DCX-Related Disorders

Tobias Geis; Gökhan Uyanik; Ludwig Aigner; Sebastien Couillard-Despres; Jürgen Winkler; Ute Hehr

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

GeneReviews^® [Internet].

Show details

GeneReviews by Title

DCX-Related Disorders

Tobias Geis, MD, Gökhan Uyanik, MD, Ludwig Aigner, PhD, Sebastien Couillard-Despres, PhD, Jürgen Winkler, MD, and Ute Hehr, MD.

Author Information and Affiliations

Initial Posting: October 19, 2007; Last Update: June 5, 2025.

Estimated reading time: 44 minutes

Summary

Clinical characteristics.

DCX-related disorders include the following neuronal migration disorders: classic thick lissencephaly (more severe anteriorly), usually in males, and subcortical band heterotopia (SBH), primarily in females. Males with DCX-related classic lissencephaly typically have early and profound cognitive and language impairment, tone abnormalities, and seizures. The clinical phenotype in females with DCX-related SBH varies widely, with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment. Seizures, which frequently are refractory to anti-seizure medications (ASMs), may be either focal or generalized, and behavioral problems may also be observed. In DCX-related lissencephaly and DCX-related SBH, severity of the clinical manifestations correlates roughly with the degree of the underlying brain malformation as observed on brain imaging.

Diagnosis/testing.

The diagnosis of a DCX-related disorder is established in a proband with a DCX pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: ASMs for seizures; deep brain stimulation may improve the seizure disorder in individuals with SBH; feeding strategies in newborns with poor suck and swallow; 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 speech therapy, educational training, and enrichment programs.

Surveillance: Regular neurologic examination and monitoring of seizure activity, EEG, and ASM levels; regular measurement of height, weight, and head circumference; evaluation of feeding and nutritional status; assessment of psychomotor, speech, and cognitive development; prompt consultation in the event of new neurologic findings or deterioration, aspiration, or infections; monitoring for orthopedic complications such as foot deformities or scoliosis.

Genetic counseling.

DCX-related disorders are inherited in an X-linked manner. A male proband may have the disorder as the result of a de novo DCX pathogenic variant or a pathogenic variant inherited from an asymptomatic or only mildly affected mother. A female proband may have the disorder as the result of a de novo pathogenic variant, a pathogenic variant inherited from an asymptomatic or only mildly affected mother, or a pathogenic variant inherited from an asymptomatic or mildly affected mosaic father. The risk to sibs depends on the clinical/genetic status of the parents. If the mother of the proband is affected and/or heterozygous for a DCX pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will usually be affected with DCX-related classic lissencephaly. Females who inherit the pathogenic variant will be heterozygous and at high risk of developing the variable phenotype associated with DCX-related SBH. If a proband has a non-mosaic DCX pathogenic variant and represents a simplex case and the pathogenic variant cannot be detected in maternal leukocyte DNA, recurrence risk to sibs of the proband has been estimated to be 5%-10% because of the possibility of parental gonadal mosaicism, mainly in the mother. Once the DCX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

GeneReview Scope

DCX-Related Disorders: Included Phenotypes ¹
Classic lissencephaly Subcortical band heterotopia (SBH)

: For synonyms and outdated names see Nomenclature.
1.: For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care [Caughey et al 2021].

DCX-related disorders are X-linked disorders involving abnormal neuronal migration observed by brain imaging; they include the following:

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

Suggestive Findings

DCX-related disorders should be considered in probands with the following characteristic brain neuroimaging findings, in combination with early-onset epilepsy, developmental delay, and/or behavioral problems. A family history consistent with X-linked inheritance is an additional supportive finding.

Neuroimaging Findings

Classic lissencephaly, usually in males [Mutch et al 2016, Di Donato et al 2017, Koenig et al 2021]

Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see Figure 1B and 1C)
More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient)
May be accompanied by:
- Diffuse thick or thin cortex, or partial SBH
- Prominent perivascular (Virchow-Robin) spaces
- Delayed or abnormal myelination or mild-to-moderate reduced white matter
- Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles
- Normal or diffusely thin corpus callosum
- No obvious cerebellar or brain stem abnormalities
- Enlarged caudate head

Figure 1.

Cerebral MRI of three individuals with DCX-related disorders A. Characteristic bilateral subcortical band heterotopia (*) in a female with heterozygous DCX exon deletion

Subcortical band heterotopia (SBH), usually in females [Bahi-Buisson et al 2013, Di Donato et al 2017, Koenig et al 2021]

Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see Figure 1A) and either diffuse or more severe anteriorly (referred to as SBH with an anterior-to-posterior (A>P) gradient).
May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration

Clinical Findings

Findings may include:

Intellectual disability or developmental delays
Speech and language impairment
Behavioral issues
Epilepsy
Microcephaly

Family History

Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission; affected males related through asymptomatic or less severely affected females). Special attention should be paid to epilepsy, miscarriages, stillbirths, children who died at a young age without a conclusive diagnosis, cognitive impairment, and/or developmental delay. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Male proband. The diagnosis of a DCX-related disorder is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in DCX identified by molecular genetic testing (see Table 1).

Female proband. The diagnosis of a DCX-related disorder is usually established in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in DCX identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous DCX variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with insufficient clinical and imaging data in whom the diagnosis of a DCX-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and neuroimaging findings suggest the diagnosis of a DCX-related disorder in the presence of a positive family history compatible with an X-linked transmission, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

Single-gene testing. Sequence analysis of DCX detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. Typically, exon or whole-gene deletions/duplications in females are not detected; however, a deletion may result in failure of PCR amplification in a male. Sequence analysis is recommended first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis is recommended to detect intragenic deletions or duplications.
A multigene panel that includes DCX and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, bioinformatic deletion/duplication analysis, and/or other non-sequencing-based tests.
For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Due to phenotypic overlap with other inherited neuronal migration disorders, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) should be considered as the preferred option especially in the absence of characteristic neuroimaging data or a positive family history. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of reported DCX pathogenic variants are within the coding region and are likely to be identified on exome sequencing. There are currently insufficient data on the frequency of deep intronic pathogenic DCX variants that are potentially detectable by genome sequencing only.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: If no germline pathogenic variant is found in DCX in the presence of characteristic neuroradiologic findings and a positive family history for X-linked transmission with additional female relatives with SBH, sequence analysis with methods to detect mosaicism should be considered as mosaicism is a common finding in DCX-related disorders [D'Agostino et al 2002, Aigner et al 2003, Quélin et al 2012, Jamuar et al 2014, Tsai et al 2016, González-Morón et al 2017].

The depth of sequencing and sample type may determine the yield of molecular diagnostic testing using the above approaches. Analysis of DNA from different tissues (e.g., buccal swabs, skin fibroblasts, hair roots), preferably using exome or genome sequencing, can be useful in the detection or confirmation of mosaicism (see Molecular Genetics, DCX-specific laboratory technical considerations).

Table 1.

Molecular Genetic Testing Used in DCX-Related Disorders

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
DCX	Sequence analysis ³	94%-96% ⁴
	Gene-targeted deletion/duplication analysis ⁵	4%-6% ⁴
	Karyotype	Rare ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects likely pathogenic or pathogenic variants in about 96% of individuals with characteristic neuroimaging findings. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Matsumoto et al [2001]; Hoischen et al [2009]; Haverfield et al [2009]; Bahi-Buisson et al [2013]; authors' own in-house database with 67 individuals with pathogenic DCX variants from 47 families [U Hehr, unpublished data]; and subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
6.: Gleeson et al [1998] reported a balanced X:2 translocation in a female that disrupted DCX between the first two coding exons.

