Maurizio Viri

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome

Objective: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). Methods: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. Results: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. Conclusion: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy

Objective: To conduct an open-label, add-on trial on safety and efficacy of levetiracetam in severe myoclonic epilepsy of infancy (SMEI). Patients and Methods: SMEI patients were recruited from different centers according to the following criteria: age ≥3 years; at least four tonic-clonic seizures/month during the last 8 weeks; previous use of at least two drugs. Levetiracetam was orally administrated at starting dose of approximately 10 mg/kg/day up to 50 to 60 mg/kg/day in two doses. Treatment period included a 5- to 6-week up-titration phase and a 12-week evaluation phase. Efficacy variables were responder rate by seizure type and reduction of the mean number per week of each seizure type. Analysis was performed using Fisher exact and Wilcoxon tests. Results: Twenty-eight patients (mean age: 9.4 ± 5.6 years) entered the study. Sixteen (57.1%) showed SCN1A mutations. Mean number of concomitant drugs was 2.5. Mean levetiracetam dose achieved was 2,016 mg/day. Twenty-three (82.1%) completed the trial. Responders were 64.2% for tonic-clonic, 60% for myoclonic, 60% for focal, and 44.4% for absence seizures. Number per week of tonic-clonic (median: 3 vs 1; p = 0.0001), myoclonic (median: 21 vs 3; p = 0.002), and focal seizures (median: 7.5 vs 3; p = 0.031) was significantly decreased compared to baseline. Levetiracetam effect was not related to age at onset and duration of epilepsy, genetic status, and concomitant therapy. Levetiracetam was well tolerated by subjects who completed the study. To date, follow-up ranges 6 to 36 months (mean, 16.2 ± 13.4). Conclusion: Levetiracetam add-on is effective and well tolerated in severe myoclonic epilepsy of infancy. Placebo-controlled studies should confirm these findings.

Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial

PURPOSE This study was to evaluate the efficacy and safety of topiramate (TPM) in patients with severe myoclonic epilepsy in infancy (SMEI) and refractory seizures. METHODS We performed a prospective multicentric open label add-on study in 18 patients (age 2-21 years, mean 9 years) with SMEI and refractory seizures of different types. TPM was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. RESULTS TPM was initiated at a daily dose of 0.5-1 mg/kg, followed by a 2-week titration at increments of 1-3 mg/kg/24 h up to a maximum daily dose of 12 mg/kg. After a mean period of 11.9 months (range 2-24 months), three patients (16.7%) had 100% fewer seizures and ten patients (55.5%) had a more than 50% seizure decrease. In no patient there was a seizure worsening. Mild to moderate adverse events were present in four patients (22.2%), represented by weight loss, hypermenorrhoea, renal microlithiasis, nervousness and dysarthric speech. CONCLUSION TPM may be a useful drug in patients with SMEI, being particularly effective against generalized tonic-clonic seizures. Further studies are needed to evaluate the early use of this drug in such a severe syndrome.

Seizure and EEG Patterns in Angelman's Syndrome

We studied the seizure and polygraphic patterns of 18 patients with Angelmans syndrome. All patients showed movement problems. Eleven patients were also reported to have long-lasting periods of jerky movements. The polygraphic recording showed a myoclonic status epilepticus in nine of them. Seven patients had partial seizures with eye deviation and vomiting, similar to those of childhood occipital epilepsies. These seizures and electroencephalographic patterns suggest that Angelmans syndrome occurs in most of the patients as a nonprogressive, age-dependent myoclonic encephalopathy with a prominent occipital involvement. These findings indicate that, whereas ataxia is a constant symptom in Angelmans syndrome, the occurrence of a transient myoclonic status epilepticus may account for the recurrence of different abnormal movements, namely the jerky ones. (J Child Neurol 1995;10:467-471).

PRRT2 Mutations are the major cause of benign familial infantile seizures

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late‐onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone. Hum Mutat 33:1439–1443, 2012.

Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance

To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal‐infantile seizures (BFNIS), and benign familial infantile seizures (BFIS).

Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences

Heterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.

A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons syndrome)

Objective: Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure‐induced EEG paroxysms, and photosensitivity. We conducted an open‐label trial of levetiracetam in EMA.

Lacosamide in pediatric and adult patients: comparison of efficacy and safety.

PURPOSE This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy. METHOD This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months. RESULTS A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B. CONCLUSION Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.

Impact of Idiopathic Epilepsy on Mothers and Fathers: Strain, Burden of Care, Worries and Perception of Vulnerability

The purpose of the study was to examine the impact of idiopathic epilepsy on mothers and fathers in terms of strain, burden of care, worries and perception of vulnerability. Data were collected and analyzed shortly after the diagnosis (T0) and 12 months later (T1).