DCX-Related Disorders

Excerpt

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.