Elena Pasini

LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.

Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine‐rich, glioma‐inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty‐five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N‐terminal leucine rich repeat (LRR) and C‐terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype–phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed. Hum Mutat 0, 1–8, 2009.

Lateral temporal lobe epilepsies: Clinical and genetic features

Lateral temporal epilepsies are still a poorly studied group of conditions, covering lesional and nonlesional cases. Within nonlesional cases, autosomal dominant lateral temporal epilepsy (ADLTE) is a well‐defined, albeit rare, condition characterized by onset in adolescence or early adulthood of lateral temporal seizures with prominent auditory auras sometimes triggered by external noises, normal conventional magnetic resonance imaging (MRI), good response to antiepileptic treatment, and overall benign outcome. The same phenotype is shared by sporadic and familial cases with complex inheritance. Mutations in the LGI1 gene are found in about 50% of ADLTE families and 2% of sporadic cases. LGI1 shows no homology with known ion channel genes. Recent findings suggest that LGI1 may exert multiple functions, but it is not known which of them is actually related to lateral temporal epilepsy.

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.

Epilepsy in primary cerebral tumors: The characteristics of epilepsy at the onset (results from the PERNO study-Project of Emilia Romagna Region on Neuro-Oncology)

To present new information on the semiology and short‐term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study.

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine‐rich, glioma‐inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis.

Genetics of Epilepsy and Relevance to Current Practice

Genetic factors are likely to play a major role in many epileptic conditions, spanning from classical idiopathic (genetic) generalized epilepsies to epileptic encephalopathies and focal epilepsies. In this review we describe the genetic advances in progressive myoclonus epilepsies, which are strictly monogenic disorders, genetic generalized epilepsies, mostly exhibiting complex genetic inheritance, and SCN1A-related phenotypes, namely genetic generalized epilepsy with febrile seizure plus and Dravet syndrome. Particular attention is devoted to a form of familial focal epilepsies, autosomal-dominant lateral temporal epilepsy, which is a model of non-ion genetic epilepsies. This condition is associated with mutations of the LGI1 gene, whose protein is secreted from the neurons and exerts its action on a number of targets, influencing cortical development and neuronal maturation.

Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1

To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA‐PME), a rare condition caused by mutations in the N‐acylsphingosine amidohydrosilase 1 (ASAH1) gene.

DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy

Mutations in the DEPDC5 (DEP domain–containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12–37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies.

Mild Lafora disease: Clinical, neurophysiologic, and genetic findings

We report clinical, neurophysiologic, and genetic features of an Italian series of patients with Lafora disease (LD) to identify distinguishing features of those with a slowly progressive course. Twenty‐three patients with LD (17 female; 6 male) were recruited. Mean age (± SD) at the disease onset was 14.5 ± 3.9 years and mean follow‐up duration was 13.2 ± 8.0 years. NHLRC1 mutations were detected in 18 patients; EPM2A mutations were identified in 5. Patients who maintained >10 years gait autonomy were labeled as “mild” and were compared with the remaining LD patients with a typical course. Six of 23 patients were mild and presented significantly delay in the age at onset, lower neurologic disability score at 4 years after the onset, less severe seizure phenotype, lower probability of showing both photoparoxysmal response on electroencephalography (EEG) and giant somatosensory evoked potentials, as compared to patients with typical LD. However, in both mild and typical LD patients, EEG showed disorganization of background activity and frequent epileptiform abnormalities. Mild LD patients had NHLRC1 mutations and five of six carried homozygous or compound heterozygous D146N mutation. This mutation was found in none of the patients with typical LD. The occurrence of specific NHLRC1 mutations in patients with mild LD should be taken into account in clinical practice for appropriate management and counseling.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties

To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.