Dcx-Related Disorders
Summary
Clinical characteristics.
DCX-related disorders include the neuronal migration disorders:
- Classic thick lissencephaly (more severe anteriorly), usually in males
- Subcortical band heterotopia (SBH), primarily in females
Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with 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 antiepileptic medication, may be either focal or generalized and behavioral problems may also be observed.
In DCX-related lissencephaly and SBH the severity of the clinical manifestation correlates roughly with the degree of the underlying brain malformation as observed in cerebral imaging.
Diagnosis/testing.
The diagnosis of a DCX-related disorder is established in a proband by identification of a DCX pathogenic variant on molecular genetic testing.
Management.
Treatment of manifestations: Antiepileptic drugs for epileptic seizures; deep brain stimulation may improve the seizure disorder in individuals with SBH; 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 speech therapy, educational training, and enrichment programs.
Surveillance: Regular neurologic examination and monitoring of seizure activity, EEG, and antiepileptic drug levels; regular measurement of height, weight, and head circumference; evaluation of feeding and nutrition status; assessment of psychomotor, speech, and cognitive development; prompt consultation in the event of novel neurologic findings or deterioration, aspiration, or infections; monitoring for orthopedic complications such as foot deformity or scoliosis.
Genetic counseling.
DCX-related disorders are inherited in an X-linked manner. Up to10% of unaffected mothers of children with a DCX pathogenic variant are presumed to have germline mosaicism with or without somatic mosaicism. A woman who is heterozygous for a DCX pathogenic variant has a 50% chance of transmitting the pathogenic variant in each pregnancy. Hemizygous male offspring usually manifest DCX-related classic lissencephaly, while heterozygous female offspring may be asymptomatic or more frequently manifest a wide phenotypic spectrum of SBH. If the pathogenic variant has been identified in the family, testing to determine the genetic status of at-risk family members and prenatal testing for pregnancies at increased risk are possible.
Diagnosis
DCX-related disorders are X-linked conditions involving abnormal neuronal migration; they include:
- Classic lissencephaly, usually in males
- Subcortical band heterotopia (SBH), primarily in females
Suggestive Findings
A DCX-related disorder should be suspected in individuals with characteristic findings in brain magnetic resonance imaging (MRI) in combination with epileptic seizures and/or developmental delay or behavioral problems. A family history consistent with X-linked inheritance is an additional supportive finding.
Brain MRI Findings
Classic thick lissencephaly, usually in males:
- Is 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) (Figure 1B-C) [Mutch et al 2016, DiDonato et al 2017];
- Is more severe anteriorly, referred to as an anterior-to-posterior (A>P) gradient;
- May be accompanied by:
- Prominent perivascular (Virchow Robin) spaces
- Delayed myelination
- 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
- Mildly to moderately diminished cerebral white matter.
Figure 1.
Cerebral MRI of three patients with DCX-related disorders A. Characteristic bilateral subcortical band heterotopia (*) in a female patient with heterozygous DCX exon deletion
Subcortical band heterotopia (SBH), usually in females, is characterized by one or more of the following:
- 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 (~70%) than thin (1-7 mm) (Figure 1A) [Bahi-Buisson et al 2013, Di Donato et al 2017].
- Normal-appearing and/or thickened cerebral cortex with or without simplified gyration
- Predominant location in the frontoparietal lobe region
Clinical Features
Findings may include:
- Intellectual disability
- Language impairment
- Psychomotor delay
- Behavioral disturbances
- Seizures
- Microcephaly
Family History
Evidence for X-linked inheritance obtained from a detailed family history. Special attention should be paid to epilepsy, miscarriages, stillbirths, children, who died at a young age without conclusive diagnosis, and cognitive impairment or developmental delay.
