Antonino Romeo

Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy

Objectives: SCN1A mutations were recently reported in several patients with severe myoclonic epilepsy in infancy (SMEI). The authors analyzed SCN1A mutations in 93 patients with SMEI and made genotype-phenotype correlation to clarify the role of this gene in the etiology of SMEI. Methods: All patients fulfilled the criteria for SMEI. The authors analyzed all patients for SCN1A mutations using denaturing high performance liquid chromatography. If a patient’s chromatogram was abnormal, the authors sequenced the gene in the patient and both parents. Results: SCN1A mutations were identified in 33 patients (35%). Most mutations were de novo, but were inherited in three patients. Parents carrying the inherited mutations had either no symptoms or a milder form of epilepsy. A greater frequency of unilateral motor seizures was the only clinical difference between patients with SCN1A mutations and those without. Truncating mutations were more frequently associated with such seizures than were missense mutations. The percentage of cases with family history of epilepsy was significantly higher in patients with SCN1A mutations. Conclusions: Unilateral motor seizures may be a specific clinical characteristic of SMEI caused by SCN1A mutations. Ten percent of SCN1A mutations are inherited from an asymptomatic or mildly affected parent, suggesting that SMEI is genetically heterogeneous. The increased frequency of familial epilepsy indicates that other genetic factors may contribute to this disorder.

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).

Benign Familial Infantile Convulsions: Mapping of a Novel Locus on Chromosome 2q24 and Evidence for Genetic Heterogeneity

In 1997, a locus for benign familial infantile convulsions (BFIC) was mapped to chromosome 19q. Further data suggested that this locus is not involved in all families with BFIC. In the present report, we studied eight Italian families and mapped a novel BFIC locus within a 0.7-cM interval of chromosome 2q24, between markers D2S399 and D2S2330. A maximum multipoint HLOD score of 6.29 was obtained under the hypothesis of genetic heterogeneity. Furthermore, the clustering of chromosome 2q24-linked families in southern Italy may indicate a recent founder effect. In our series, 40% of the families are linked to neither chromosome 19q or 2q loci, suggesting that at least three loci are involved in BFIC. This finding is consistent with other autosomal dominant idiopathic epilepsies in which different genes were found to be implicated.

Eyelid myoclonia with absences (Jeavons syndrome): A well‐defined idiopathic generalized epilepsy syndrome or a spectrum of photosensitive conditions?

Eyelid myoclonia with absences (EMA), or Jeavons syndrome, is a generalized epileptic condition clinically characterized by eyelid myoclonia (EM) with or without absences, eye closure‐induced electroencephalography (EEG) paroxysms, and photosensitivity; in addition, rare tonic–clonic seizures may also occur. Although first described in 1977 and widely reported by several authors within the last few years, EMA has not been yet recognized as a definite epileptic syndrome. However, when strict criteria are applied to the diagnosis, EMA appears to be a distinctive condition that could be considered a myoclonic epileptic syndrome, with myoclonia limited to the eyelids, rather than an epileptic syndrome with absences.

Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations.

Summary:  Introduction: To determine the occurrence of neuroradiological abnormalities and to perform genotype–phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome).

STXBP1 encephalopathy A neurodevelopmental disorder including epilepsy

Objective: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. Methods: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. Results: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. Conclusion: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Recommendations for the management of febrile seizures : Ad hoc Task Force of LICE Guidelines Commission

Febrile seizures are the most common seizure disorder in childhood, affecting 2–5% of children. Simple febrile seizure is defined as a short (<15 min) generalized seizure, not recurring within 24 h, that occurs during a febrile illness not resulting from an acute disease of the nervous system in a child aged between 6 months and 5 years, with no neurologic deficits and no previous afebrile seizures. These recommendations address the instructions for management of the first febrile seizures, giving criteria for hospital admission, diagnosis, differential diagnosis, and treatment of a prolonged seizure. The authors stressed the benign prognosis of the majority of cases and the risk factors for recurrence of febrile seizures and appearance of epilepsy later on. Both continuous and intermittent anticonvulsant therapy are efficacious in preventing single febrile seizures, but side effects may be so important to overcome the benefits. These treatments are indicated in very selected patients.

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.

Past and present public knowledge and attitudes toward epilepsy in Italy.

A nationwide survey was performed in Italy to assess awareness and attitudes of the public about epilepsy. Knowledge about epilepsy, its clinical features, and attitudes towards its social/individual implications were tested in a telephone interview. Included were 819 women and 737 men aged 18+years. 93.4% declared they knew epilepsy, 56.6% knew a person with epilepsy, and 45.1% saw someone seizing. Only 29.2% gave an exact estimate of the prevalence of the disease. 50.4% were unaware of the causes, 56.1% indicated that epilepsy was a psychological/psychiatric disease, 36.5% a form of insanity, and 4.1% an evil spirit possession. Epilepsy was incurable according to 35.5%. Moderate-to-severe restrictions to driving, regular employment, military career, and leisure activities were suggested by 79.8, 57.0, 71.1, and 57.6%. Limitations included marriage and procreation for 46.2 and 38.7%. Knowledge and attitudes varied with education, age and gender. These findings are partly in keeping with other worldwide reports.