Autosomal dominant epilepsy with auditory features (ORPHA:101046)
A rare, genetic, familial partial epilepsy disease characterized by focal seizures associated with prominent ictal auditory symptoms, and/or receptive aphasia, presenting in two or more family members and having a relatively benign evolution.
Epidemiology
The prevalence of autosomal dominant epilepsy with auditory features (ADEAF) is unknown but likely to be very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy and only a fraction of these have clinical features consistent with ADEAF.
Clinical description
ADEAF usually presents in adolescence or early adulthood (but can range from 4-50 years of age) with the onset of focal epilepsy originating predominantly in the lateral temporal lobe. Seizures may be precipitated by specific sounds (i.e. telephone ringing or speech) but in most cases there are no recognizable triggers. Ictal manifestations include auditory symptoms (such as humming, buzzing, ringing and, less frequently, more complex sounds such as voices, songs or volume changes) and receptive aphasia. Rarely, additional ictal manifestations, such as other sensory symptoms (e.g. visual or olfactory), as well as motor, psychic, and autonomic symptoms, have been reported. In many cases, focal seizures are followed by secondarily generalized seizures (e.g. generalized tonic-clonic seizures), which can manifest with loss of consciousness and convulsions (often during sleep). Disease course is usually benign with patients often being seizure free following treatment with anti-seizure medications.
Etiology
In approximately one-third of cases, ADEAF is caused by mutations in the LGI1 gene (10q23.33), encoding leucine-rich glioma-inactivated protein 1 and mutations in the RELN gene (7q22.1), encoding reelin. These proteins are thought to play key regulatory roles in both the developing and adult brain. In 50% of cases, the etiology is unknown.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical manifestations, a family history suggesting autosomal dominant inheritance, and normal brain imaging studies (using magnetic resonance imaging and computer tomography scans). Epileptiform interictal EEG abnormalities can be present in up to 2/3 of cases. Molecular genetic testing, identifying a causative mutation, confirms diagnosis.
Differential diagnosis
Differential diagnoses include other forms of focal epilepsy, such as autosomal dominant sleep-related hypermotor epilepsy and familial focal epilepsy with variable foci (FFEVF).
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has been previously identified in a family member. Variable penetrance is observed. In practice prenatal testing is not usually performed.
Genetic counseling
ADEAF is inherited in an autosomal dominant manner. Genetic counseling should inform parents with a pathogenic variant of the 50% risk of passing it on to their offspring. Due to the reduced and age-dependent penetrance seen in ADEAF, approximately 61% of patients who inherit the pathogenic variant will manifest symptomatology.
Management and treatment
ADEAF is treated with antiepileptic drugs that are routinely used in clinical practice (e.g. carbamazepine, phenytoin, valproate), with seizure control attained in the majority of cases. Evaluation of relatives is important in order to identify those who may be at risk and might benefit from early treatment initiation and/or measures to reduce risk in the event of seizure onset.
Prognosis
Although it is a life-long condition, the prognosis is generally good as ADEAF has a benign course and seizures are usually controlled with medication.

                            Last update: 
                            April 2019


                            - Expert reviewer(s): 
                            Pr Ruth OTTMAN