Myoclonus epilepsy with ragged-red fibers
Jun. 18, 2022
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Recognition of a genetic basis of temporal lobe epilepsy in some families represents a major advance. In familial forms of lateral temporal lobe epilepsy with auditory features, LGI1 or RELN genes are mutated in approximately 50% of kindreds. In this article, the author reports on a large cohort of patients with epilepsy and auditory features in which a third of 112 cases were familial, with an underlying genetic diagnosis in 8% of individuals, including LGI-1, RELN, SCNA1, and DEPDC5 mutations. Moreover, the author highlights that patients with familial lateral temporal lobe epilepsy with RELN mutations can present with drug-resistant seizures and be associated with structural and functional neuroimaging temporal lobe abnormalities.
• Familial lateral temporal lobe epilepsy is typically characterized by auditory auras, but other types of clinical manifestations can be present in affected individuals.
• Drug-resistant seizures and neuroimaging abnormalities might be present in some affected individuals.
• Mutations in LGI1, RELN, DEPDC5, and SCNA1 genes have been reported.
• Approximately 50% of families have a genetic diagnosis clarified, of which mutations in the LGI1 gene or RELN gene are the most frequent.
Genetic factors in the causation of epilepsy have been recognized since the time of Hippocrates. However, until the second half of the 20th century, generalized epilepsies were thought to be genetic in origin, whereas focal epilepsies were largely attributed to environmental factors, such as birth injuries, infections, postnatal head trauma, and brain lesions such as tumors and vascular insults.
In a series of publications (05; 01; 02; 03) based on patients operated for focal epilepsy at the Montreal Neurological Hospital, Eva Andermann was able to demonstrate that genetic factors were important in patients with focal epilepsy, particularly temporal lobe epilepsy, and that both generalized and focal epilepsies fit a model of multifactorial inheritance (now termed complex inheritance), with interaction of 1 or more genes and environmental factors.
It was only in the 1990s that several autosomal dominant forms of focal epilepsy were described by the group of Berkovic and colleagues (12). These included: autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, familial focal epilepsy with variable foci, and autosomal dominant rolandic epilepsy with speech dyspraxia.
Familial temporal lobe epilepsy was included in the proposals for classification of epileptic syndromes by the International League Against Epilepsy, supporting it as a well-defined syndrome (36; 35; 09).
The first description of familial lateral temporal lobe epilepsy was in 1995 by Ottman and colleagues, who reported an autosomal dominant focal epilepsy syndrome with auditory features (72). Autosomal dominant partial epilepsy syndrome with auditory features corresponds to a neocortical or lateral temporal lobe epilepsy.
After detailed descriptions of many families with temporal lobe epilepsy, it has been possible to define 2 groups of familial temporal lobe epilepsy based on clinical and molecular characteristics (91; 04): familial mesial temporal lobe epilepsy, with clinical features of mesial temporal onset and no clear-cut molecular definition to date (57; 54); and familial lateral temporal lobe epilepsy, first described in association with LGI1 gene mutations in chromosome 10q (72; 51; 70).
It is important to recognize that it is impossible to distinguish familial and nonfamilial temporal lobe epilepsy patients based solely on the clinical presentation, for both mesial and lateral forms. As the family history is not always accurately documented and because some family members are asymptomatic or only mildly affected, many so-called “sporadic” or “isolated” patients may actually have a familial epilepsy syndrome.
The identification of a positive family history of seizures in patients with lateral temporal lobe epilepsy is not sufficient for a diagnosis of familial lateral temporal lobe epilepsy. The best definition of familial lateral temporal lobe epilepsy is based on the familial recurrence of lateral temporal lobe epilepsy, which is defined by clinical-EEG criteria according to the International League Against Epilepsy recommendations, in the absence of any suggestion of other focal or generalized epilepsy syndromes in other affected family members (27). Thus, the observation of at least 2 lateral temporal lobe epilepsy patients in 1 family is necessary, but not sufficient for the definition of familial lateral temporal lobe epilepsy. The observation of an autosomal dominant inheritance pattern with incomplete penetrance implies the presence of asymptomatic carriers of the genetic abnormalities, who can transmit the disease to their offspring. Therefore, we should consider inclusion of families not only with affected first-degree relatives, but also with affected second- and third-degree relatives.