Establishing the Diagnosis
The diagnosis of a DCX-related disorder is established in a proband by identification of one of the following on molecular genetic testing (see Table 1):
- A hemizygous DCX pathogenic variant in a male proband
- A heterozygous DCX pathogenic variant in a female proband
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, 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. Because the phenotype of DCX-related disorders is broad, 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 datain whom the diagnosis of aDCX-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a DCX-related disorder molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of DCX detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically exon or whole-gene deletions/duplications in females are not detected; however, a deletion may result in PCR failure in a male. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 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 at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants 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, 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) is the best option especially in the absence of sufficient clinical and imaging data. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: Somatic 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]. Sequence analysis methods, such as Sanger or next-generation sequencing, vary in their ability to detect mosaicism and should be evaluated for their detection rate. Due to assay sensitivity, the proportion of somatic mosaicism in both affected individuals and parents may be underestimated. Analysis of DNA from different tissues (e.g., hair roots, buccal swabs) can be useful in the detection or confirmation of somatic mosaicism.
Table 1.
Molecular Genetic Testing Used in DCX-Related Disorders
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| DCX | Sequence analysis 3, 4 | 96% 5 |
| Gene-targeted deletion/duplication analysis 6 | 4% 5 | |
| Karyotype | Single case 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Matsumoto et al [2001]; Hoischen et al [2009]; Bahi-Buisson et al [2013]; Authors, unpublished data
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Gleeson et al [1998] reported a balanced X:2 translocation in a female which disrupted DCX between the first two coding exons.
Clinical Characteristics
Clinical Description
An individual with a DCX-related disorder usually presents with epileptic seizures and/or developmental delay and behavioral disturbances [Matsumoto et al 2001, Bahi-Buisson et al 2013] and with the characteristic findings on brain MRI noted during clinical evaluation.
Males
DCX-related classic lissencephaly usually manifests with early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures.
Development. Severity of symptoms usually correlates with the degree of the underlying brain malformation observed in cerebral imaging.
Motor development is compromised, but overall better than in patients with PAFAH1B1-associated classic lissencephaly.
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.
- Almost half of the individuals in the study did not develop any speech.
Behavioral disturbances may include agitation and irritability or autistic features.
Epileptic seizures occur in more than 80% of affected males 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]. Seizure control remains insufficient in more than half of the affected individuals [Bahi-Buisson et al 2013].
Other findings
- Disturbed muscle tone and immobility may result in contractures and scoliosis.
- More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration.
- Head circumference may decline postnatally and result in postnatal microcephaly.
Life span. Individuals with severe classic lissencephaly may survive into adulthood. However, life span overall is shortened due to complications either directly related to the seizure disorder (including sudden unexplained death in epilepsy or in the course of a developing epileptic encephalopathy), or resulting from disturbed cerebral regulation of vital functions (e.g., breathing abnormalities) or aspiration during respiratory infections or associated with food intake.
The rare male with the milder cerebral manifestation of subcortical band heterotopia (SBH) has findings similar to those in females with SBH [D'Agostino et al 2002, Aigner et al 2003].
Females
The SBH clinical phenotype in heterozygous females is markedly milder than the classic lissencephaly clinical phenotype in males, very variable, and roughly correlated with the extent and thickness of the subcortical band as observed in cerebral imaging.
Bahi-Buisson et al [2013] proposed two distinct subgroups among females with DCX pathogenic variants: a more severe clinical phenotype usually observed in sporadic cases and a milder phenotype mainly observed in heterozygous asymptomatic females with normal cerebral MRI or only thin frontal subcortical bands.
Severe phenotype associated with thicker SBH typically includes:
- Developmental delay
- Moderate-to-severe intellectual disability
- Severe language impairment
- Behavioral problems
- Seizures (frequently refractory to antiepileptic medication) that may be either focal or generalized (~50% each) and in more severe cases eventually progress to Lennox-Gastaut syndrome [Dobyns 2010]
Mild phenotype associated with thin frontal band heterotopia or normal-appearing cerebral MRI may include:
- 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
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. As an example, such variability has been observed in monozygous female twins heterozygous for a recurrent 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 broader 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.
Somatic Mosaicism
Somatic mosaicism for DCX pathogenic variants has been repeatedly documented in both females and males with milder manifestations [D'Agostino et al 2002, Aigner et al 2003, Bahi-Buisson et al 2013, Jamuar et al 2014].
