachygyria in XLAG is posteriorly pronounced (P>A gradient). Furthermore, the corpus callosum is absent in all affected individuals [Kato et al 2004]. The genital abnormalities in individuals with a 46,XY karyotype range from micropenis and cryptorchidism to ambiguous to nearly normal female external genitalia. Other findings of XLAG include refractory seizures usually beginning within hours after birth, abnormal body temperature regulation with a tendency for hypothermia, and chronic diarrhea refractory to treatment.

Microlissencephaly is characterized by extreme microcephaly at birth with thickened cortex and broadened gyration, whereas severe microcephaly at birth is observed in neither DCX- nor LIS1-related disorders. Microlissencephaly should further be differentiated from the heterogeneous group of microcephalies with simplified gyration (MSG) [Dobyns & Barkovich 1999].

Baraitser-Winter syndrome (OMIM 243310) was initially clinically characterized by the combination of iris coloboma with ptosis, hypertelorism, and intellectual disability. The observation of affected sibs of normal parents suggested autosomal recessive inheritance. The underlying genetic alteration is currently unknown; however, two affected individuals were reported to have a pericentric inversion inv(2)(p12q14) [Pallotta 1991]. Affected individuals in addition may present with pachygyria as well as subcortical band heterotopia or periventricular nodular heterotopia, suggesting an associated neuronal migration defect [Shiihara et al 2010].

RELN-related lissencephaly. Hong et al [2000] reported mutations of RELN, the gene encoding reelin, in two consanguineous families with autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Affected individuals had pronounced frontal pachygyria, marked brain stem and cerebellar hypoplasia, and lymphedema of the hands.

Cobblestone lissencephaly (formerly also called lissencephaly type 2) comprises a group of autosomal recessive syndromic disorders associated with congenital muscular dystrophy and eye malformations (anterior chamber malformation, cataract, coloboma, retinal detachment, persistent hyperplastic primary vitreous). Walker-Warburg syndrome (WWS), muscle-eye-brain (MEB) disease, and Fukuyama congenital muscular dystrophy (FCMD) are the most common clinically defined forms. (See Congenital Muscular Dystrophy Overview.) The lissencephalic cortex is thinner than in classic lissencephaly and has areas with pachygyria and areas with polymicrogyria, giving a cobblestone-like appearance that led to the name "cobblestone lissencephaly" [Barkovich 1998]. The shared underlying molecular defect in the autosomal inherited syndromic forms of cobblestone lissencephaly is disturbed O-gylcosylation (O-mannosylation) leading to hypogylcosylated α-dystroglycan, which can be recognized by α-dystroglycan staining of a skeletal muscle biopsy [van Reeuwijk et al 2005]. Currently mutations in POMT1, POMT2, POMGNT1, FKTN, FKRP, and LARGE together account for about 50% of characteristic pre- and postnatally diagnosed cases [Bouchet et al 2007, Mercuri et al 2009].

Polymicrogyria (PMG) is characterized by a small and increased number of gyri of the cortex and now also be considered as cobblestone malformation. (See Polymicrogyria Overview.) Cerebral MR imaging is required to establish the diagnosis because ultrasound examination and CT scan are often unable to distinguish polymicrogyria from pachygyria. Different forms, distinguished by cortical pattern, include perisylvian PMG, bilateral frontal PMG, bilateral frontoparietal PMG, bilateral posterior PMG, parasagittal parietooccipital PMG, and bilateral generalized PMG [Chang et al 2004]. Non-genetic factors leading to PMG such as intrauterine infections (e.g., cytomegalovirus) have been postulated. Familial occurrence supports the notion that genetic factors may cause PMG. In individuals with bilateral frontoparietal polymicrogyria (BFFP), mutations in GPR56 have been identified [Piao et al 2004, Bahi-Buisson et al 2010]. More recently, de novo mutations in TUBB2B were identified in some individuals with frontally pronounced asymmetric PMG [Jaglin et al 2009].

Periventricular nodular heterotopia (PVNH). Although the findings in cerebral MR imaging are quite distinct, SBH is sometimes confused with periventricular nodular heterotopia, the accumulation of nodules of grey matter along the walls of both lateral ventricles. PVHN in females predominantly results from heterozygous loss-of-function mutations in the X-linked gene FLNA. See X-Linked Periventricular Heterotopia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the individual clinical manifestation of a DCX-related disorder, the following evaluations are recommended:

  • Neurologic/neuropediatric evaluation, including EEG and cerebral MRI
  • Developmental assessment including assessment of motor skills, cognition, and speech
  • Ophthalmologic evaluation
  • Feeding and swallowing assessment in individuals lacking head control or the ability to sit without support

Treatment of Manifestations

Epileptic seizures require antiepileptic drugs (AEDs). Individual treatment strategies should be developed depending on the type and frequency of seizures, EEG results, and responsiveness.

In addition, appropriate management can prolong survival and improve quality of life for individuals with classic lissencephaly.