Age of onset is variable, usually in the second or third decades of life, and seizures are with a few exceptions described in the literature easily controlled with antiseizure drugs. Familial lateral temporal lobe epilepsy is an overall benign epilepsy syndrome characterized by auditory auras (buzzing, roaring, radio- or motor-like sounds, distortions in sounds and words). Although other manifestations such as psychic, cephalic and other sensory and motor phenomena can occur, the auditory auras are a landmark for this syndrome (72; 96; 95). Sometimes ictal aphasia and visual misperceptions can occur, and in some families, secondarily generalized tonic-clonic seizures are frequent (78; 96; 95; 20; 46; 56; 68). Families with rather psychic symptoms or with visual ictal manifestations associated with LGI1 mutations have also been described (87; 31). A report from the Epi4K Consortium families highlighted that amongst kindreds with temporal lobe epilepsy, a small proportion of them presented affected individuals that could have either mesial or lateral seizure semiology (37). A family with a mother and her offspring with drug-resistant seizures with a combination of auditory symptoms and ictal fear of left temporal onset has been described (65).
The presence of family members with episodes of either generalized tonic-clonic seizures only, with no witnessed onset, or with febrile seizures alone does not exclude the diagnosis of familial lateral temporal lobe epilepsy as these do not fulfill criteria for other epilepsy syndromes. Families with individuals who have such clinical manifestations should also be considered to have familial lateral temporal lobe epilepsy as long as at least 2 affected individuals fulfill the clinical and EEG criteria for lateral temporal lobe epilepsy.
EEGs may show temporal epileptiform discharges, but are frequently normal. No clear-cut signs of hippocampal atrophy are seen in MRI studies but a range of anatomical variations have been described in rare cases. A lateral temporal malformation pattern has been observed in 45% of affected individuals in 1 large Brazilian family with an LGI-1 mutation, including 1 asymptomatic carrier (56). The left temporal lobes of these individuals seemed enlarged and sometimes there was a protrusion of the brain parenchyma laterally, with an “encephalocele-like” appearance. Anterior temporal lobe volumetry showed a significant global increase in volumes in only 2 individuals. Subtle abnormalities in the posterior aspect of the left middle temporal gyrus were identified in familial lateral temporal lobe epilepsy patients as compared to controls using voxel-based analysis of fractional anisotropy maps (90). More recently, a patient with an RELN mutation with normal 3T MRI was shown to have altered functional connectivity in the left hemisphere (22). Two Italian patients (proband and mother) with a missense RELN variant [c.6631C>T (p.Arg2211Cys)] and refractory seizures were investigated with video-EEG recording and neuroimaging, with ictal onset over the left temporal region, where structural and metabolic neuroimaging abnormalities were found: [18F]FDG-PET showed left temporal hypometabolism and 3T MRI revealed a mild left temporal hypotrophy, slight blurring of the white and grey matter in the left temporal lobe, and hyperintensity of the left hippocampus (65).
Familial lateral temporal lobe epilepsy has overall a benign clinical course with 2 refractory patients reported to date (72; 78; 96; 95; 20; 68; 65). Many patients may present only a few episodes and then have spontaneous remission.
A study reported on long-term follow-up in patients with epilepsy with auditory features, including 123 patients with a median follow-up of 11 years (14). Approximately 32% of these patients reported a family history of epilepsy; 15 of them (12.2%) belonged to 11 familial lateral temporal lobe epilepsy pedigrees. The authors analyzed patients who were in seizure remission for at least 5 years at last follow-up. Poor prognostic factors for seizure control were: age at onset younger than 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG.
Neurologic disabilities in the form of auditory and language processing dysfunction have also been documented in families with familial lateral temporal lobe epilepsy and LGI1 mutations (76; 73).
In approximately 50% of families, a molecular diagnosis can be determined through identification of mutations in the LGI1 as well as RELN genes being most often described. Other less frequently implicated genes have also been described but they account for a minority of families in whom a mutation has been identified.
The LGI1 gene is mutated in approximately 30% of families with familial lateral temporal lobe epilepsy (10; 74). A large Italian study identified LGI1 mutations in only 30% of kindreds (67). Although LGI1 mutations appear to be specific for this type of temporal lobe epilepsy, the identification of LGI1 mutations in only one half of families presenting the typical phenotype (10; 74) suggests genetic heterogeneity in the families. A linkage to chromosome 19q13.11-q13.31 has been found in a large Brazilian kindred presenting with auditory auras (15).