Clinical Characteristics

Clinical Description

DCX pathogenic variants cause an X-linked neuronal migration disorder neuroradiologically comprising an anterior predominant "agyria-pachygyria-band" spectrum of cortical malformations. This includes lissencephaly, referring to a "smooth brain" with a thick cortex and absent (agyria) and/or abnormally wide gyri (pachygyria) in hemizygous males with or without subcortical band heterotopia (SBH). Heterozygous females or rare males with mosaic or "mild" pathogenic variants present with diffuse thick or thin or anterior-predominant SBH, which may be accompanied by frontoparietal pachygyria [Koenig et al 2021].

To date, more than 300 individuals have been identified with a pathogenic variant in DCX [Gleeson et al 1998, Gleeson et al 2000]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of DCX-Related Disorders

Feature ¹	Males ² (n=76)	Heterozygous Females ³
Feature ¹	Males ² (n=76)	Ascertained Through Familial Testing ⁴ (n=92)	Ascertained Through Diagnostic Workup of Clinical Features ⁵ (n=62)
Asymptomatic	0%	15%	NA
Abnormal brain imaging (i.e., cortical malformations incl classic lissencephaly)	100%	85%	100%
Neonatal normal	33/33
Moderate-to-severe motor impairment	18/33
Non-ambulatory	13/33
Walking w/support	5/33
Walking independently w/o support	15/33
Significant speech & language impairment	15/33
Moderate-to-severe intellectual disability	100%		100%
Moderate-to-severe behavioral disturbances (incl autistic features, sleep disorder, &/or agitation)	10/33		60%
Truncal hypotonia or spasticity	7/11		29%
Postnatal microcephaly (OFC >2 SDs below the mean)	30%		16%
Seizures	83%		85%
Intractable seizures	49%		78%

: NA = not applicable; OFC = orbitofrontal cortex; SD = standard deviation
1.: Leger et al [2008], Bahi-Buisson et al [2013]
2.: Median age at examination was 7.5 years for 33 individuals reported by Leger et al 2008 (range: 1.5-37 years); age range for 43 individuals reported by Bahi-Buisson et al [2013] was 0.8-37 years.
3.: Heterozygous females may be identified through either molecular genetic testing for a familial pathogenic variant or during a diagnostic workup of clinical features; estimated frequencies of clinical features in both groups are provided here and include asymptomatic heterozygous females.
4.: Age range for 78 females with DCX-related SBH was 1-45 years and for 14 asymptomatic heterozygous females was 10-65 years (median age: 37 years) [Bahi-Buisson et al 2013].
5.: A group of 62 females with de novo DCX pathogenic variants had SBH as well as other clinical findings [Bahi-Buisson et al 2013].

Affected Males

Males with a hemizygous DCX pathogenic variant are rare and usually present with early-onset epilepsy and/or developmental delay and behavioral disturbances with characteristic findings on brain imaging [Matsumoto et al 2001, Bahi-Buisson et al 2013].

Neuroimaging findings. Hemizygous pathogenic DCX variants result in diffuse or frontal-predominant agyria or pachygyria with thick cortex, also described as classic thick lissencephaly. Rarely, hemizygous males may present with a mixed cortical phenotype of frontal-predominant pachygyria and posterior (predominant) SBH [Di Donato et al 2018].

Neuropathologically, DCX-related lissencephaly consists of a thick four-layered cortex with an anterior more severe than posterior gradient and a relatively thin superficial cellular layer (layer 2) [Forman et al 2005].

Neurodevelopment. The severity of symptoms usually correlates with the degree of the underlying brain malformation observed on brain imaging.

Motor development is delayed but overall better than in individuals with PAFAH1B1-related lissencephaly / subcortical band heterotopia.

Leger et al [2008] reported on the development of 33 males with DCX-related lissencephaly:

At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment.
All affected individuals had significant cognitive and language impairment.
Almost half of the individuals in the study did not develop any speech.
Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%.

Epilepsy. Epilepsy occurs in about 75% of affected males with two age peaks: either within the first six months of life (in about half) or at a median age of 6 years (range: 2-17 years) [Leger et al 2008]. Multiple seizure types have been observed, including infantile epileptic spasms syndrome (IESS) with or without characteristic hypsarrhythmia [Leger et al 2008, Dobyns 2010]. Seizures are intractable in more than half of affected individuals [Bahi-Buisson et al 2013]. Early seizure onset correlates with refractory epilepsy.

Other manifestations

Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis.
More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration.
Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [Leger et al 2008].

Life span. Males with classic thick lissencephaly may survive into adulthood. However, life span overall is shortened due to complications either directly related to the seizure disorder or resulting from disturbed cerebral regulation of vital functions (e.g., breathing abnormalities) or aspiration during respiratory infections or in association with food intake. In their cohort of 33 males with lissencephaly due to pathogenic DCX variants, Leger et al [2008] reported ten adults up to age 37 years at the time of examination.

Rarely, males may have milder cerebral manifestations of SBH similar to those in females [D'Agostino et al 2002, Aigner et al 2003].

Heterozygous Females

Most heterozygous females typically develop some clinical manifestations. The most common cortical malformation is SBH and variable anterior-predominant pachygyria. The phenotype of heterozygous females is usually milder than the classic lissencephaly phenotype in males. It is very variable between and to a lesser extend even within families and roughly correlates with the extent and thickness of the subcortical band as observed on brain imaging.

Bahi-Buisson et al [2013] proposed two distinct subgroups among females with DCX pathogenic variants: (1) a more severe clinical phenotype with thicker SBH usually observed in simplex cases and (2) a milder phenotype mainly observed in heterozygous asymptomatic females with normal brain MRI or only thin frontal subcortical bands.

Severe phenotypes associated with thicker SBH typically include the following:

Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years).
Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands
Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands
Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen.
Truncal hypotonia or spasticity (about 29%)
Microcephaly (16%)
Hyperkinetic movements (less frequent than other features)

Neuroimaging findings. Heterozygous DCX pathogenic variants in females result in a diffuse thick (>8 mm) or thin (4-7 mm) frontal-predominant SBH [Bahi-Buisson et al 2013, Di Donato et al 2018], which may include frontal-predominant pachygyria.

Additional findings observed on brain imaging of female DCX heterozygotes may include [Bahi-Buisson et al 2013]:

Thin or dysmorphic corpus callosum;
Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia;
Dilatation of the fourth ventricle.

Clinical variability. As in other X-linked disorders, X-chromosome inactivation has been postulated to contribute to inter- and intrafamilial phenotypic variability in females heterozygous for a DCX pathogenic variant. However, no convincing evidence for any diagnostic or predictive value of the assessment of X inactivation in individuals heterozygous for a DCX pathogenic variant has been identified to date. As an example, such variability has been observed in monozygotic female twins who were heterozygous for a recurrent pathogenic DCX nonsense variant [Martin et al 2004]. Both twins had thick generalized SBH, clearly delineated from the cortex by a small band of white matter. However, one twin had a thicker heterotopic band than the other, including frontal pachygyria associated with more profound cognitive and psychomotor impairment and a more abnormal EEG than observed in her twin sister.

Notable clinical variability has also been reported between female relatives of the same family; in one family with a heterozygous DCX pathogenic variant (p.Lys201Glu in the C-DC domain), the 78-year-old grandmother and her 50-year-old daughter had no seizures and normal IQ and neuropsychological profile in the presence of frontocentral SBH-pachygyria, while her 35-year-old granddaughter had bilateral predominant frontocentral SBH with mixed pachygyria on the overlying cortex and seizures beginning at the age nine years [Procopio et al 2024].

Milder phenotypes with virtually absent or less severe abnormalities on brain imaging (e.g., as thin frontal band heterotopia) may include the following:

Average or mildly impaired cognitive skills [Guerrini et al 2003]
No additional symptoms
Recognition only after prenatal or postnatal diagnosis of a DCX-related disorder in an offspring or other family member

In the cohort reported by Bahi-Buisson et al [2013], of 25 heterozygous mothers of probands, 14 (56%) were asymptomatic and had normal brain imaging, particularly in the presence of the missense pathogenic variant at position p.Arg196 (see Genotype-Phenotype Correlations).

