Longitudinal assessments in discordant twins with SMA.

We report longitudinal clinical and neurophysiological assessments in twins affected by spinal muscular atrophy (SMA) with discordant phenotypes. The boy had the homozygous deletion of SMN1, a typical type 1 SMA course, and died at the age of eight months. His twin sister, asymptomatic at the time of the diagnosis in her brother, had the same genetic defect but she developed clinical and electrophysiological signs of type 2 SMA. The reduction of tendon reflexes was the first clinical sign at the age of 4 months, followed within few weeks, by a mild decrement in the amplitude of the compound motor action potentials. After the age of 9 months, she showed a sudden clinical and electrophysiological deterioration. Among molecular tests, we determined SMN2 copy number, SMN2 and Plastin 3 transcript levels in peripheral blood, and observed no relevant differences between twins.

6MWT can identify type 3 SMA patients with neuromuscular junction dysfunction.

The aim of the study was to establish if the decrease in gait velocity on the 6 minute walk test relates to signs of neuromuscular junction dysfunction in spinal muscular atrophy type 3 patients. 6 minute walk test and low-rate repetitive nerve stimulation test were performed in fifteen ambulant patients with spinal muscular atrophy type 3 of age between 9 and 66 years. The 6 minute walk distance ranged between 66 and 575 m. The difference between the first and the 6th minute ranged between 0 and -69%. The low-rate repetitive nerve stimulation test measured in % of loss ranged between -31.7% to +4.2% to the axillary nerve. The correlation between 6 minute walk test changes and low-rate repetitive nerve stimulation test changes was 0.86. Our data suggest that the 6 minute walk test can identify fatigue in the ambulant type 3 patients who have a concurrent neuromuscular junction dysfunction. The identification of fatigue with a simple clinical test may help to target patients who may benefit from drugs that facilitate neuromuscular transmission.

Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study.

OBJECTIVE: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. METHODS: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. RESULTS: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. SIGNIFICANCE: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.

Cognitive-behavioral profiles in teenagers with Dravet syndrome.

AIM: To investigate behavior and cognitive performances of teenage patients with Dravet syndrome (DS). METHODS: We enrolled 20 teenage patients (12 females and 8 males) with DS, followed in the Child Neurology Unit of the Catholic University (Rome). Patients underwent a full clinical examination including behavioral and cognitive assessments (respectively, CBCL and Wechsler scales). RESULTS: All patients showed behavior disorders and mental retardation, mild in six cases, moderate in seven and severe in the remaining seven. Among mildly retarded patients visual function, particularly visuo-motor abilities resulted mostly impaired in Wechsler subtests, whereas verbal skills were relatively preserved. In contrast, a general cognitive impairment was observed in moderately and severely retarded patients. CONCLUSIONS: Our teenage patients with DS compared with other series at different ages (young childhood, adulthood) suggest a progressivity of neurological and neuropsychological signs. A visuomotor default and a relative preservation of verbal skills, like what has been found in previous reports of younger patients, are still evident in mildly impaired cases. Therefore, the progression over time of these cases toward a generalized impairment may be suggested, but only longitudinal studies can confirm it. There was a possible responsibility of some epileptic disorders in worsening the neuropsychological outcome (early myoclonic seizures and atypical absences, as well as persistent EEG background slowness in the last 3years).

Sleep-potentiated epileptiform activity in early thalamic injuries: Study in a large series (60 cases).

OBJECTIVE: The study aims at a better definition of continuous spike-waves during sleep (CSWS) with an early thalamic lesion, focusing on various grades of sleep-potentiated epileptiform activity (SPEA). Their possible relationship with different clinical features was studied to try to define prognostic factors of the epileptic disorder, especially relating to behavior/cognitive outcome, in order to improve prevention and treatment strategies. METHODS: Sixty patients with early thalamic injury were followed since the first registration of SPEA with serial neurological, long term EEG monitoring and neuropsychological examinations, as well as neuroimaging and a detailed clinical history. They were classified in three different groups according to the sleep spike-waves (SW) quantification: electrical status epilepticus during sleep (ESES), more than 85% of slow sleep; overactivation between 50% and 85% and simple activation between 10 and 50%). Results were then examined also with a statistical analysis. RESULTS: In our series of CSWS occurring in early brain injured children with unilateral thalamic involvement there is a common neuropathologic origin but with various grades of SPEA severity. Statistical analysis showed that patients evolving toward ESES presented more commonly the involvement of the mediodorsal part of thalamus nuclei and a bilateral cortico-subcortical brain injury, epilepsy was more severe with a delayed onset; moreover, in the acute stage .ESES patients presented the worst behavior/cognitive performances. As to cognitive and behavior outcome, longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase appear linked to a poor outcome; some particular neuropathology (ischemic stroke and haemorrhagic infarction) as well as hydrocephalus shunting are associated with behavior disorders. CONCLUSIONS: Discrete features seem to support different underlying mechanisms in ESES patients in comparison with less severe SPEA; they represent negative prognostic factors. Longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase seem predictive of a worse cognitive/behavior outcome.

Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder.

OBJECTIVE: Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K(+) /H(+) exchange and in Ca(2+) homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. METHODS: Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1. RESULTS: Three unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1. SIGNIFICANCE: We consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Cognitive decline in Dravet syndrome: is there a cerebellar role?

PURPOSE: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern. METHODS: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills. RESULTS: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders. CUNCLUSIONS: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies.

Posterior resection for childhood lesional epilepsy: neuropsychological evolution.

The aim of this study was to provide information on the neuropsychological evolution of children with symptomatic epilepsy who have undergone surgical resection of posterior (occipitoparietal) lesions. Twelve children with epilepsy with parietal and/or occipital lesions were enrolled in the study and followed after surgical resection: full clinical and epileptic examinations were performed before and after surgery, as was a neuropsychological study of both general and specific cognitive abilities. Epilepsy evolution was generally good (Engel classification IA in nine cases) with persistent selective neurological impairments (eye field defects, sensory unilateral spatial neglect) in some cases, consistent with the lesion site. Neuropsychological defects before surgery in the absence of refractory epilepsy were minimal with a normal global cognitive competence; yet, the relatively low performance scores with some impairment of specific cognitive skills were strictly correlated with defects in visual perceptive skills in both right- and left-sided lesions. Surgery seems to have improved performance abilities, whereas other abnormal specific skills did not change with the exception of working memory that in some cases was defective before surgery and normalized after lesion removal. Our study in this particular cohort of children with epileptogenic occipitoparietal lesions thus confirmed a trend toward a benign epileptic and neurodevelopmental outcome after surgical resection of the lesion.