A comprehensive review on LGI1 mutations in lateral temporal lobe epilepsy can be found in a paper by Nobile and colleagues (71) and in a review on pathogenic mechanisms in LGI1 mutations (99). The LGI1 gene was cloned from a glioblastoma cell line, and although previous studies have suggested that LGI1 represents a tumor suppressor gene (26), a more recent study was unable to establish a correlation between the gene and malignant glioma suppression (45). LGI1 (also known as Epitempin) is a secreted neuronal protein characterized by a central leucine-rich repeat region (49), which is involved in regulation of cell growth, adhesion, and migration.
The role of LGI1 in the epileptogenic process began to be clarified in the past decade. Fukata and colleagues demonstrated that LGI1 binds to the postsynaptic membrane protein ADAM22, thus, linking LGI1 with modulation of glutamate-AMPA synaptic transmission (43). In addition, defective LGI1 could lead to presynaptic changes in inactivation kinetics of A-type potassium channels through an effect on voltage-gated potassium channel subunit (Kv1.1), thus, increasing excitability (83).
Two protein isoforms of LGI1 are differentially expressed in the human brain, with a much higher concentration in the temporal neocortex than in the hippocampus, which could explain the characteristic auditory auras in patients with LGI1 mutation (44). The association of lateral temporal malformation patterns in some families may be indicative of a probable role of LGI1 in the development of the temporal lobes (56; 90).
At least 43 LGI1 mutations have been described today. LGI1 mutations in familial lateral temporal lobe epilepsy patients are associated with loss-of-function, with the LGI1 protein either not secreted, misfolded, or unstable (77; 85; 59). Exceptions are the mutations described by Striano and colleagues and Di Bonaventura and colleagues, as they do not affect LGI1 protein secretion (34; 87). Striano and colleagues also reported that the mutation found in their family does not induce large structural rearrangements although could destabilize its interactions with target proteins. Investigating LGI1 mutations described in familial lateral temporal lobe epilepsy as well as epilepsy due to LGI1 autoantibodies, Dazzo and colleagued have validated and introduced the concept that LGI1 mutations can be secretion-defective or secretion-competent, the latter resulting in impaired interaction between secreted LGI1 with neuronal receptors ADAM22 and ADAM23 (29). For a review of the interactions between LGI1 and ADAM receptors please refer to Yamagata and Fukai (99).
Many different mutations have been described in different kindreds worldwide, all located in the coding region or exon splice sites (46; 51; 70; 41; 56; 68; 77; 10; 18; 48; 74; 76; 25; 71; 53; 34; 87; 31; 52; 61). Bovo and colleagues analyzed the promoter region of the LGI1 gene in sporadic and familial lateral temporal lobe epilepsy patients and found no mutations in the promoter sequence (19).
LGI1 microdeletions have been identified in families that tested negative for exon sequencing, suggesting that copy number variation analysis could help further understand mutation negative patients or families (40; 39). This has not been confirmed in a series of 8 families, and 20 sporadic patients tested negative for known LGI1 mutations (63).
LGI1 mutations have been identified in about 2% of nonfamilial cases (71). No mutations in LGI2, LGI3, or LGI4 have been identified in 71 families with various types of temporal lobe epilepsy, including 4 with familial lateral temporal lobe epilepsy (10; 07). Finally, no mutations related to the ADAM22 gene (23; 32) or Kv1 channel genes (32) have been identified in kindreds with familial lateral temporal lobe epilepsy without LGI1 mutations.
Anderson has proposed, based on evidence from in vitro studies in transgenic mice (100), that LGI1 modulates a mechanism that could lead to epileptogenesis via persistent immaturity of glutamatergic circuitries (06). Interestingly, LGI1 has been demonstrated as the autoantigen for antibodies found in patients with limbic encephalitis, which had been previously attributed to voltage-gated potassium channels (58). These 2 observations point to a role of LGI1 in the maturation of glutamatergic neurotransmission and also in the etiology of acquired epilepsies.
Further insights about the mechanisms underlying epileptogenicity derived from LGI1 mutations have been unraveled in vitro using hippocampal CA3 neurons (84). LGI1 deletion resulted in downregulation of axonal Kv1.1 and Kv1.2 channels, thus, impairing the capacity of axonal D-type current to limit glutamate release. This could be a potential mechanism through which LGI1 regulates intrinsic excitability of neurons and promotes development of epileptogenicity.
