Anna Volzone

Familial periventricular heterotopia Missense and distal truncating mutations of the FLN1 gene

ObjectiveTo examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1 (FLN1) gene. BackgroundClassical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. MethodsClinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. ResultsIn Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. ConclusionMissense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria‐SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β‐sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X‐inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X‐inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non‐syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003

Generalized Epilepsy with Febrile Seizures Plus (GEFS+): Clinical Spectrum in Seven Italian Families Unrelated to SCN1A, SCN1B, and GABRG2 Gene Mutations

Summary:  Purpose: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations.

Association of adenosine deaminase polymorphism with mild mental retardation

The etiology of mild mental retardation remains undefined in about 60% of cases. Even though the causes of mild mental retardation are likely to be heterogeneous, the evidence for genetic involvement is increasing, along with the development of specific diagnostic techniques. To improve our understanding of the genetic basis of mild mental retardation, we explored the role of polymorphisms of adenosine deaminase, an enzyme that is supposed to act as a neuroregulatory protein. To this end, we conducted an association study comparing children with mild mental retardation of unknown origin with two groups of controls: (1) apparently healthy children and (2) children with moderate or severe mental retardation of known etiology. Overall, 338 participants were enrolled in the study. Cases (ie, 80 children) were more likely than controls (ie, 153 healthy children and 105 children with moderate or severe mental retardation) to have the low-activity ADA-Asn 8 (ADA1 *2) polymorphism (P < .05) and to present the ADA1 *2/ ADA2 *1 haplotype. No significant differences were found with respect to adenosine deaminase polymorphisms when comparing the group with moderate or severe mental retardation of known causes and healthy controls. In conclusion, our findings suggest a possible role for a low-activity genotype (ADA-8Asn) (ADA1 *2) of adenosine deaminase in the pathogenesis of mild mental retardation. (J Child Neurol 2006;21:753—756; DOI 10.2310/7010.2006.00180).

Nocturnal frontal lobe epilepsy in mucopolysaccharidosis

Nocturnal frontal lobe epilepsy (NFLE) is an epileptic syndrome that is primarily characterized by seizures with motor signs occurring almost exclusively during sleep. We describe 2 children with mucopolysaccharidosis (MPS) who were referred for significant sleep disturbance. Long term video-EEG monitoring (LT-VEEGM) demonstrated sleep-related hypermotor seizures consistent with NFLE. No case of sleep-related hypermotor seizures has ever been reported to date in MPS. However, differential diagnosis with parasomnias has been previously discussed. The high frequency of frontal lobe seizures causes sleep fragmentation, which may result in sleep disturbances observed in at least a small percentage of MPS patients. We suggest monitoring individuals with MPS using periodic LT-VEEGM, particularly when sleep disorder is present. Moreover, our cases confirm that NFLE in lysosomal storage diseases may occur, and this finding extends the etiologic spectrum of NFLE.

Educational, cognitive, behavioral and language development issues.

Publisher Summary Cerebral malformations are responsible for several developmental disabilities that are heterogeneous both in type and severity. Virtually any type of disorder—cognitive, motor, behavioral, speech, and language—can be present. The cognitive, language, and educational treatment for children affected by brain malformations is complex and requires a multidisciplinary approach. Treatment can range from therapy to management according the severity of the clinical picture and type of disorder. The current knowledge on treatment efficacy is still limited, although a lot of progress has been made. A better integration of a functional approach with up-to-date information on genetics and natural history may lead to the identification of undetected deficits that are known to be associated with a specific genetic disorder or malformation, possibly leading to earlier and better treatment. A correct analysis of the childs environment and the appropriate involvement of the family in sharing the therapeutic objectives are essential because the quality of life of both family and child represents the final goal of every rehabilitative process.

Association between D18S474 locus on chromosome 18q12 and idiopathic generalized epilepsy

Idiopathic generalized epilepsy is one of the most common forms of epilepsy. The aetiology of IGE is genetically determined, but the pattern of inheritance is still undefined. Recent studies in common IGE showed evidence for linkage on chromosome 18q12 at the D18S474 locus. The aim of our study was to compare the distribution of allelic variants of D18S474 locus in children affected by generalized tonic-clonic seizures and in healthy controls. We studied 295 children: 121 cases and 174 controls. We found that the D18S474(8) allele was significantly more frequent and D18S474(9) significantly less frequent in cases compared with controls (p<.001). In conclusions, our findings show the association between the D18S474 marker and IGE in which early onset GTCS represent the most prevalent seizure type.

Lack of Evidence for Association Between D2S124 and D2S111 Polymorphisms of the SCN2A Gene and Idiopathic Generalized Epilepsy With Generalized Tonic—Clonic Seizures

Idiopathic generalized epilepsy syndromes are generally considered as brain channelopathies due to alteration of several genes. The aim of our study was to compare the distribution of D2S124 and D2S111 genetic polymorphisms of the SCN2A gene between cases with a specific idiopathic generalized epilepsy subtype (with generalized tonic—clonic seizures) and healthy controls. Allele frequencies of both the D2S111 and the D2S124 polymorphisms were not significantly different between cases and control. Further studies are needed to investigate if possible polymorphic variants of SCN2A gene may influence seizures susceptibility of idiopathic generalized epilepsy with tonic—clonic seizures.

Electrical status epilepticus during sleep in Mowat–Wilson syndrome

AIM Mowat-Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70-75% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients. Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern). METHODS A retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study. RESULTS Five out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index>85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced. CONCLUSIONS The clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS.

Neuropsicologia delle encefalopatie epilettiche : analisi delle variabili più significative e descrizione della nostra esperienza con un gruppo pediatrico affetto da epilessia mioclono-astatica

Sono discussi i punti cruciali della clinica epilettologica e neuropsicologica delle encefalopatie epilettiche, con l’intento di documentare la relazione complessa e non sempre diretta che intercorre tra questi due livelli di osservazione in particolare riferimento all’outcome cognitivo. Segue la descrizione del profilo neuropsicologico del nostro campione clinico (n = 10), riguardo al quale possiamo dimostrare un andamento duplice, di tipo rispettivamente avverso o piu propizio in funzione della maggiore o minore frequenza delle manifestazioni elettrocliniche e della poli- o monoterapia. Il gruppo con outcome cognitivo piu favorevole (n = 7) documenta un’ampia variabilita dei risultati e si presenta mediamente con disabilita intellettiva lieve, difficolta grafomotorie e attenzione entro limiti di norma, in innesto a variabili psicopatologiche borderline tipo attenuazione del tono dell’umore e disattenzione-iperattivita. Poiche la storia clinica mette in evidenza che questi soggetti risultano essere quelli liberi da tempo da crisi e con non piu di due principi in terapia, le evidenze neuropsicologiche supportano dunque una relazione causale tra la malignita del quadro e l’outcome cognitivo.