Clinical Characteristics

Major clinical features or initial diagnoses are developmental and epileptic encephalopathy with or without movement disorders. Some patients show movement disorders without epilepsy. Acute encephalopathic episodes including temporal hemiparesis, which is similar to acute hemiplegia in childhood, are also characteristically seen. A few patients show stereotypic hand movement or dysmorphic face leading to the diagnosis of Rett syndrome or Pitt-Hopkins syndrome, respectively.

The first symptom of the patients with a RHOBTB2 mutation is seizures in most cases. Seizures start between 4 days and 4 years of age, mainly less than 1 year. Developmental delay prior to seizures is rarely seen. Episodes of hemiparesis, acute encephalopathy, and movement disorders precede in some patients.

Focal seizures or focal to bilateral tonic-clonic seizures are more frequent than generalized seizures. Half of the patients with seizures show status epilepticus. A third patients with RHOBTB2 mutation show fever-sensitivity. Seizures are refractory in 9 of 34 patients. Regression mainly correlating with the onset or worsening of epilepsy is seen in 10 patients.

Intellectual disability is commonly seen. Two thirds of the patients show profound or severe intellectual disability. Motor ability is also impaired, but half of the patients can walk alone or with support.

A variety of movement disorders, such as dystonia, ataxia, chore, dyskinesia, and hand stereotypies, are frequently associated with RHOBTB2 mutation in the manner of continuous or paroxysmal signs.

Acute encephalopathic episodes are seen in half of the patients. Three patients have episodes of minor head trauma prior to encephalopathy.

Postnatal microcephaly (≤ -2 SD) can be seen in half of the patients.

The findings of brain MRI are initially normal, then some patients show atrophic change, thin corpus callosum, or delayed myelination.

Episodes of autonomic dysregulation, such as peripheral vasomotor disturbances, marked skin color change, and gastrointestinal symptoms, are seen in some patients. Lactic acidemia, elevated serum creatine kinase, and aplasia cutis congenita are rarely reported.