Pathophysiology
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
Genotype-Phenotype Correlations
About one third of all DCX pathogenic variants are recurrent, resulting in rather 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].
- DCX pathogenic nonsense variants in males are very rare and have mainly been observed as postzygotic mosaic events.
- 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 were more frequently associated with generalized subcortical bands; missense variants were 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].
For further information on postulated functional consequences of various DCX pathogenic missense variants and the observed clinical manifestations in male and female patients see Bahi-Buisson et al [2013].
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.
- Males with postzygotic mosaic pathogenic variants may have milder clinical manifestations or, in rare cases, be asymptomatic (see Clinical Description, Somatic Mosaicism).
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 the mothers with a heterozygous or mosaic pathogenic variant in DCX whose children presented with DCX-related disorders [Bahi-Buisson et al 2013].
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.
Classic lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia.
Classic lissencephaly is morphologically and etiologically distinct from lissencephaly type 2, which is also called cobblestone lissencephaly, and from thin 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 (X-SCLH)
- Subcortical band heterotopia, X-linked (SBHX)
DCX-related lissencephaly and SBH have also been referred to as double cortex syndrome.
Prevalence
The incidence of all forms of type 1 lissencephaly has been estimated at 1:100,000 births [Orphanet], with the majority resulting from heterozygous pathogenic variants of PAFAH1B1 (LIS1). No specific data on the prevalence of lissencephaly due to pathogenic variants in DCX are available.
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 lissencephaly (38% of all males, but only rare females);
- About 53%-85% of all SBH, about 80% of sporadic SBH, and about 29% of SBH in males [Pilz et al 1998, Gleeson et al 1999, Matsumoto et al 2001, Guerrini & Filippi 2005].
Differential Diagnosis
See Tables 2a, 2b, and 2c for disorders to consider in the differential diagnosis of DCX-related disorders.
Table 2a.
Disorders with Lissencephaly-Pachygyria with Classic or Thick Lissencephaly (cortex 10-20 mm) to Consider in the Differential Diagnosis
| Disorder | Gene(s) | MOI | Clinical Features Differentiating This Disorder from DCX Disorders |
|---|---|---|---|
| PAFAH1B1- associated lissencephaly | PAFAH1B1 | AD |
|
| Miller-Dieker syndrome | Microdeletion of 17p13.3 2 | AD |
|
| TUBA1A- related lissencephaly (see Tubulinopathies Overview) | TUBA1A | AD |
|
| DYNC1H1- related pachygyria (OMIM 614563) | DYNC1H1 | AD | Posterior or anterior predominant pachygyria or dysgyria 5 |
| KIF5C-related pachygyria (OMIM 615282) | KIF5C | AD |
|
| Baraitser- Winter syndrome (OMIM PS243310) | ACTB ACTG1 | AD |
|
| CDK5-related lissencephaly (OMIM 616342) | CDK5 | AR |
|
A = anterior; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; P = posterior; SBH = subcortical band heterotopia
- 1.
Uyanik et al [2007]
- 2.
Miller-Dieker syndrome is caused by either small cytogenetically visible deletions or FISH-detectable microdeletions of 17p13.3 that include LIS1 (officially designated as PAFAH1B1) and YWHAE, and intervening genes.
- 3.
Bruno et al [2010]
- 4.
Bahi-Buisson et al [2014]
- 5.
Poirier et al [2013]
- 6.
Di Donato et al [2016a], Di Donato et al [2016b]
- 7.
Magen et al [2015]
Table 2b.
Disorders with Lissencephaly-Pachygyria with Thin Lissencephaly (cortex 5-10 mm) to Consider in the Differential Diagnosis
| Disorder | Gene(s) | MOI | Clinical Features Differentiating This Disorder from DCX Disorders |
|---|---|---|---|
| X-linked lissencephaly w/ambiguous genitalia (OMIM 300215) | ARX | XL |
|
| RELN-related lissencephaly (OMIM 257320) | RELN | AR |
|
| VLDLR- associated cerebellar hypoplasia | VLDLR | AR |
|
| CRADD related lissencephaly (OMIM 614499) | CRADD | AR |
|
A = anterior; AR = autosomal recessive; MOI = mode of inheritance; P = posterior; XL = X-linked
- 1.
