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Summary: Purpose: To describe the phenotypic expression of a new family with familial lateral temporal lobe epilepsy with aphasic seizures, and to compare the findings with the clinical features of previously reported families linked to chromosome 10q22-q24.
Methods: Medical records were collected from 12 living affected members. The patients underwent a personal interview and a clinical neurologic examination. Results from interictal scalp EEGs and neuroimaging examinations were obtained.
Results: The cardinal ictal symptom was a brief sensory aphasia in eight of the patients. In four, this was accompanied by auditory symptoms, usually in the form of monotonous unformed sounds. Simple partial seizures with psychic or somatosensory seizures also were present. Visual ictal symptoms and complex partial seizures were absent. All patients had generalized tonic–clonic seizures. Magnetic resonance imaging (MRI) or computed tomography (CT) did not reveal morphologic correlates. Improvement with age seemed to occur in many patients. Significant linkage to chromosome 10q22-q24 was established by testing 17 polymorphic microsatellite markers.
Conclusions: The epilepsy of this family appears to represent a variety of autosomal dominant lateral temporal lobe epilepsy. Aphasic seizures and a peculiar seizure-precipitating effect of the activation of speech (initiation or perception) may serve as markers for identifying further families with this phenotype.
Recently various syndromes of nonlesional, localization-related epilepsies with simple inheritance have been described: autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (1–3), autosomal dominant lateral temporal lobe epilepsy (ADLTLE) (4,5), and autosomal dominant partial epilepsy with variable foci (6). The ictal symptoms are characterized by the respective anatomic localizations of seizure initiation. Onset is usually at a young age, and improvement may occur with time. Most patients become seizure free with standard antiepileptic treatment, but there are exceptions. Both interfamilial and intrafamilial clinical variability is wide. Some family members are afflicted with psychiatric or behavioral abnormalities to a variable degree, particularly in ADNFLE, but the seizures are usually the only or major neurologic abnormality (7).
TLEs, including the familial forms, can be divided into two main categories according to the seizure semiology, one with medial temporal lobe symptoms (8) and one with lateral symptoms (4,5). The clinical expression of the familial TLE of the medial type is similar to the ictal manifestations of mesial temporal sclerosis and consists of autonomic auras, perceptual changes, and psychic and dysmnestic symptoms including déjà vu, usually evolving to complex partial seizures (CPSs) and/or secondary generalization (8). The symptoms of ADLTE usually consist of simple partial seizures (SPSs) with mainly acoustic and sometimes even visual hallucinations (4,5,8–10). Accordingly, this syndrome was designated “autosomal dominant partial epilepsy with auditory features” (ADPEAF) when it was first described (4,9). Recently a small Japanese family with SPSs in the form of aphasic symptoms and secondary generalization was reported (11). We now describe the phenotypic and genetic features of a large Norwegian pedigree with familial partial epilepsy characterized by aphasic as well as auditory ictal symptoms, and discuss them with respect to the previously published families with ADLTE
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- PATIENTS AND METHODS
Although the phenotype of this family bears strong similarities to the clinical pictures of previously reported ADLTE families (4,5,9,10,15), some differences are apparent. The transmission pattern also is consistent with an autosomal dominant inheritance with incomplete penetrance. The mean age at seizure onset (18 years; range, 4–42 years) was similar to the German family (19 years; range, 11–50 years), but higher than that in the U.S. family (13 years; range, 8–19 years) (4) and lower than that in the Basque patients (24 years; range, 11–40 years) (5). The ictal semiology of our patients varied (Table 2), but the central element was a stereotypic loss of comprehension of the spoken word, as a flash of sensory aphasia (eight patients). This disturbance of auditory perception, along with positive acoustic symptoms, clearly suggests the implication of the lateral, neocortical part of the temporal lobe, usually of the dominant hemisphere. However, medial temporal lobe onset (patient IV:27) and extratemporal lobe onsets, parietal (patients IV:5 and IN:31) or frontal, cannot be ruled out.
Aphasic symptoms were not reported in the other families with proven 10q-linked partial epilepsy, except in one member of the U.S. family who described an aura in which “it would sound like people would be talking backwards or something”(9). However, ictal aphasia was a hallmark in a newly described, small Japanese kindred with familial epilepsy (11). Auditory symptoms were present in six of our 12 patients, in the form of unformed sounds in five and as additional music and voices in one. SPSs seem to start several years ahead of GTCs in this condition, and the aphasic and simple auditory phenomena may easily be misdiagnosed (e.g., in IV:31 as common tinnitus). Auditory auras were the only focal seizure component in the German family (10) and in the three living affected members of the small Italian family with autosomal dominant partial epilepsy reported by Michelucci (15). It also was the most frequent aura in the U.S. family (six of 11) (9), whereas in the Basque patients, it was less common (four of 11) (5). In the latter family, visual symptoms predominated (six of 11). Visual symptoms were rare in the U.S. patients (two of 11) (9) and completely absent in our as well as in the German family (10). Vertiginous sensations also have been a rare symptom in previously described ADLTE series, present in only one member of the U.S. family (9), but in two of our patients. Somatosensory symptoms were a distinct feature in one of our patients (IV:9), but were not described in the other families. CPSs were reported in as many as seven of 11 patients in the U.S. family (9), but in only two of 11 and in one of nine in the Basque and German families, respectively (7,10). In the Italian family, the three affected living patients exclusively had SPSs with secondary generalization (15). There was no evidence of CPSs in our patients. CPSs seem to be a relatively rare manifestation of ADLTE, in contrast to the medial temporal lobe epilepsies. The symptomatogenic zone usually seems to be restricted to the lateral neocortex in these patients and less often spreads to the medial archicortex or limbic structures.