Genotype-Phenotype Correlations

About one third of all DCX pathogenic variants are recurrent, resulting in similar pathogenic variant-specific cortical phenotypes in and between families [Bahi-Buisson et al 2013].

A slight effect of the type and location of the DCX pathogenic variant on the resulting severity of the brain malformation for both SBH and classic lissencephaly has been suggested [Leventer 2005, Bahi-Buisson et al 2013, Di Donato et al 2018].

DCX pathogenic nonsense variants in males are very rare and have mainly been observed as postzygotic mosaic events. Early truncating pathogenic variants result in severe lissencephaly as near-complete agyria, difficult to distinguish from severe lissencephaly due to de novo pathogenic variants in PAFAH1B1 or TUBA1A.
To date, males with lissencephaly resulting from a constitutional hemizygous DCX whole-gene deletion or hemizygous nonsense variant appear to be extremely rare, suggesting that DCX loss-of-function variants are likely lethal [Leger et al 2008, Haverfield et al 2009].
Hemizygous de novo pathogenic variants result in a more severe clinical presentation when compared to maternally inherited DCX pathogenic variants.
Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [Gleeson et al 1999, Leger et al 2008, Bahi-Buisson et al 2013].
Hemizygous DCX missense variants within the N-terminal DC tandem repeat domain tend to result in more severe forms of lissencephaly than missense variants in the C-DC domain.
Truncating variants are more frequently associated with generalized subcortical bands; missense variants are more commonly associated with frontal band heterotopia only [Matsumoto et al 2001, Leventer 2005, Leger et al 2008, Haverfield et al 2009].
DCX-related SBH in males appears to result predominantly from either mosaicism for a DCX pathogenic variant or specific missense variants with residual function [Leger et al 2008].
Hot spot variants, observed multiple times, account for more than one third of identified sequence variants; these include p.Arg39Ter, p.Arg303Ter, p.Arg78Cys, p.Arg78His, p.Arg78Leu, p.Arg192Trp, p.Arg186Cys, p.Arg186His, and p.Arg186Leu [Bahi-Buisson et al 2013].
Asymptomatic heterozygous females more frequently have missense pathogenic variants at the hot spot position p.Arg196.

Penetrance

Males. No instances of asymptomatic males with germline hemizygous DCX pathogenic variants have been reported, thus suggesting full penetrance of germline DCX pathogenic variants in males. However, males with postzygotic mosaic pathogenic variants may have milder clinical manifestations or, in rare cases, be asymptomatic. Mild clinical manifestations in the presence of hemizygous DCX pathogenic variants in the mosaic state have been anecdotally reported. As an example, a nine-year-old boy with thin subcortical band heterotopia and low hemizygosity (with a variant allele fraction of 13.6% for a p.Arg186His DCX pathogenic variant) developed focal seizures with motor onset primarily triggered by exercise at age 13 years [Miller & Kremer 2020]. Another example is a five-year-old boy with a de novo mosaic DCX deletion (c.30_31delAA) who was diagnosed with developmental delay and autism spectrum disorder and developed a seizure disorder at age 13 years. Brain imaging showed pachygyria of the frontal and temporal lobes [Zare et al 2019].

Females. Heterozygous females with germline missense or nonsense DCX variants may have no obvious brain malformation or seizures [Aigner et al 2003, Guerrini et al 2003].

Penetrance was reported to be less than 50% in mothers with a heterozygous or mosaic pathogenic variant in DCX whose children presented with DCX-related disorders [Bahi-Buisson et al 2013].

Nomenclature

Classic thick lissencephaly has been called lissencephaly type 1 in older publications. In the absence of associated intra- or extracranial malformations it is also termed isolated lissencephaly sequence.

Classic thick lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia.

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

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

X-linked lissencephaly (XLIS) or lissencephaly, X-linked (LISX);
Isolated lissencephaly, X-linked (ILSX);
Subcortical laminar heterotopia, X-linked (X-SCLH);
Subcortical band heterotopia, X-linked (SBHX).

DCX-related lissencephaly and DCX-related SBH have also been referred to as double cortex syndrome.

Prevalence

The incidence of all forms of lissencephaly has been estimated at 1-4:100,000 births [Barkovich et al 2014], with the majority resulting from heterozygous pathogenic variants of PAFAH1B1 (LIS1).

DCX-related disorders account for:

Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH;
About 10% of all persons with classic thick lissencephaly (38% of all males, but only rarely females);
About 53%-85% of all SBH, up to 88% of simplex SBH, and about 29% of SBH in males [Pilz et al 1998, Gleeson et al 1999, Matsumoto et al 2001, Guerrini & Filippi 2005, Bahi-Buisson et al 2013].

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in DCX.

Differential Diagnosis

Genes of interest in the differential diagnosis of DCX-related disorders are listed in Table 3.

Table 3.

Genes of Interest in the Differential Diagnosis of DCX-Related Disorders

Gene	Lissencephaly Gradient ¹				Other Features / Comment
Gene	Diffuse lissencephaly	Posterior-predominant gradient (p>a) ²	Anterior-predominant gradient (a>p)	Temporal-predominant gradient (t>p>a)	Other Features / Comment
ACTB			+		Baraitser-Winter cerebrofrontofacial syndrome: multiple congenital anomaly syndrome characterized by typical craniofacial features & ID Wasting of shoulder girdle muscles, sensory impairment due to iris or retinal coloboma, &/or sensorineural deafness
ACTG1			+
ARX				+	Agenesis of corpus callosum; brain stem & cerebellum appear normal Perinatal encephalopathy w/intractable seizures Ambiguous or underdeveloped genitalia Chronic diarrhea High lethality in 1st 3 mos of life ³
CDK5	+				Agyria, agenesis of corpus callosum, severe cerebellar & pontine hypoplasia, dilated subarachnoid spaces Dysmorphic facial features, lymphedema, arthrogryposis multiplex Early lethality ⁴
CRADD			+		Megalencephaly ⁵ Thick or thin lissencephaly Normal cerebellum
DYNC1H1		+	+		Usually posterior-predominant pachygyria Other brain malformations typically seen include polymicrogyria, nodular heterotopia, thin corpus callosum, & cerebellar & basal ganglia abnormalities Axonal neuropathy seen in some persons
KIF2A		+			Typically assoc w/thick cortex w/pachygyria or agyria Other malformations can include SBH, thin corpus callosum, & dysmorphic basal ganglia
KIF5C		+	+		Severe IUGR Arthrogryposis Microcephaly ⁶
NDE1	+				Microcephaly Simplified cortical gyral pattern Thin or absent corpus callosum Microhydranencephaly can be seen
PAFAH1B1		+			Most frequent cause of classic or thick lissencephaly Miller-Dieker syndrome, a contiguous gene deletion syndrome involving at least PAFAH1B1 & YWHAE, often w/deletion of additional genes, is assoc w/severe lissencephaly & other features. ⁷
RELN			+		Assoc w/severe cerebellar hypoplasia ⁸ Other features include lissencephaly &/or simplified cortical gyral pattern & ventriculomegaly
RNU4ATAC	+				Assoc w/several phenotypes incl microcephalic osteodysplastic primordial dwarfism type I/III, Roifman syndrome, & Lowry-Wood syndrome Brain imaging abnormalities include pachygyria, heterotopia, agenesis of corpus callosum, & cerebellar vermis hypoplasia
TUBA1A	+	+			Tubulinopathies comprise wide & overlapping range of brain malformations & other clinical features Lissencephaly ranges from thickened cortex & agyria to thickened cortex & pachygyria Characteristic brain malformations include dysmorphic basal ganglia; dysplasia of superior cerebellum, esp vermis (w/"diagonal" folia, i.e., folia crossing midline at oblique angle); & brain stem hypoplasia, usually asymmetric w/midline ventral indentation & asymmetric inferior & middle cerebellar peduncles
TUBA8		+
TUBB		+
TUBB2B	+	+
TUBB3	+	+
TUBG1		+
VLDLR			+		Hypoplasia of inferior portion of cerebellar vermis & hemispheres, simplified gyration of cerebral hemispheres, & small brain stem, esp pons Non-progressive congenital ataxia, predominantly truncal, results in delayed ambulation, ID, dysarthria, strabismus, & seizures