Heterozygous mutations in the gene encoding for the secreted protein reelin (RELN) on chromosome 7q have been found in 17% of kindreds that tested negative for LGI1 mutations, providing an interesting new venue for understanding the pathophysiology of this epilepsy syndrome (28; 69). Homozygous RELN mutations cause lissencephaly with cerebellar hypoplasia, and as the authors found an inhibitory effect of mutations on protein secretion and co-localization of LGI1 and RELN in many rat brain regions, they bring to discussion the regulatory role these 2 proteins exert in brain development.
Pippucci and colleagues used whole exome sequencing to investigate probands who tested negative for known LGI1 mutations and found CNTNAP2 intragenic deletion, 2 truncating mutations of DEPDC5 gene, and a missense SCN1A change (75). Interestingly, CNTNAP2 encodes CASPR2 pertaining to the voltage-gated potassium channel complex with which LGI1 interacts, whereas DEPDC5 has been originally identified in familial focal epilepsy with variable foci and now in about 10% of focal epilepsies, including patients with an underlying malformation of cortical development. No DEPDC5 mutations were found in another cohort of familial lateral temporal lobe epilepsy patients who tested negative for LGI1 mutations (88).
More recently, Leonardi and colleagues screened 28 familial lateral temporal lobe epilepsy kindreds that had tested negative for LGI1 and RELN mutations and found no CNTNAP2 (contactin associated protein like 2) mutations with next-generation sequencing and copy number variation analyses (60).
Using whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis, Dazzo and colleagues described 2 variants in the MICAL-1 (microtubule-associated monooxy-genase, calponin, and lim domain containing 1) gene in 2 different families with familial lateral temporal lobe epilepsy (30). Dysregulation of the actin cytoskeleton dynamics was proposed by the authors as a possible mechanism for these pathogenic variants.
Finally, 2 possibly pathogenic missense variants in the SCN1A gene were identified in 3.8% of sporadic patients in a cohort of lateral temporal lobe epilepsy with no antecedent of febrile seizures (13). Patients within GEFS+ families could present with typical semiology with auditory features and carry SCN1A mutations.
In the most recent and large genetic study in lateral temporal lobe epilepsy including 112 unrelated cases (of whom 33 were familial patients), Bisulli and colleagues applied next-generation sequencing and confirmed an underlying genetic abnormality in 8% of individuals (16). Pathogenic or likely pathogenic variants were identified in LGI1 (2.7%), RELN (1.8%), SCN1A (2.7%), and DEPDC5 (0.9%).
There is no predominance of familial lateral temporal lobe epilepsy in any particular ethnic group. Familial lateral temporal lobe epilepsy has been studied in the USA, Brazil, Japan, Germany, Korea, France, Italy, Spain, Australia, Pakistan, and China. The actual worldwide prevalence of familial lateral temporal lobe epilepsy is probably underestimated because of the usually mild phenotypes and predominantly good outcomes.
Although amniocentesis and mutation detection are now possible in offspring of known mutation carriers, prenatal diagnosis is not likely to be practiced routinely because the usually mild phenotype of lateral temporal lobe epilepsy probably would not warrant termination of pregnancy.
The 2 main differential diagnoses for familial lateral temporal lobe epilepsy are sporadic lateral temporal lobe epilepsy and familial mesial temporal lobe epilepsy, which can be clarified most of the time with a detailed history and seizure description. In addition, familial focal epilepsy with variable foci should be considered.
The presence of patients with lateral temporal lobe epilepsy but without a positive family history was highlighted by Bisulli and colleagues (17). The authors termed this syndrome idiopathic focal epilepsy with auditory features, and performed a clinical and genetic study in 53 sporadic cases. Mutations in LGI1 were excluded in all these patients with idiopathic partial epilepsy with auditory features although, except for the absence of family history, these patients had identical clinical manifestations to those seen in familial lateral temporal lobe epilepsy, including the always-good prognosis (17). After the first description of their large series, the same authors reported a de novo mutation in the LGI1 gene in 1 patient with sporadic lateral temporal lobe epilepsy (18). A de novo LGI1 mutation has also been reported in a patient with idiopathic epilepsy and telephone-induced seizures (66). However, other series of patients with sporadic lateral temporal lobe epilepsy found no LGI1 mutations (42; 19). Overall, approximately 2% of nonfamilial cases will show an LGI1 mutation (71).