The EEG abnormalities recorded in our patients were usually mild, and focal findings were predominantly left-sided (Table 2). Most patients who had abnormal tracings also had other recordings described as completely normal. In the U.S. family, normal routine EEGs were reported in all examined subjects (9), whereas in the Basque family, two of seven showed epileptiform potentials over the left temporooccipital area; the others were normal. In the present patients, brain imaging or past history gave no clues as to specific causes of epilepsy in agreement with most other reports on ADLTE (4,5,10,15). Seizures were the only neurologic symptom, and according to the current classification (16), this new entity should be classified among the idiopathic localization-related epilepsies. However, it is noteworthy that MRI revealed a neuronal migration disorder (not further specified) in one of the Japanese patients with aphasic seizures (11). One may speculate whether this finding may represent the tip of the iceberg of cytoarchitectonic abnormalities in ADLTE, and that other patients with this syndrome may have more subtle forms of cortical dysgenesis that are beyond the resolution of current neuroimaging methods.
The overall prognosis is reported to be good in the dominantly inherited partial epilepsies (7). GTCs were controlled in all our patients, but pharmacoresistant SPSs were present in 50%. It is noteworthy that two subjects with a history of seizures in this family had a sudden unexpected death.
Five of our patients reported that seizures were sometimes precipitated by the activation of speech, usually when addressed orally or taking the phone, particularly in stressful situations. In two of the four reported Japanese patients with aphasic seizures, it is specified that seizures occurred when “talking on the phone”(11). It was also suggested that two members of the U.S. family had seizures provoked by auditory stimuli (9). Some of our patients felt that it was the initiation to speak that could precipitate a seizure, whereas others believed that it was merely the sudden perception of talking. Different forms of language-induced epilepsy have previously been described. Primary reading epilepsy also is classified among the idiopathic localization-related epilepsies (16). According to Geschwind and Sherwin (17), other forms may involve seizure precipitation by speaking as well as by writing (17).
The significant results obtained by linkage analysis for chromosome 10q22-q24 markers indicate that the epilepsy in our family is probably caused by the same gene as in the U.S., Basque, and German families. Genetic analyses in the latter families revealed linkage to chromosome 10q22-q24, indicating the localization of an unknown epilepsy gene in an overlapping 3-cM region (4,5). Haplotype analysis in the small Italian families also was consistent with this localization (15). The most likely region for an ADLTE gene in our family as defined by recombination events includes the overlapping regions on chromosome 10q22-q24 defined in previous reports (4,5), but does not exclude a more distal localization.
Despite some phenotypic differences, there are impressive similarities in these families. In all of them, simple, auditory ictal symptoms have been present. The U.S. group called this disorder “autosomal dominant partial epilepsy with auditory features (ADPEAF).” However, in many patients, other symptoms from the lateral temporal lobe predominate, indicating that the most important feature is the localization of the epileptogenic zone in this area. In our patients, the aphasic symptoms, the precipitation by speech, along with the prevailing left-sided EEG abnormalities give rise to speculations whether the mutant gene may be specifically coupled to the function of speech. At present, it is difficult to decide whether the most appropriate designation for this epilepsy should reflect the symptoms, the brain area involved, or the localization of the responsible gene. Rather than basing the nomenclature on the variable phenotype, the term 10q-linked partial epilepsy may be relevant. Future genetic studies will show if all the chromosome 10q–linked partial epilepsies are indeed caused by the same gene, or if, as known for other chromosomal regions, more than one epilepsy-causing gene is located in close vicinity (3,18,19). If it is only one gene, it will be interesting to learn which mechanisms are responsible for the observed phenotypic differences.
The epilepsy in our family seems to belong to the spectrum of ADLTE, which is a subgroup of familial TLE. However, brief sensory aphasia is a striking ictal symptom in most of our patients, which has not been reported as a distinctive feature in previous families with linkage to chromosome 10q22-q24. A peculiar seizure-precipitating effect of the activation of speech seems to be present in some patients. Secondarily generalized, nocturnal GTCs are common. Although SPSs and occasional GTCs may persist in adult age, this condition seems to share a good prognosis with most other idiopathic partial epilepsies. Nevertheless, sudden unexpected death occurred in two subjects with a history of seizures in this family. The significant results of linkage analysis indicate that the epilepsy in our family is caused by a mutation in an unknown gene located in the 10q22-q24 region, which was previously implicated in the etiology of ADLTE.