: ID = intellectual disability; IUGR = intrauterine growth restriction; SBH = subcortical band heterotopia
1.: Di Donato et al [2017]
2.: Including perisylvian lissencephaly
3.: Uyanik et al [2003], Coman et al [2017]
4.: Magen et al [2015]
5.: Di Donato et al [2016a], Di Donato et al [2016b]
6.: Poirier et al [2013]
7.: Other features include characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities. The facial changes consist of tall and prominent forehead, bitemporal narrowing, short nose with anteverted nares, protuberant vermilion of the upper lip with downturned corners of the mouth, and small jaw (see PAFAH1B1-Related Lissencephaly / Subcortical Band Heterotopia, Genetically Related Disorders.)
8.: Valence et al [2016]

Other disorders to consider based on observed cortical abnormalities include cobblestone lissencephaly (i.e., Walker-Warburg syndrome, muscle-eye-brain disease [see OMIM PS236670], and Fukuyama congenital muscular dystrophy), disorders with polymicrogyria, and disorders with periventricular nodular heterotopia (see FLNA Deficiency).

Management

No clinical practice guidelines for DCX-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Note: The clinical spectrum observed in individuals with DCX pathogenic variants is extremely broad, from rare, very severely affected males with limited life expectancy to healthy females with a heterozygous or mosaic pathogenic DCX variant who may never develop any clinical features of a DCX-related disorder. Therefore, the information provided in the management section aims to address any clinical issues that may arise, and hence the more severely affected individuals within this clinical spectrum.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a DCX-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

DCX-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Neurologic	Neurologic eval	At initial diagnosis & at least annually thereafter, esp for mgmt of epilepsy that should include an epilepsy specialist Prolonged video EEGs may be required to fully characterize epilepsy burden or spells of unclear clinical etiology To incl early brain imaging to characterize & assess brain malformation
Constitutional	Measurements of OFC, length/height, & weight
Development	Primary care / developmental assessment	To include motor, adaptive, cognitive, & speech-language evals Evals for early intervention / special education
Ophthalmologic/ Vision	Ophthalmology eval	Assess visual acuity, abnormal ocular movement, refractive errors, & strabismus. Assess cerebral visual impairment.
Gastrointestinal/ Feeding	Primary care / gastroenterology / nutrition / feeding team evals	To include eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (>30 min/meal), &/or aspiration risk.
Respiratory	Pulmonologist eval	Following aspiration pneumonia or for excessive or chronic cough or mgmt of oral secretions
Musculoskeletal/ADL	Rehab / SLP / PT & OT evals	To incl assessment of: Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Need for augmentative communication devices & strategies
Genetic counseling	By genetics professionals ¹	To obtain a pedigree & inform affected persons & their families re nature, X-linked MOI, & implications of DCX-related disorders to facilitate medical & personal decision making, esp for further pregnancies of close female relatives who may have the familial PV
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: ADL = activities of daily living; MOI = mode of inheritance; OFC = orbitofrontal cortex; OT = occupational therapy; PT = physical therapy; PV = pathogenic variant; SLP = speech-language pathology
1.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for DCX-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Regular lifelong neuropediatric and, later, neurologic evaluations at a center with expertise in the diagnosis and treatment of epilepsy is strongly recommended for any individual with a DCX-related disorder in order to assess the potential manifestation of a seizure disorder and its progression and to closely monitor the effects of anti-seizure medications (ASMs).

Table 5.

DCX-Related Disorders: Treatment of Manifestations

Manifestation/Concern	Treatment	Considerations/Other
Developmental delay / Intellectual disability	See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy	Standardized treatment w/ASM by experienced neurologist based on specific seizure type & frequency	Education of parents/caregivers ¹ An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs ²
Epilepsy	Non-pharmacologic treatment	Surgical resection of heterotopic brain tissue has been tried in a few persons w/SBH; overall, it was not effective in ↓ seizure activity & thus was not recommended. ³ Deep brain stimulation has been suggested to improve the seizure disorder in persons w/SBH based on results in small cohorts. ⁴ In a review of non-pharmacologic treatment options for persons w/SBH & drug-resistant epilepsy, an improvement in seizure severity was observed in 16/26. Interventions used included surgical measures such as corpus callosotomy, temporal lobectomy, & (less frequently) vagus nerve stimulation or thalamic deep brain stimulation. ⁵
Poor weight gain / Failure to thrive / Aspiration	Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues.	Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs of dysphagia (choking, chronic cough, history of aspiration pneumonia) or prolonged feeding times (30 min/meal)
Constipation	Pharmacologic therapies	Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
Cerebral visual impairment	Address in psychoeducational activities & therapies.	Include in early intervention programs &/or school district consistent w/federal law re access to educational services by visually impaired persons.
Neurobehavioral/ Psychiatric	Therapies to address anxiety, ASD	Pharmacologic therapies w/sedative side effects should be carefully weighed against overall benefits & effect on abilities to participate in education, therapies, sleep, & general quality of life.
Musculoskeletal (incl spasticity)	Vitamin D supplementation if indicated PT & OT incl stretching to support avoidance of contractures & falls Referral for orthopedic surveillance & correction	PT helps maintain & promote mobility & prevent contractures. Special adaptive chairs/positioners or other measures may support sitting & mobility. OT may help improve fine motor skills & oral motor control. Orthopedic corrections may be indicated for scoliosis &/or large joint displacements. Consider need for positioning & mobility devices.
Family/Community	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.	Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. Referral to community or online family support resources such as Parent to Parent patient advocacy groups for further support and resources.

: ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SBH = subcortical band heterotopia
1.: Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.
2.: Limited data on ASM use for DCX-related epilepsy is available. In a report of two cases, infantile spasms in one infant were controlled with phosphocreatine, prednisone, topiramate, and nitrazepam. At age three years, seizures recurred and were drug resistant [Gao et al 2023]. One child in a lissencephaly cohort had neonatal-onset seizures and multiple seizure types including tonic seizures, generalized tonic-clonic seizures, and unknown motor-onset seizures. ASMs used were adrenocorticotropic hormone, vigabatrin, levetiracetam, phenobarbital, and topiramate; however, no information is provided on the efficacy of the ASMs used [Kolbjer et al 2021]. Five individuals with DCX pathogenic variants in another lissencephaly cohort were reported with a seizure frequency of 0-3 seizures daily; infantile spasms occurred only in one individual. In the total cohort of 47 individuals with lissencephaly, valproic acid and lamotrigine were found to be the most effective ASMs [U Hehr, unpublished data].
3.: Bernasconi et al [2001]
4.: Franco et al [2016]
5.: Kurzbuch et al [2023]

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- Vision consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox^®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

DCX-Related Disorders: Recommended Surveillance

System/Concern	Evaluation	Frequency
Neurologic	Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.	At each visit
Feeding	Measurement of growth parameters Eval of nutritional status & safety of oral intake
Gastrointestinal	Monitor for constipation.
Development	Monitor developmental progress & educational needs.
Neurobehavioral/Psychiatric	Assessment for anxiety, ADHD, ASD, aggression, & self-injury
Musculoskeletal	Physical medicine & OT/PT assessment of mobility, scoliosis, & self-help skills
Ophthalmologic involvement	Eval of refraction & visual acuity	Per treating ophthalmologist(s)
Ophthalmologic involvement	Low vision services	Per treating clinicians
Respiratory	Monitor for evidence of aspiration, respiratory insufficiency.	At each visit
Family/Community	Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit
Transition to Adult Care	Develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).	Starting by age ~10 yrs

: ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

To date avoidance of any medications or other agents has not been suggested for individuals with DCX pathogenic variants. However, for all individuals with seizure disorders, trigger situations should be explored and avoided as much as possible.