  • Feeding problems in newborns may require special strategies including placement of a percutaneous endoscopic gastrostomy (PEG) tube to deal with weak or uncoordinated sucking.
  • Physical therapy helps to maintain and promote mobility and prevent contractures. Special adaptive chairs or positioners may be required.
  • Occupational therapy may help improve fine motor skills and oral motor control.
  • A full range of educational training and enrichment programs should be available.

Prevention of Secondary Complications

Adequate antiepileptic treatment is important to reduce the number of seizures, which may be associated with irreversible and life-threatening complications.

Surveillance

The following are appropriate:

  • Monitoring of seizure activity by regular neurologic examination and EEG
  • In the event of new neurologic findings or neurologic deterioration, evaluation for seizures
  • Measurement of height, weight, and head circumference as well as assessment of psychomotor development as a part of regular health maintenance evaluations
  • Monitoring of orthopedic complications including foot deformity and scoliosis

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Episodically, callosotomy (surgical disconnection of the cerebral hemispheres by cutting through the corpus callosum) had been reported to improve drop attacks in persons with SBH [Landy et al 1993]. In contrast individuals with focal seizures appear not to benefit from focal resection of epileptogenic tissue [Bernasconi et al 2001].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DCX-related disorders are inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a proband

  • Individuals diagnosed with a DCX-related disorder may either have inherited the DCX mutation from their asymptomatic or only mildly affected mother or have the disorder as the result of a de novo DCX mutation.
  • A woman with two or more affected children or with at least one affected child and one affected sibling is an obligate carrier of the DCX mutation.
  • The father of an affected male will not have the disease, nor could he have passed the DCX mutation to his son. However, theoretically, somatic mosaicism including the germline in an asymptomatic or mildly affected father with SBH may also result in a DCX-related disorder in his daughters.
  • Preliminary data suggest that as many as 10% of unaffected mothers of persons with a DCX mutation may have somatic mosaicism or germline mosaicism [Gleeson et al 2000].
  • Recommendations for evaluation of the mother of a proband with an identified DCX mutation include the following:
    • Molecular genetic testing for the DCX mutation identified in her offspring.
    • If the DCX mutation is not identified in the mother, neurologic and/or clinical examination of the mother is warranted. If cerebral MR imaging reveals SBH in the mother, additional maternal tissues should be examined for the DCX mutation identified in her offspring.
  • If molecular genetic testing of the proband was not informative or if such testing is not possible (e.g., DNA from the proband is not available), cerebral MRI of the mother can be helpful because some heterozygous females with subcortical band heterotopia (SBH) can be asymptomatic. In addition, it is important to note that asymptomatic heterozygous females without obvious structural changes of the brain have been reported [Demelas et al 2001, Aigner et al 2003].

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • If the proband's mother is heterozygous for a DCX mutation, the chance of transmitting the DCX mutation in each pregnancy is 50%.
    • Males who inherit the mutation will usually be affected with DCX-related classic lissencephaly.
    • Females who inherit the mutation will be heterozygous and will be at risk of developing the variable phenotype associated with SBH.
  • If the DCX mutation identified in the proband cannot be detected in the DNA extracted from the mother's leukocytes, the risk to sibs of the proband is approximately 5% because of the possibility of germline mosaicism in the mother [Gleeson et al 2000, Guerrini & Filippi 2005].

Offspring of a proband. Males with classic lissencephaly are usually severely affected and do not reproduce; to date, no instances of offspring have been reported. However, a somatic DCX mutation may also be compatible with a milder phenotype or normal development in a male and result in the risk of transmission of a DCX mutation to some of his daughters.

Females with DCX-related SBH will pass the DCX mutation to 50% of their offspring:

  • Males who inherit the mutation will usually be affected with DCX-related classic lissencephaly.
  • Females who inherit the mutation will be heterozygous and will be at risk of developing the variable phenotype associated with SBH.

Carrier Detection

Molecular genetic testing for at-risk family members is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Risks to family members of individuals with mild disease forms resulting from somatic mosaicism for DCX mutations. Several females and males with less severe forms of the disease resulting from somatic mosaicism for DCX mutations (e.g., SBH in males) have been reported [Demelas et al 2001, D'Agostino et al 2002, Poolos et al 2002, Aigner et al 2003].

  • Recurrence risks to offspring of an individual mosaic for a mutation depend on the proportion of cells in the germ line with the mutation and may be as high as those for the offspring of persons heterozygous or even hemizygous for the mutation.
  • In contrast, somatic mosaicism usually occurs de novo in the individual mosaic for a mutation during early development and no increased risk for his/her own sibs would be expected.

