| Autosomal Dominant Epilepsy with Auditory Features
Synonyms: ADEAF, Autosomal Dominant Lateral Temporal Epilepsy (ADLTE)
Roberto Michelucci, MD, PhD and Carlo Nobile, PhD.
Author Information
Roberto Michelucci, MD, PhD
Chief of Neurology, IRCCS Institute of Neurological Sciences
Neurology Unit
Bellaria Hospital
Bologna, Italy
Carlo Nobile, PhD
Senior Research Scientist, CNR Institute of Neuroscience
Padua, Italy
Summary
Clinical characteristics.
Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Most affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by "focal aware" and "focal impaired-awareness" seizures, with auditory symptoms as a major focal aware seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset is usually in adolescence or early adulthood (range: age 4-50 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy.
Diagnosis/testing.
The clinical diagnosis of ADEAF is established in a proband with characteristic clinical features, normal brain imaging (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing establishes the diagnosis if other findings are inconclusive.
Management.
Treatment of manifestations: Seizure control is usually readily achieved with antiepileptic drugs used routinely in clinical practice (including but not limited to carbamazepine, phenytoin, valproate, and levetiracetam).
Evaluation of relatives at risk: Interviewing relatives at risk to identify those with suggestive findings may enable early treatment in those who develop seizures.
Genetic counseling.
ADEAF is inherited in an autosomal dominant manner. Most individuals with ADEAF have an affected parent; the proportion of cases caused by a de novo pathogenic variant is believed to be very low. Each child of an individual with ADEAF has a 50% chance of inheriting the pathogenic variant. The chance that the offspring who inherits the pathogenic variant will manifest ADEAF is between 55% and 78%, depending on the penetrance. While prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if the pathogenic variant in the family is known, prenatal testing and preimplantation genetic diagnosis are rarely requested for conditions that (like ADEAF) do not affect intellect and are usually easily treated.
Diagnosis
Suggestive Findings
Autosomal dominant epilepsy with auditory features (ADEAF) should be suspected in individuals with the following clinical, imaging, and EEG findings and family history.
Clinical findings
•A history consistent with focal epilepsy from the affected individual and witnesses. Other causes of epilepsy (e.g., antecedent illness or injury to the central nervous system, such as severe head trauma, stroke, and brain tumor) must be excluded.
•Auditory symptoms that occur in temporal association with seizures as one of the following:
◦An aura immediately preceding generalized tonic-clonic convulsions
◦A component of focal aware or focal impaired-awareness seizures
◦The only ictal symptom
Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history. Since tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events or to raise a strong suspicion of the ictal nature of the auditory symptom if not associated with other clinical features.
•Aphasia that accompanies seizure onset. Aphasia may be difficult to distinguish from nonspecific confusion or alteration of consciousness; therefore, specific questions to assess the inability to understand spoken language in the absence of general confusion should be included in the clinical history. Note: Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration in consciousness).
Brain imaging (MRI or CT). Normal
Interictal EEG. Often normal. However, focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of individuals.
Family history. Consistent with autosomal dominant inheritance (with reduced and age-dependent penetrance).Two or more family members (including the proband) must have a history of focal epilepsy with either ictal auditory symptoms or ictal aphasia. Other family members may have different seizure types, usually tonic-clonic (undetermined whether focal or generalized).
Establishing the Diagnosis
The clinical diagnosis of ADEAF is established in a proband with the above clinical features, normal brain imaging studies (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing (Table 1) establishes the diagnosis if other findings are inconclusive.
A multigene panel that includes LGI1, MICAL1, RELN, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: Serial single-gene testing of LGI1, MICAL1, and RELN is impractical given the relatively large number of exons in the latter two genes.
www.ncbi.nlm.nih.gov/books/NBK1537/
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