Evaluation of Relatives at Risk

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

Pregnancy Management

For pregnant women with DCX-related subcortical band heterotopia (SBH) and known history of seizures or current epileptic seizures, close medical surveillance by a neurologist familiar with the treatment of seizures (preferably at an epilepsy center) is recommended.

Counseling should include discussion of the teratogenic risks associated with the currently used anti-seizure medication (ASM). For some ASMS or a combination, a substantially increased risk for fetal malformations may prompt reconsideration of the dosage or drug combination. Pregnant women should, however, be encouraged to continue medical seizure control under close surveillance and be informed about the risks associated with discontinuation of treatment.

Counseling should also cover the preferred mode of delivery based on the current neurologic findings as well as any recommended postnatal measures for the newborn related to fetal medication exposure and its postnatal drop.

Whenever possible, women should discuss the current ASM or any recommended replacement of medication with higher teratogenic potential prior to any planned pregnancy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DCX-related disorders – encompassing classic lissencephaly (primarily in males) and subcortical band heterotopia (primarily in females) – are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

The father of an affected male will not have the disorder nor will he be hemizygous for the DCX pathogenic variant; therefore, he does not require further evaluation/testing.
A male proband may have the disorder as the result of a de novo DCX pathogenic variant or a DCX pathogenic variant inherited from an asymptomatic or only mildly affected mother.
The mothers of more than half of males with DCX pathogenic variants are clinically asymptomatic. Asymptomatic heterozygous females without obvious structural changes of the brain have been reported [Demelas et al 2001, Aigner et al 2003].
In a family with more than one affected individual, the mother of an affected male is presumed to have a heterozygous or (depending on family history) mosaic DCX pathogenic variant.
- If a mother has more than one affected child and no other affected relatives and if the DCX pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal (or somatic and gonadal) mosaicism. Preliminary data suggest that as many as 10% of unaffected mothers of probands with a DCX pathogenic variant may have gonadal mosaicism with or without somatic mosaicism [Gleeson et al 2000].
  Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Molecular genetic testing of the mother for the DCX pathogenic variant identified in the proband is recommended to evaluate her genetic status and inform recurrence risk assessment. If the DCX pathogenic variant is not identified in maternal leukocyte DNA, additional maternal tissues (e.g., hair roots, buccal swabs) may be examined for the DCX pathogenic variant identified in her offspring. In addition, the possibility of maternal somatic mosaicism may be assessed by neurologic and/or clinical examination of the mother and brain MRI to search for subcortical band heterotopia (SBH).

Parents of a female proband

A female proband may have the disorder as the result of a de novo DCX pathogenic variant or as the result of a DCX pathogenic variant inherited from:
- An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [Bahi-Buisson et al 2013]. Asymptomatic heterozygous females without obvious structural changes of the brain have been reported [Demelas et al 2001, Aigner et al 2003].
- An asymptomatic or mildly affected father with a de novo postzygotic pathogenic variant and gonadal (or somatic and gonadal) mosaicism [Moreira et al 2015].
The parents of approximately 90% of female probands are clinically unaffected. The DCX pathogenic variants in these probands may be either de novo or inherited from an asymptomatic heterozygous or mosaic parent.
Molecular genetic testing of the mother for the DCX pathogenic variant identified in the proband is recommended. If the DCX pathogenic variant is not identified in maternal leukocyte DNA, additional maternal tissues (e.g., hair roots, buccal swabs) may be examined for the DCX pathogenic variant identified in her offspring. In addition, the possibility of maternal somatic mosaicism may be assessed by neurologic and/or clinical examination of the mother and brain MRI to search for SBH. Preliminary data suggest that as many as 10% of unaffected mothers of probands with a DCX pathogenic variant may have gonadal mosaicism with or without somatic mosaicism [Gleeson et al 2000].
If the DCX pathogenic variant identified in a female proband is not identified in her mother, genetic testing (with sufficient sensitivity to uncover rare paternal somatic mosaicism) of paternal leukocyte DNA and additional paternal tissues for the DCX pathogenic variant may be considered.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to sibs depends on the clinical/genetic status of the parents.

If the mother of the proband is affected and/or heterozygous for a DCX pathogenic variant, the chance of transmitting the DCX pathogenic variant in each pregnancy is 50%.
- Males who inherit the pathogenic variant will usually be affected with DCX-related classic thick lissencephaly.
- Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, Heterozygous Females).
If a male proband is hemizygous for a DCX pathogenic variant and represents a simplex case (i.e., a single occurrence in a family) and if the DCX pathogenic cannot be detected in maternal leukocyte DNA, recurrence risk to sibs of the proband has been estimated between 5% and 10% because of the possibility of maternal gonadal mosaicism [Gleeson et al 2000, Guerrini & Filippi 2005].
If a female proband is heterozygous for a DCX pathogenic variant and represents a simplex case and if the DCX pathogenic cannot be detected in maternal leukocyte DNA, recurrence risk to sibs of the proband has been estimated between 5% and 10% because of the possibility of parental gonadal mosaicism, mainly in the mother [Gleeson et al 2000, Guerrini & Filippi 2005] and rarely in the father. Paternal transmission of a DCX pathogenic variant from an asymptomatic or mildly affected father with somatic and gonadal mosaicism to his daughters has been reported [Moreira et al 2015].
If somatic mosaicism for a de novo DCX pathogenic variant due to a postzygotic event in the proband is suggested based on molecular genetic test results in a proband presenting a simplex case, sibs would not be considered at increased risk. Somatic mosaicism for DCX pathogenic variants has been documented in many male and female probands with milder manifestations [D'Agostino et al 2002, Aigner et al 2003, Bahi-Buisson et al 2013, Jamuar et al 2014].

Offspring of a proband

Males with DCX-related lissencephaly are usually severely affected and are not known to reproduce; to date, no instances of offspring have been reported.
Females with a DCX-related disorder have a 50% chance of transmitting the pathogenic variant to each child:
- Males who inherit the pathogenic variant will usually be affected with DCX-related lissencephaly.
- Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, Heterozygous Females).
For male or female probands with mild phenotypes resulting from mosaicism for DCX pathogenic variants (e.g., SBH in males), recurrence risk to offspring depends on the proportion of germ (gonadal) cells with the pathogenic variant and may be as high as the formal risk assumed for the offspring of individuals heterozygous or, theoretically, hemizygous for the pathogenic variant [Moreira et al 2015].

Other family members

If the mother of the proband has a heterozygous DCX pathogenic variant, the proband's maternal grandmother and maternal aunts are at risk of being heterozygous for the familial DCX pathogenic variant.
The offspring of all heterozygous females have a 50% chance of inheriting a DCX pathogenic variant and having a DCX-related disorder.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection in Asymptomatic Females

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the DCX pathogenic variant has been identified in the proband.

Note: Females who are heterozygous for this X-linked disorder may be clinically unaffected or may present with a wide range of clinical manifestations (see Clinical Description, Heterozygous Females).

Related Genetic Counseling Issues

X-chromosome inactivation. As in other X-linked disorders, X-chromosome inactivation has been postulated to contribute to inter- and intrafamilial phenotypic variability in females heterozygous for a DCX pathogenic variant. Note: Testing for skewed X-chromosome inactivation in any available pre- or postnatal sample is of no value in predicting the clinical manifestations of a heterozygous DCX pathogenic variant in any individual.