X-chromosome inactivation. As in other X-linked disorders, X-chromosome inactivation may further significantly contribute to a wide inter- and intrafamilial phenotypic variability in females heterozygous for the mutation. However, data obtained from a peripheral blood sample may not represent the proportion of cells with the active mutant DCX allele in other tissues. Furthermore, testing for skewed X-chromosome inactivation in any available pre- or postnatal sample does not allow any prediction of the clinical manifestations of a heterozygous DCX mutation in an individual patient.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 16 to 18 weeks' gestation or chorionic villus sampling (CVS) at about 12 weeks' gestation. The disease-causing allele in the family member must be identified before prenatal testing can be performed. Accurate prediction of the expected clinical manifestations in a female fetus prenatally diagnosed to be heterozygous for a DCX mutation is not possible. Therefore, prenatal testing of a female fetus should be offered only after discussion with the expecting parents regarding the reduced penetrance and wide phenotypic variability in females heterozygous for a DCX mutation.

Fetal ultrasonography/MRI. During fetal development, first gyri appear around the 20th week of gestation and a reduced gyration pattern when compared to postnatal images remains physiologic until late gestation. Therefore, in the absence of a positive family history, DCX-related classic lissencephaly may not be recognized even during late gestation by fetal sonography; SBH in most cases will not be recognized until birth. However, occasional detection of SBH or X-linked lissencephaly by fetal MRI and/or ultrasound examination at later stages of gestation has been reported [Ghai et al 2006].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Lissencephaly Network, Inc (Canada)
    1549 Regent Street
    Regina Saskatchewan S4N 1S1
    Canada
    Phone: 306-569-0146
    Fax: 306-522-1153
  • Lissencephaly Network, Inc. (USA)
    10408 Bitterroot Court
    Fort Wayne IN 46804
    Fax: 260-432-4310
    Email: lissnet@lissencephaly.org; LissencephalyOne@aol.com
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. DCX-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
DCXXq23Neuronal migration protein doublecortinDCX homepage - Mendelian genesDCX

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for DCX-Related Disorders (View All in OMIM)

300067LISSENCEPHALY, X-LINKED, 1; LISX1
300121DOUBLECORTIN; DCX

Molecular Genetic Pathogenesis

DCX shares homology with a group of genes that have a conserved doublecortin (DC) domain comprising two tandemly repeated 80-amino acid regions (pep1 and pep2) [Sapir et al 2000, Taylor et al 2000]. This gene family comprises eleven paralogs in human and in mouse and includes genes such as RP1 (OMIM 603937), associated with a form of retinitis pigmentosa, and DCDC2 (OMIM 605755), associated with dyslexia [Reiner et al 2006].

Normal allelic variants. DCX spans 118 kb of genomic DNA and comprises nine exons; exons 1-3 are untranslated. NM_000555.3, transcript variant 1, is the reference sequence of the longest isoform.

Pathologic allelic variants. Disease-causing alleles include missense mutations (~80%) and nonsense mutations, frameshifts, intragenic and gene deletions, and small deletions or insertions. The majority of missense mutations occur in the two evolutionary conserved domains, the N-DC and C-DC domains [Gleeson et al 1999, Sapir et al 2000, Leger et al 2008].

Normal gene product. Neuronal migration protein doublecortin (DCX) is a microtubule-binding protein containing two in-tandem-organized microtubule-binding domains, in the so-called DCX domain, not previously described in other microtubule-associated proteins (MAPs). Microtubules constitute a central element of the cytoskeleton and as such play a crucial role in many cellular processes such as cell division, cell migration, and maintenance of cellular morphology. In vitro, DCX can promote microtubule polymerization and stabilization of the microtubules.

DCX associates with the 13-protofilaments microtubules to stabilize them and can even override the nucleotide dependence of microtubule polymerization [Moores et al 2006, Fourniol et al 2010]. DCX is particularly enriched at the end neuronal processes where microtubules enter the growth cone [Friocourt et al 2003]. DCX also appears to be enriched in axonal regions capable of generating collaterals [Tint et al 2009]. Therefore, DCX is thought to promote elongation and stabilization of the microtubule network during process outgrowth. Moreover, DCX could also be involved in the somal translocation occurring during neuroblast migration and influence the course of neuroblast proliferation.

DCX is a phosphoprotein that can be a substrate for several protein kinases including JNK, PKA, MARK, and Cdk5. Phosphorylation of DCX alters its interaction with microtubules and thereby possibly its function. The impact of DCX phosphorylation on its reported interaction with other proteins, such as LIS1, neurabin II, or clathrin-associated protein µ1A, remains to be investigated.

Abnormal gene product. Abnormal DCX products may affect proper microtubule formation and perturb the mitotic machinery, although not all abnormal products appear to do so to the same extent [Sapir et al 2000, Couillard-Despres et al 2004]. The effect of DCX mutations on protein function is therefore not yet fully understood.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 230. Available online. Accessed 3-22-11.

Chapter Notes

Revision History

  • 24 March 2011 (me) Comprehensive update posted live
  • 19 October 2007 (me) Review posted to live Web site
  • 31 March 2006 (jw) Original submission
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