Clinical Characteristics

BRAT1 related disorder is a neurodevelopmental disorder characterized by different phenotypes representing varying levels of severity.

The severe phenotype is referred to as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), associated with neonatal presentations of intractable epilepsy, microcephaly, cerebral and cerebellar atrophy, hypotonia, hypertonia (spasticity, rigidity), autonomic instability (apnea, bradycardia), and death in the neonatal period/early infancy from cardiopulmonary arrest. A moderate form of the disorder can have similar features as RMFSL but with later seizure onset and increased survival past infancy. A mild form of the disorder can present with global developmental delay/intellectual disability, cerebellar atrophy, hypotonia, and ataxia.

In the moderate and severe presentations, MRI brain can be normal or show frontal hypoplasia, cerebral and cerebellar atrophy, and/or myelination abnormalities. In the milder presentations, MRI brain can show cerebellar atrophy.

Epilepsy and EEG abnormalities are commonplace in BRAT1 related disorder. The RMFSL phenotype is associated with neonatal-onset epileptic encephalopathy with EEG features that include absent posterior dominant rhythm, background slowing, burst suppression, and focal/multifocal epileptiform activity. In those with the milder phenotype, clinical seizures can occur in some but not all cases, and EEG may be normal or show background slowing as well as different types of epileptiform abnormalities.

Affected individuals have variable facial dysmorphisms. These include a wide face, epicanthal folds, downslanting palpebral fissures, supraorbital fullness, flattened nose, low-set and posteriorly rotated ears, cupped upper helices, high arched palate, and tented upper lip.