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 or are at risk of having a DCX pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the DCX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Accurate prediction of the expected clinical manifestations in a female fetus prenatally diagnosed as heterozygous for a DCX pathogenic variant is not possible. Therefore, prenatal testing of a female fetus should be offered only after thorough discussion with the expecting parents regarding the reduced penetrance and wide phenotypic variability in females heterozygous for a DCX pathogenic variant.

Fetal ultrasonography/MRI. During fetal development first gyri appear around the 20 weeks' gestation, and a reduced gyration pattern (compared to postnatal images) remains physiologic until late gestation. Therefore, in the absence of a positive family history, DCX-related lissencephaly may only be recognized after 27 weeks' gestation or not at all (even during late gestation by fetal sonography); earlier suggestive findings may include ventriculomegaly or delayed opercularization [Koenig et al 2021]. 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, Quélin et al 2012].

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professional would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

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.

American Association on Intellectual and Developmental Disabilities (AAIDD)
Phone: 202-387-1968
aaidd.org
American Epilepsy Society (AES)
aesnet.org
Epilepsy Foundation
Phone: 800-332-1000
Email: ContactUs@efa.org
epilepsy.com

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	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
DCX	Xq23	Neuronal migration protein doublecortin	DCX database	DCX	DCX

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

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

Molecular Pathogenesis

DCX encodes neuronal migration protein doublecortin (DCX) is a microtubule-binding protein containing two in-tandem microtubule-binding domains, 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 promotes microtubule polymerization and stabilization of the microtubules. 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 has also been shown to be expressed during embryonal development in motor neurons and skeletal muscle at the neuromuscular junctions, with loss of DCX resulting in disturbed neuromuscular junction formation [Bourgeois et al 2015].

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 pathogenic variants on protein function is therefore not yet fully understood. Functional studies indicate loss of function for several abnormal DCX products, which may, however, be mediated by different cellular or off-pathway mechanisms [Yap et al 2016]. Most missense variants occur in the two evolutionary conserved domains, the N-terminal N-DC and C-terminal C-DC domains [Gleeson et al 1999, Sapir et al 2000, Leger et al 2008].

In hemizygous males, all neurons express the pathogenic variant and are disturbed in their migratory properties, leading to the smoothened and disorganized thickened cortex observed in classic lissencephaly.

In females heterozygous for a DCX pathogenic variant, inactivation of one of the two X chromosomes in neural/somatic cells is thought to result in two neuronal populations [Forman et al 2005, Marcorelles et al 2010, Wynshaw-Boris et al 2010]:

Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex;
Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons.

Mechanism of disease causation. Loss of function

DCX-specific laboratory technical considerations.

Nomenclature. DCX variants in most older publications are described using the reference cDNA NM_178153. The current reference sequence in the Ensemble genome as well as Clinvar is NM_0011955553. This has additional 15 bp at the end of exon 5 and additional 3 bp at the end of exon 6, shifting variant positions while conserving the reading frame.
Mosaicism. Somatic mosaicism for DCX pathogenic variants has been documented in females and males with milder manifestations [D'Agostino et al 2002, Aigner et al 2003, Bahi-Buisson et al 2013, Jamuar et al 2014]. Therefore, pathogenic variants in DCX may not be detectable in peripheral blood and testing alternative tissue samples (such as hair follicles or swabs of mouth mucosa) may be warranted if testing blood is negative. Note: Sensitivity to detect low-level mosaicism of a mosaic pathogenic variant is greatest using next-generation sequencing in tissues other than blood [Jamuar et al 2014]. The proportion of somatic mosaicism in both affected individuals and parents for DCX deletions or duplications may be underestimated given limitations of testing methodologies.

Table 7.

DCX Pathogenic Variants Referenced in This GeneReview

Reference Sequences	DNA Nucleotide Change (Alias ¹)	Predicted Protein Change (Alias ¹)	Comment [Reference]
NM_0011955553.2 NP_001182482.1	c.601A>G	p.Lys201Glu	Clinical variability reported for this variant [Procopio et al 2024]
	c.557G>A	p.Arg186His	Variant reported as mosaic in male w/mild clinical manifestations [Miller & Kremer 2020]
	c.30_31delAA	p.Asp12Ter	Variant reported as mosaic in male w/mild clinical manifestation [Zare et al 2019]
	c.115C>T	p.Arg39Ter	Hot spot variants observed multiple times that together account for more than one third of identified pathogenic DCX sequence variants [Bahi-Buisson et al 2013]
	c.232C>T	p.Arg78Cys
	c.233G>A	p.Arg78His
	c.233G>T	p.Arg78Leu
	c.556C>T	p.Arg186Cys
	c.557G>T	p.Arg186Leu
	c.557G>A	p.Arg186His
	c.574C>T	p.Arg192Trp
	c.907C>T	p.Arg303Ter

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

www.humangenetik-regensburg.de

Revision History

5 June 2025 (gm) Comprehensive update posted live
7 February 2019 (ha) Comprehensive update posted live
24 March 2011 (me) Comprehensive update posted live
19 October 2007 (me) Review posted live
31 March 2006 (jw) Original submission

