DCX-Related Disorders

Excerpt

Clinical characteristics: DCX-related disorders include the neuronal migration disorders:

1. Classic thick lissencephaly (more severe anteriorly), usually in males

2. 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 anti-seizure 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: Anti-seizure medication 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 anti-seizure 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.