Maria Luisa Lispi

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.

The ketogenic diet in children, adolescents and young adults with refractory epilepsy: An Italian multicentric experience

PURPOSE This collaborative study by three Italian groups of child neuropsychiatrists was carried on to evaluate the efficacy and safety of the classic 4:1 ketogenic diet as add-on treatment in refractory partial or generalized epilepsy in children, adolescents and young adults. METHODS We performed a prospective add-on study in 56 refractory epilepsy young patients (age 1-23 years, mean 10.4 years), all with both symptomatic and cryptogenic, generalized or partial epilepsies. Child neuropsychiatrists worked with nutritional team for sample selection and patients management. The ketogenic diet was added to the baseline antiepileptic drugs and the efficacy was rated according to seizure type and frequency. During treatment, seizure frequency, side effects, urine and blood ketone levels and other parameters were systematically evaluated. RESULTS Patients have been treated for 1-18 months (mean 5 months). A >50% reduction in seizure frequency was gained in 37.5 and 26.8% of patients after 3 and 6 months, respectively, at 12 months, this number fell by 8.9%. No significant relationship between diet efficacy and seizure or epilepsy type, age at diet onset, sex and etiology of epilepsy was noted. Nevertheless, it seems noteworthy that 64% of our patients with neuronal migration disorders improved on this diet. Adverse effects occurred, mainly in the first weeks of treatment, in 32 patients (57.1%), but were generally mild and transient. In seven patients (12.5%) it was possible to withdraw one to two AED after 3-4 months on ketogenic diet. CONCLUSION This initial experience with the ketogenic diet was effective in difficult-to-treat patients with partial and generalized epilepsies, though its efficacy dropped significantly by 9-12 months.

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.

A Novel SCN2A Mutation in Family with Benign Familial Infantile Seizures

Summary:  Benign familial infantile seizures (BFIS) is a clinical entity characterized by focal seizures with or without secondary generalization, occurring mostly in clusters, and usually first seen between 4 and 8 months of life. Psychomotor development is normal, and seizures usually resolve within the first year of life. BFIS is a genetically heterogenous condition with loci mapped to chromosomes 19 and 16. Mutations in the voltage‐gated sodium channel α2 subunit (SCN2A) gene on chromosome 2 were recently identified in families affected by neonatal and infantile seizures (benign familial neonatal–infantile seizures, BFNIS) with typical onset before 4 months of life. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS show overlapping clinical features.

Clinical and molecular findings in patients with giant axonal neuropathy (GAN)

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder of early onset, clinically characterized by a progressive involvement of both peripheral and CNS. The diagnosis is based on the presence of characteristic giant axons, filled with neurofilaments, on nerve biopsy. Recently, the defective protein, gigaxonin, has been identified and different pathogenic mutations in the gigaxonin gene have been reported as the underlying genetic defect. Gigaxonin, a member of the BTB/kelch superfamily proteins, seems to play a crucial role in the cross talk between the intermediate filaments and the membrane network. The authors report clinical and molecular findings in five Italian patients with GAN. This study shows the allelic heterogeneity of GAN and expands the spectrum of mutations in the GAN gene. The frequent occurrence of private mutations stresses the importance of a complete gene analysis.

Lack of SCN1A mutations in familial febrile seizures.

Summary:  Purpose: Mutations in the voltage‐gated sodium channel subunit gene SCN1A have been associated with febrile seizures (FSs) in autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) families and severe myoclonic epilepsy of infancy. The present study assessed the role of SCN1A in familial typical FSs.

Early onset benign occipital susceptibility syndrome: video-EEG documentation of an illustrative case

Early onset benign occipital susceptibility syndrome (EBOSS) is a recently delineated form of idiopathic childhood partial epilepsy, which is still not recognized by the International League Against Epilepsy as a distinct epileptic syndrome. It occurs with generally nocturnal, prolonged partial seizures, which can become a status epilepticus. The seizures are characterized by tonic eye deviation, vomiting, progressive impairment of consciousness, autonomic symptoms, frequent progression to hemiconvulsions or generalized tonic-clonic seizures. Age at onset is usually between 3 and 7 years, frequency is remarkably low (often a single seizure), and outcome is excellent. Interictal EEG shows occipital paroxysms with fixation-off sensitivity. We present the first video-EEG documentation of a typical case of EBOSS and discuss the clinical and EEG features of the case. The documentation is useful for a better definition of the syndrome and also permits a differential diagnosis with respect to other occipital forms of epilepsy and other sleep related paroxysmal disorders.

Linkage Analysis and Disease Models in Benign Familial Infantile Seizures: A Study of 16 Families

Summary:  Purpose: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12‐13.1 and 16p12‐q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis.

Functional and Gait Assessment in Children and Adolescents Affected by Friedreich's Ataxia: A One-Year Longitudinal Study.

Friedreich’s ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich’s ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich’s ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich’s ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs.

The impact of vision on the dynamic characteristics of the gait: strategies in children with blindness

Visually impaired persons present an atypical gait pattern characterized by slower walking speed, shorter stride length and longer time of stance. Three explanatory hypotheses have been advanced in the literature: balance deficit, lack of an anticipatory mechanisms and foot probing the ground. In the present study, we compared the three hypotheses by applying their predictions to gait analysis and posturography of blind children without neurological impairment and compared their performance with that of an age-matched control group. The gait analysis results documented that blind children presented reduced walking velocity and step length, increased step width and external rotation of the foot progression angle, reduced ground reaction force and ankle maximum angle, moment and power in late stance, increased head flexion, decreased thorax flexion and pelvis anteversion, compared with the control group. The posturographic analysis showed equal skill level between blind children and normally sighted children when they close their eyes. The results are consistent with only one of the three hypotheses: namely, they prove that blind children’s gait is influenced only by the absence of visually driven anticipatory control mechanisms. Finally, rehabilitative recommendations for children with blindness are advanced in discussion.