References

Literature Cited

Aigner L, Uyanik G, Couillard-Despres S, Ploetz S, Wolff G, Morris-Rosendahl D, Martin P, Eckel U, Spranger S, Otte J, Woerle H, Holthausen H, Apheshiotis N, Fluegel D, Winkler J. Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders. Neurology. 2003;60:329–32. [PubMed: 12552055]
Bahi-Buisson N, Souville I, Fourniol FJ, Toussaint A, Moores CA, Houdusse A, Lemaitre JY, Poirier K, Khalaf-Nazzal R, Hully M, Leger PL, Elie C, Boddaert N, Beldjord C, Chelly J, Francis F, et al. New insights into genotype-phenotype correlations for the double cortin-related lissencephaly spectrum. Brain. 2013;136:223–44. [PMC free article: PMC3562079] [PubMed: 23365099]
Barkovich AJ, Moore KR, Grant E, Jones BV, Vézina G, Koch BL, Raybaud C, Blaser S, Hedlund GL, Illner A. Diagnostic Imaging: Pediatric Neuroradiology. 2 ed. Elsevier; 2014.
Bernasconi A, Martinez V, Rosa-Neto P, D'Agostino D, Bernasconi N, Berkovic S, MacKay M, Harvey AS, Palmini A, da Costa JC, Paglioli E, Kim HI, Connolly M, Olivier A, Dubeau F, Andermann E, Guerrini R, Whisler W, de Toledo-Morrell L, Morrell F, Andermann F. Surgical resection for intractable epilepsy in "double cortex" syndrome yields inadequate results. Epilepsia. 2001;42:1124–9. [PubMed: 11580758]
Bourgeois F, Messéant J, Kordeli E, Petit JM, Delers P, Bahi-Buisson N, Bernard V, Sigoillot SM, Gitiaux C, Stouffer M, Francis F, Legay C. A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human. Neuromuscul Disord. 2015;25:461–73. [PubMed: 25817838]
Caughey AB, Krist AH, Wolff TA, Barry MJ, Henderson JT, Owens DK, Davidson KW, Simon MA, Mangione CM. USPSTF approach to addressing sex and gender when making recommendations for clinical preventive services. JAMA. 2021;326:1953-61. [PubMed: 34694343]
Coman D, Fullston T, Shoubridge C, Leventer R, Wong F, Nazaretian S, Simpson I, Gecz J, McGillivray G. X-linked lissencephaly with absent corpus callosum and abnormal genitalia: an evolving multisystem syndrome with severe congenital intestinal diarrhea disease. Child Neurol Open. 2017;4:2329048X17738625. [PMC free article: PMC5680935] [PubMed: 29152528]
Couillard-Despres S, Uyanik G, Ploetz S, Karl C, Koch H, Winkler J, Aigner L. Mitotic impairment by doublecortin is diminished by doublecortin mutations found in patients. Neurogenetics. 2004;5:83–93. [PubMed: 15045646]
D'Agostino MD, Bernasconi A, Das S, Bastos A, Valerio RM, Palmini A, Costa da Costa J, Scheffer IE, Berkovic S, Guerrini R, Dravet C, Ono J, Gigli G, Federico A, Booth F, Bernardi B, Volpi L, Tassinari CA, Guggenheim MA, Ledbetter DH, Gleeson JG, Lopes-Cendes I, Vossler DG, Malaspina E, Franzoni E, Sartori RJ, Mitchell MH, Mercho S, Dubeau F, Andermann F, Dobyns WB, Andermann E. Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females. Brain. 2002;125:2507–22. [PubMed: 12390976]
Demelas L, Serra G, Conti M, Achene A, Mastropaolo C, Matsumoto N, Dudlicek LL, Mills PL, Dobyns WB, Ledbetter DH, Das S. Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology. 2001;57:327–30. [PubMed: 11468322]
Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, Barkovich AJ, Guerrini R, Dobyns WB. Lissencephaly: expanded imaging and clinical classification. Am J Med Genet A. 2017;173:1473–88. [PMC free article: PMC5526446] [PubMed: 28440899]
Di Donato N, Jean YY, Maga AM, Krewson BD, Shupp AB, Avrutsky MI, Roy A, Collins S, Olds C, Willert RA, Czaja AM, Johnson R, Stover JA, Gottlieb S, Bartholdi D, Rauch A, Goldstein A, Boyd-Kyle V, Aldinger KA, Mirzaa GM, Nissen A, Brigatti KW, Puffenberger EG, Millen KJ, Strauss KA, Dobyns WB, Troy CM, Jinks RN. Mutations in CRADD result in reduced caspase-2-mediated neuronal apoptosis and cause megalencephaly with a rare lissencephaly variant. Am J Hum Genet. 2016a;99:1117–29. [PMC free article: PMC5097945] [PubMed: 27773430]
Di Donato N, Kuechler A, Vergano S, Heinritz W, Bodurtha J, Merchant SR, Breningstall G, Ladda R, Sell S, Altmüller J, Bögershausen N, Timms AE, Hackmann K, Schrock E, Collins S, Olds C, Rump A, Dobyns WB. Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. Am J Med Genet A. 2016b;170:2644–51. [PubMed: 27240540]
Di Donato N, Timms AE, Aldinger KA, Mirzaa GM, Bennett JT, Collins S, Olds C, Mei D, Chiari S, Carvill G, Myers CT, Rivière JB, Zaki MS; University of Washington Center for Mendelian Genomics; Gleeson JG, Rump A, Conti V, Parrini E, Ross ME, Ledbetter DH, Guerrini R, Dobyns WB. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med. 2018;20:1354-64. [PMC free article: PMC6195491] [PubMed: 29671837]
Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia. 2010;51 Suppl 1:5–9. [PubMed: 20331703]
Forman MS, Squier W, Dobyns WB, Golden JA. Genotypically defined lissencephalies show distinct pathologies. J Neuropathol Exp Neurol. 2005;64:847–57. [PubMed: 16215456]
Franco A, Pimentel J, Campos AR, Morgado C, Pinelo S, Ferreira AG, Bentes C. Stimulation of the bilateral anterior nuclei of the thalamus in the treatment of refractory epilepsy: two cases of subcortical band heterotopia. Epileptic Disord. 2016;18:426–30. [PubMed: 27965181]
Friocourt G, Koulakoff A, Chafey P, Boucher D, Fauchereau F, Chelly J, Francis F. Doublecortin functions at the extremities of growing neuronal processes. Cereb Cortex. 2003;13:620–6. [PubMed: 12764037]
Gao C, Liu N, Ma J, Zhao J, Zhao B, Song F, Dong R, Li Z, Lv Y, Liu Y, Gai Z. DCX variants in two unrelated Chinese families with subcortical band heterotopia: Two case reports and review of literature. Heliyon. 2023;9:e22323. [PMC free article: PMC10692899] [PubMed: 38045215]
Ghai S, Fong KW, Toi A, Chitayat D, Pantazi S, Blaser S. Prenatal US and MR imaging findings of lissencephaly: review of fetal cerebral sulcal development. Radiographics. 2006;26:389–405. [PubMed: 16549605]
Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell. 1998;92:63–72. [PubMed: 9489700]
Gleeson JG, Minnerath S, Kuzniecky RI, Dobyns WB, Young ID, Ross ME, Walsh CA. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am J Hum Genet. 2000;67:574–81. [PMC free article: PMC1287517] [PubMed: 10915612]
Gleeson JG, Minnerath SR, Fox JW, Allen KM, Luo RF, Hong SE, Berg MJ, Kuzniecky R, Reitnauer PJ, Borgatti R, Mira AP, Guerrini R, Holmes GL, Rooney CM, Berkovic S, Scheffer I, Cooper EC, Ricci S, Cusmai R, Crawford TO, Leroy R, Andermann E, Wheless JW, Dobyns WB, Ross ME, Walsh CA. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann Neurol. 1999;45:146–53. [PubMed: 9989615]
González-Morón D, Vishnopolska S, Consalvo D, Medina N, Marti M, Córdoba M, Vazquez-Dusefante C, Claverie S, Rodríguez-Quiroga SA, Vega P, Silva W, Kochen S, Kauffman MA. Germline and somatic mutations in cortical malformations: molecular defects in Argentinean patients with neuronal migration disorders. PLoS One. 2017;12:e0185103. [PMC free article: PMC5617183] [PubMed: 28953922]
Guerrini R, Filippi T. Neuronal migration disorders, genetics, and epileptogenesis. J Child Neurol. 2005;20:287–99. [PubMed: 15921228]
Guerrini R, Moro F, Andermann E, Hughes E, D'Agostino D, Carrozzo R, Bernasconi A, Flinter F, Parmeggiani L, Volzone A, Parrini E, Mei D, Jarosz JM, Morris RG, Pratt P, Tortorella G, Dubeau F, Andermann F, Dobyns WB, Das S. Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations. Ann Neurol. 2003;54:30–7. [PubMed: 12838518]
Haverfield EV, Whited AJ, Petras KS, Dobyns WB, Das S. Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia. Eur J Hum Genet. 2009;17:911–8. [PMC free article: PMC2986498] [PubMed: 19050731]
Hoischen A, Landwehr C, Kabisch S, Ding XQ, Trost D, Stropahl G, Wigger M, Radlwimmer B, Weber RG, Haffner D. Array-CGH in unclear syndromic nephropathies identifies a microdeletion in Xq22.3-q23. Pediatr Nephrol. 2009;24:1673–81. [PubMed: 19444485]
Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, Servattalab S, Mehta BK, Topcu M, Amrom D, Andermann E, Dan B, Parrini E, Guerrini R, Scheffer IE, Berkovic SF, Leventer RJ, Shen Y, Wu BL, Barkovich AJ, Sahin M, Chang BS, Bamshad M, Nickerson DA, Shendure J, Poduri A, Yu TW, Walsh CA. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371:733–43. [PMC free article: PMC4274952] [PubMed: 25140959]
Koenig M, Dobyns WB, Di Donato N. Lissencephaly: Update on diagnostics and clinical management. Eur J Paediatr Neurol. 2021;35:147-52. [PubMed: 34731701]
Kolbjer S, Martin DA, Pettersson M, Dahlin M, Anderlid BM. Lissencephaly in an epilepsy cohort: Molecular, radiological and clinical aspects. Eur J Paediatr Neurol. 2021;30:71-81. [PubMed: 33453472]
Kurzbuch AR, Cooper B, Israni A, Ellenbogen JR. Non-pharmacological treatment options of drug-resistant epilepsy in subcortical band heterotopia: systematic review and illustrative case. Childs Nerv Syst. 2023;39:451-62. [PubMed: 35933521]
Leger PL, Souville I, Boddaert N, Elie C, Pinard JM, Plouin P, Moutard ML, des Portes V, Van Esch H, Joriot S, Renard JL, Chelly J, Francis F, Beldjord C, Bahi-Buisson N. The location of DCX mutations predicts malformation severity in X-linked lissencephaly. Neurogenetics. 2008;9:277–85. [PubMed: 18685874]
Leventer RJ. Genotype-phenotype correlation in lissencephaly and subcortical band heterotopia: the key questions answered. J Child Neurol. 2005;20:307–12. [PubMed: 15921231]
Magen D, Ofir A, Berger L, Goldsher D, Eran A, Katib N, Nijem Y, Vlodavsky E, Tzur S, Behar DM, Fellig Y, Mandel H. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5. Hum Genet. 2015;134:305–14. [PubMed: 25560765]
Marcorelles P, Laquerrière A, Adde-Michel C, Marret S, Saugier-Veber P, Beldjord C, Friocourt G. Evidence for tangential migration disturbances in human lissencephaly resulting from a defect in LIS1, DCX and ARX genes. Acta Neuropathol. 2010;120:503–15. [PubMed: 20461390]
Martin P, Uyanik G, Wiemer-Kruel A, Schneider S, Gross C, Hehr U, Winkler J. Different clinical and morphological phenotypes in monozygotic twins with identical DCX mutation. J Neurol. 2004;251:108–10. [PubMed: 14999500]
Matsumoto N, Leventer RJ, Kuc JA, Mewborn SK, Dudlicek LL, Ramocki MB, Pilz DT, Mills PL, Das S, Ross ME, Ledbetter DH, Dobyns WB. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet. 2001;9:5–12. [PubMed: 11175293]
Miller D, Kremer K. Frequent Awakenings and Fits With Aerobics. Pediatr Neurol. 2020;106:72-3. [PubMed: 32127224]
Moreira I, Bastos-Ferreira R, Silva J, Ribeiro C, Alonso I, Chaves J. Paternal transmission of subcortical band heterotopia through DCX somatic mosaicism. Seizure. 2015;25:62–4. [PubMed: 25645638]
Mutch CA, Poduri A, Sahin M, Barry B, Walsh CA, Barkovich AJ. Disorders of microtubule function in neurons: imaging correlates. AJNR Am J Neuroradiol. 2016;37:528–35. [PMC free article: PMC4792764] [PubMed: 26564436]
Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM, Walsh CA, Barkovich AJ, Dobyns WB, Ledbetter DH, Ross ME. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet. 1998;7:2029–37. [PubMed: 9817918]
Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C, Parrini E, Valence S, Pierre BS, Oger M, Lacombe D, Geneviève D, Fontana E, Darra F, Cances C, Barth M, Bonneau D, Bernadina BD, N'guyen S, Gitiaux C, Parent P, des Portes V, Pedespan JM, Legrez V, Castelnau-Ptakine L, Nitschke P, Hieu T, Masson C, Zelenika D, Andrieux A, Francis F, Guerrini R, Cowan NJ, Bahi-Buisson N, Chelly J. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature Genet. 2013;45:639–47. [PMC free article: PMC3826256] [PubMed: 23603762]
Procopio R, Fortunato F, Gagliardi M, Talarico M, Sammarra I, Sarubbi MC, Malanga D, Annesi G, Gambardella A. Phenotypic Variability in Novel Doublecortin Gene Variants Associated with Subcortical Band Heterotopia. Int J Mol Sci. 2024;25:5505. [PMC free article: PMC11122195] [PubMed: 38791543]
Quélin C, Saillour Y, Souville I, Poirier K, N'guyen-Morel MA, Vercueil L, Millisher-Bellaiche AE, Boddaert N, Dubois F, Chelly J, Beldjord C, Bahi-Buisson N. Mosaic DCX deletion causes subcortical band heterotopia in males. Neurogenetics. 2012;13:367–73. [PubMed: 22833188]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA, Wolf SG, Francis F, Chelly J, Elbaum M, Pietrokovski S, Reiner O. Doublecortin mutations cluster in evolutionarily conserved functional domains. Hum Mol Genet. 2000;9:703–12. [PubMed: 10749977]
Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
Tint I, Jean D, Baas PW, Black MM. Doublecortin associates with microtubules preferentially in regions of the axon displaying actin-rich protrusive structures. J Neurosci. 2009;29:10995–1010. [PMC free article: PMC2757270] [PubMed: 19726658]
Tsai MH, Kuo PW, Myers CT, Li SW, Lin WC, Fu TY, Chang HY, Mefford HC, Chang YC, Tsai JW. A novel DCX missense mutation in a family with X-linked lissencephaly and subcortical band heterotopia syndrome inherited from alow-level somatic mosaic mother: genetic and functional studies. Eur J Paediatr Neurol. 2016;20:788–94. [PubMed: 27292316]
Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schäfer H, Hehr U, Winkler J. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003;61:232–5. [PubMed: 12874405]
Valence S, Garel C, Barth M, Toutain A, Paris C, Amsallem D, Barthez MA, Mayer M, Rodriguez D, Burglen L. RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes. Clin Genet. 2016;90:545–9. [PubMed: 27000652]
Wynshaw-Boris A, Pramparo T, Youn YH, Hirotsune S. Lissencephaly: mechanistic insights from animal models and potential therapeutic strategies. Semin Cell Dev Biol. 2010;21:823–30. [PMC free article: PMC2967611] [PubMed: 20688183]
Yap CC, Digilio L, McMahon L, Roszkowska M, Bott CJ, Kruczek K, Winckler B. Different doublecortin (DCX) patient alleles show distinct phenotypes in cultured neurons: evidence for divergent loss-of-function and "off-pathway" cellular mechanisms. J Biol Chem. 2016;291:26613–26. [PMC free article: PMC5207172] [PubMed: 27799303]
Zare I, Paul D, Moody S. Doublecortin Mutation in an Adolescent Male. Child Neurol Open. 2019;6:2329048X19836589. [PMC free article: PMC6591519] [PubMed: 31259193]