Uyanik et al [2003], Coman et al [2017]
- 2.
Valence et al [2016]
- 3.
Di Donato et al [2016a], Di Donato et al [2016b]
Table 2c.
Disorders with Subcortical Band Heterotopia to Consider in the Differential Diagnosis
| Disorder | Gene(s) | MOI | Clinical Features Differentiating This Disorder from DCX Disorders |
|---|---|---|---|
| PAFAH1B1- associated subcortical band heterotopia | PAFAH1B1 | AD | More prominent in the posterior regions of the brain, w/a P>A gradient (DCX-related SBH presents w/an A>P gradient.) 1 |
| Baraitser- Winter syndrome (OMIM 243310, 614583) | ACTB ACTG1 | AD |
|
A = anterior; AD = autosomal dominant; MOI = mode of inheritance; P = posterior; SBH = subcortical band heterotopia
- 1.
Uyanik et al [2007]
- 2.
Di Donato et al [2016a], Di Donato et al [2016b]
Other disorders to consider include those with cobblestone lissencephaly (i.e., Walker-Warburg syndrome, muscle eye brain disease [see OMIM PS236670], and Fukuyama congenital muscular dystrophy) as well as tubulinopathies (see Tubulinopathies Overview), disorders with polymicrogyria, and disorders with periventricular nodular heterotopia (see FLNA-Related Periventricular Nodular Heterotopia).
Management
Evaluations Following Initial Diagnosis
To establish the individual clinical manifestation of a DCX-related disorder, the following evaluations are recommended if they have not already been completed:
- Neurologic evaluation, including EEG and cerebral MRI. This is best performed by a pediatric neurologist or neurologist with special expertise in the diagnosis, treatment, and surveillance of individuals with multiple disabilities and difficult-to-treat seizures
- Developmental evaluation including motor skills, cognition, and speech
- Growth and head circumference
- Nutrition and feeding evaluation (including a swallowing assessment in individuals lacking head control or the ability to sit unsupported) to enable early recognition of malnutrition or risk constellations for aspiration that would require special medical surveillance or measures (e.g., tube feeding)
- Ophthalmologic evaluation for impaired vision, potentially correctable by glasses
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Epileptic seizures require antiepileptic medication. Individual treatment strategies should be based on the type and frequency of seizures, EEG results, and responsiveness.
Surgical resection of heterotopic brain tissue has been tried in only a few individuals with SBH; overall it has not been effective in reducing seizure activity and thus is not recommended [Bernasconi et al 2001]. More recently, deep brain stimulation has been suggested to improve the seizure disorder in individuals with SBH based on first results in small treated cohorts [Franco et al 2016].
In addition, appropriate interdisciplinary management should start at the time of diagnosis and can prolong survival and improve quality of life for individuals with a DCX-related disorder:
- Feeding problems in newborns may require special strategies including placement of a percutaneous endoscopic gastrostomy tube to deal with weak or uncoordinated sucking.
- Physical therapy helps to maintain and promote mobility and prevent contractures. Special adaptive chairs or positioners or other measures may support sitting and mobility.
- Occupational therapy may help improve fine motor skills and oral motor control.
- Speech therapy may improve communication
- A full range of educational training and enrichment programs should be available.
- Parents should be informed early and repeatedly on the common presentation and appropriate management of seizures. For parents of individuals with a severe manifestation of a DCX-related disorder this should also include appropriate discussion of the level of care in sudden critical situations.
- For information on non-medical interventions and coping strategies for parents or caregivers of children with seizure disorders see Epilepsy & My Child Toolkit.
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:
- Regular neuropediatric or neurologic examination including monitoring of seizure activity, EEG, and antiepileptic drug (AED) levels
- Regular measurement of height, weight, and head circumference