Marianna Pezzella

Clinical Significance of Rare Copy Number Variations in Epilepsy A Case-Control Survey Using Microarray-Based Comparative Genomic Hybridization

OBJECTIVE To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. DESIGN Prospective cohort study. SETTING Epilepsy centers in Italy. PATIENTS Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURES Identification of copy number variations (CNVs) and gene enrichment. RESULTS Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. CONCLUSIONS Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.

Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death

There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene. Functional studies showed that the mutation induces severe loss of function. This observation provides further evidence for a possible link between idiopathic epilepsy and LQTS.

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Purpose:  Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome‐wide linkage meta‐analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type–related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively.

Severe pulmonary congestion in a near miss at the first seizure: Further evidence for respiratory dysfunction in sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most important direct seizure-related cause of death, and most cases usually occur in patients with intractable, longstanding epilepsy. Suspected mechanisms for SUDEP include central and obstructive apnea, cardiac arrhythmia, postictal respiratory arrest, and primary cessation of brain activity. We report a patient who experienced a near SUDEP following his first prolonged tonic-clonic seizure requiring intubation. Chest X-ray examination showed severe bilateral congestion of the middle and superior pulmonary fields and an enlarged heart. Observations of pulmonary compromise in near-miss patients are extremely rare. Our patient showed marked cyanosis and respiratory distress after the index seizure, in agreement with the view that respiratory distress was the primary etiology in this case. Moreover, this observation confirms that SUDEP is not exclusively an issue for patients with chronic, uncontrolled epilepsy.

Life-threatening status epilepticus following gabapentin administration in a patient with benign adult familial myoclonic epilepsy.

We report the case of a 57‐year‐old man who experienced life‐threatening myoclonic status after the administration of gabapentin. Based on familial data, the patient was determined to be a member of a previously described family with benign adult familial myoclonic epilepsy (BAFME). The myoclonic status did not respond to benzodiazepines, but resolved after discontinuing the gabapentin. As for other idiopathic generalized epilepsies, gabapentin may precipitate myoclonic status in a benign syndrome, such as BAFME, as is reported herein for the first time. A correct diagnosis and prompt discontinuation of the drug may reverse a potentially severe, life‐threatening condition.

A pilot open-label trial of zonisamide in Unverricht-Lundborg disease†

Action myoclonus frequently remains the primary cause of disability in Unverricht‐Lundborg disease (EPM1) patients. Pharmacological treatment of myoclonus in these patients continues to be challenging; indeed conventional AEDs may be poorly effective in monotherapy or even in combination. We carried out a pilot, open‐label trial of add‐on zonisamide (ZNS) in patients with EPM1. Twelve EPM1 patients with epilepsy and action myoclonus were included in the study. Oral ZNS was gradually titrated until the target dose of 6 mg/Kg/day. Unified Myoclonus Rating Scale was obtained in each subject before and after ZNS add‐on. A significant reduction of myoclonus severity was reached after ZNS introduction. ZNS was generally well tolerated and only two patients withdrew due to mild adverse effects. Our trial suggests that ZNS may be a valuable therapeutic option in EPM1 patients.

Early‐onset absence epilepsy: SLC2A1 gene analysis and treatment evolution

To determine the prevalence of SLC2A1 mutations in children with early‐onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure‐free with anti‐epileptic drug (AED) monotherapy (group I) and those who needed add‐on treatment of a second AED (group II).

Long-term follow-up in two siblings with pyridoxine-dependent seizures associated with a novel ALDH7A1 mutation

Pyridoxine-dependent seizures (PDS) is a rare disorder characterized by seizures resistant to anticonvulsants but controlled by daily pharmacologic doses of pyridoxine. Mutations in the antiquitin (ALDH7A1) gene have recently reported to cause PDS in most of patients. We report the long-term follow-up in two PDS siblings carrying a novel ALDH7A1 mutation.

A clinical and genetic study of 33 new cases with early-onset absence epilepsy.

PURPOSE To investigate the electroclinical features and the outcome of patients with typical absences starting before the 3 years of life. METHODS We reviewed the clinical data of patients with absences started before 3 years observed over a 15-year period. Mutation analysis of SLC2A1 (GLUT-1) gene was performed when possible. Their clinical features were compared with those of subjects with a diagnosis of childhood absence epilepsy (CAE). RESULTS Among 33 children with absence epilepsy starting before 3 years of life, there were 20 boys and 13 girls. Mean seizure onset was at 28.0 ± 8.3 (range: 8-36) months of life. Two children displayed borderline intellectual functioning at long-term follow-up. Twenty-eight (85%) patients showed excellent response to therapy. Three subjects evolved into a different form of idiopathic generalized epilepsy (IGE). No SLC2A1 mutation was identified in 20 (60.6%) patients tested. The main clinical features of patients with early-onset absences did not differ from those of CAE except for increased prevalence of males (p=0.002) and longer treatment duration (p=0.001) in the former. CONCLUSIONS Strong similarities in the electroclinical features and outcome between children with early-onset absences and those with CAE support the view that these conditions are part of the wide spectrum of IGE.

Clinical dissection of early onset absence epilepsy in children and prognostic implications

To investigate whether patients with typical absence seizures (TAS) starting in the first 3 years of life, conformed to Panayiotopouloss definition of childhood absence epilepsy (CAE), show different electroclinical course than those not fulfilling CAE criteria.