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (https://www.genereviews.org) and copyright (© 1993-2026 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: addmast@wu.edu

Bookshelf ID: NBK1185PMID: 20301364

GeneReviews by Title

PubReader
Print View
Cite this Page
Geis T, Uyanik G, Aigner L, et al. DCX-Related Disorders. 2007 Oct 19 [Updated 2025 Jun 5]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
PDF version of this page (797K)
Disable Glossary Links

Bulk Download

Bulk download GeneReviews data from FTP

GeneReviews Links

Tests in GTR by Gene

Related information

MedGen
Related information in MedGen
OMIM
Related OMIM records
PMC
PubMed Central citations
PubMed
Links to PubMed
Gene
Locus Links

Recent Activity

Clear Turn Off Turn On

DCX-Related Disorders - GeneReviews®
DCX-Related Disorders - GeneReviews®

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Bookshelf

GeneReviews® [Internet].

DCX-Related Disorders

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

GeneReview Scope

Diagnosis

Suggestive Findings

Neuroimaging Findings

Figure 1.

Clinical Findings

Family History

Establishing the Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

Table 2.

Affected Males

Heterozygous Females

Genotype-Phenotype Correlations

Penetrance

Nomenclature

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Table 3.

Management

Evaluations Following Initial Diagnosis

Table 4.

Treatment of Manifestations

Table 5.

Developmental Delay / Intellectual Disability Management Issues

Motor Dysfunction

Neurobehavioral/Psychiatric Concerns

Surveillance

Table 6.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Pregnancy Management

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Heterozygote Detection in Asymptomatic Females

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 7.

Chapter Notes

Author Notes

Revision History

References

Literature Cited

Views

In this GeneReview

Bulk Download

GeneReviews Links

Tests in GTR by Gene

Related information

Similar articles in PubMed

Recent Activity

GeneReviews^® [Internet].