IRF2BPL-Related Disorder

Excerpt

Clinical characteristics: IRF2BPL-related disorder is characterized by mild-to-profound developmental delay (with regression in many individuals), intellectual disability, seizures (generalized tonic-clonic, myoclonic, absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures), movement disorder (ataxia, dystonia, tremor, and parkinsonism), spasticity, and neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis). Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported. Brain MRI can show focal or diffuse cortical and/or subcortical atrophy, cerebellar atrophy (particularly of the vermis), brainstem atrophy, and corpus callosum abnormalities including thinning/atrophy or thickening. Onset is highly variable and can be in the first year of life through the sixth decade. In some individuals the course of the disorder is progressive or debilitating.

Diagnosis/testing: The diagnosis of IRF2BPL-related disorder is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in IRF2BPL identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational support; standard treatment of epilepsy and movement disorder by an experienced neurologist; standard treatment of spasticity per orthopedist, neurologist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist; feeding support for poor weight gain; standard treatment for gastric dysmotility; treatment of vision deficits per ophthalmologist with treatment of more complex findings per ophthalmic subspecialist; treatment of pubertal delay per endocrinologist; family and social work support.

Surveillance: At each visit, assess developmental progress, educational needs, cognitive function, seizures, movement disorder, spasticity, contractures, behavioral issues, growth, nutritional status, gastrointestinal dysmotility, and family needs; physical medicine and/or occupational and physical therapy assessment for mobility and self-help skills at each visit; dilated eye exam per treating ophthalmologist; assessment of pubertal development at each visit through adolescence.

Genetic counseling: IRF2BPL-related disorder is inherited in an autosomal dominant manner. The majority of individuals diagnosed with IRF2BPL-related disorder have the disorder as the result of a de novo pathogenic variant; approximately 9% of individuals reported to date have an affected parent. Each child of an individual with IRF2BPL-related disorder has a 50% chance of inheriting the IRF2BPL pathogenic variant. Once the IRF2BPL pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.