To date, no families with familial mesial temporal lobe epilepsy have been found to have an LGI1 mutation, even in those families where 1 or more family members had auditory features alone or in association with mesial symptoms (79; 08; 10). This further supports the fact that familial lateral temporal lobe epilepsy and familial mesial temporal lobe epilepsy constitute separate genetic syndromes. The implication of LGI1 with seizures of mesial temporal origin rather than neocortical onset is, however, suggested by the study of Chabrol and colleagues using LGI1 knockout mice (24). Frequent spontaneous seizures originating from the hippocampus were seen in homozygous animals, and hippocampal pathology consistent with sclerosis was observed. In contrast, heterozygous animals showed only auditory stimuli-induced seizures.
Patients with temporal lobe epilepsy are found in other familial epilepsy syndromes. In familial epilepsy with variable foci, different family members may present with various forms of epilepsy, including temporal lobe epilepsy (55), but the focus remains the same in each affected individual. Most reported families mapped to chromosome 22q (82; 98; 97; 21; 11). Subsequently, mutations in the DEPDC5 gene encoding the poorly characterized DEP domain containing 5 protein were described not only in FFEVF families, but also in other familial focal epilepsies (50; 33; 64).
In generalized epilepsy with febrile seizure plus (GEFS+), related to mutations in genes SCN1A, SCN1B, SCN2A, and GABRG2 (94; 92; 93; 38; 62; 89; 47), patients may present heterogeneous epilepsy phenotypes. Febrile seizures are the most common phenotype, followed by febrile seizures plus (FS+), where individuals have seizures with fever that may persist beyond the age of 6 years and may be associated with afebrile generalized tonic-clonic seizures (80; 86). Less frequent phenotypes seen in generalized epilepsy with febrile seizure plus involve other generalized seizure types, including temporal lobe epilepsy (80; 86; 93; 81). Patients with focal seizures typical of lateral temporal lobe epilepsy have been described within the context of GEFS+ kindreds, without febrile seizures and bearing an SCN1A mutation (13; 16).
It is essential to evaluate the phenotype of all possibly affected individuals before classifying the family to have a specific familial syndrome. In addition, because phenotypes may vary, we can never be absolutely sure that an “isolated” or “sporadic” lateral temporal lobe epilepsy patient does not have familial lateral temporal lobe epilepsy. Molecular studies with testing for mutations of genes previously identified in these families, as well as other genes associated with related familial epilepsies can be helpful.
As it is impossible to distinguish, so far, familial from nonfamilial lateral temporal lobe epilepsy in a single individual, it is necessary to obtain a detailed family history with the mother or the grandmother of each patient to exclude familial recurrence (which is often hidden in families). All family members with suggestive symptoms of epilepsy should be interviewed personally or by telephone, and medical records should be obtained whenever possible.
Familial lateral temporal lobe epilepsy patients should have the same investigations as nonfamilial patients. Routine and sleep EEG should be performed, as well as MRI, to rule out the presence of any treatable lesion. Video telemetry can also be performed to record the origin of the seizures.
Molecular studies can now be performed, including the search for all described gene mutations, in suspected cases of familial lateral temporal lobe epilepsy. If other familial epilepsy syndromes are suspected, specific molecular testing for these syndromes can also be performed. Although the yield is very low (approximately 2%), LGI1 mutations should be looked for in sporadic lateral temporal lobe epilepsy patients as well.
Treatment should be based on the patient’s response to anti-epileptic drugs and the rationale is similar to that in nonfamilial patients. Usually, familial lateral temporal lobe epilepsy patients are well controlled with small doses of anti-epileptic drugs indicated in epilepsies. Due to the benign nature of this syndrome as compared to familial mesial temporal lobe epilepsy these patients are not, with rare exceptions, candidates for surgical therapy (65).
No differences as compared to other epilepsy syndromes.
No differences as compared to other epilepsy syndromes.
Eliane Kobayashi MD PhD
Dr. Kobayashi of Montreal Neurological Institute at McGill University received a research grant from UCB Canada as a clinical trial investigator.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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