Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.

Glycopyrrolate for drooling in children with medical complexity under three years of age.

BACKGROUND: The aim of the study is to determine that Glycopirrolate is safe and effective in decreasing drooling in children with medical complexity under 3 years of age. Medical treatment is based on anticholinergic drugs as transdermal scopolamine, benzotropine and GLY. GLY (Glycopyrronium bromide) is a synthetic quaternary ammonium anticholinergic agent with poor blood-brain barrier penetration and consequently has limited central effects. Actually, the oral GLY formulation was approved by the United States Food and Drug Administration (FDA) to treat drooling in children aged 3-16 years. Five studies reported on GLY use for the treatment of drooling in children with cerebral palsy and other conditions with neurological impairment; four are prospective studies while one a retrospective review. METHODS: this is a case report of eighteen children (sex ratio 11/8, median age 17 months, range 2-36 months) under three years of age, followed by a multidisciplinary team at the Bambino Gesù Children Hospital. The median follow-up was of 31.5 months (range 1-69 months). Response to treatment was assessed according to the Drooling Impact Scale administered at time 0 and after 1 month. All patients have an important neurological impairment: nine patients have a cerebral palsy (Gross Motor Function Classification System class V) and nine a genetic/malformative syndrome. Twelve patients have a tracheostomy and two need mechanical ventilation. Gastrostomy is present in 16 out of 18 patients. All patients received Glycopirrolate. The median starting daily dose was 0.065 mg/kg/die (range 0.02-0.21 mg/kg/die) three times a day. The drooling impact scale was administered at time O and after 1 month. RESULTS: Four out 18 patients stopped treatment for adverse event, lack of efficacy or parental decision. The mean Drooling Impact Scale at time 0 was 89 (range 81-100) and after 1 month 61(range 43-78); the difference was statistically significant (P < 0.001). The overall response to treatment was 94%. CONCLUSIONS: This is the first study to determine the safety and effectiveness of Glycopyrrolate in decreasing drooling in a specific subset of patients. No major side effects were observed. Further comparative studies are needed to confirm our results.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Robotic Technology in Pediatric Neurorehabilitation. A Pilot Study of Human Factors in an Italian Pediatric Hospital.

The introduction of robotic neurorehabilitation among the most recent technologies in pediatrics represents a new opportunity to treat pediatric patients. This study aims at evaluating the response of physiotherapists, patients and their parents to this new technology. The study considered the outcomes of technological innovation in physiotherapists (perception of the workload, satisfaction), as well as that in patients and their parents (quality of life, expectations, satisfaction) by comparing the answers to subjective questionnaires of those who made use of the new technology with those who used the traditional therapy. A total of 12 workers, 46 patients and 47 parents were enrolled in the study. Significant differences were recorded in the total workload score of physiotherapists who use the robotic technology compared with the traditional therapy (p < 0.001). Patients reported a higher quality of life and satisfaction after the use of the robotic neurorehabilitation therapy. The parents of patients undergoing the robotic therapy have moderately higher expectations and satisfaction than those undergoing the traditional therapy. In this pilot study, the robotic neurorehabilitation technique involved a significant increase in the patients' and parents' expectations. As it frequently happens in the introduction of new technologies, physiotherapists perceived a greater workload. Further studies are needed to verify the results achieved.

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine.

OBJECTIVE: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms. METHODS: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families. RESULTS: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family. CONCLUSION: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.

Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.

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.

The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.

Neuropsychological development in children with Dravet syndrome.

PURPOSE: Aim of this study is to report a detailed profile of neuropsychological development in children with Dravet syndrome. METHODS: Twelve children with Dravet syndrome were longitudinally assessed using a detailed clinical and neuropsychological evaluation. Six had typical features of severe myoclonic epilepsy in infancy (SMEI) whereas the other six resulted borderline. All twelve underwent serial neuropsychological assessments with neurodevelopmental scales and further assessment of specific cognitive abilities. RESULTS: Our results reported an apparent normal development before disease onset, a general evolution in two main stages, more active the first one and with a general trend towards a clinical stabilization afterwards. The onset of cognitive decline was generally later than what is reported in other series; furthermore, the impairment of cognitive development is less severe, especially in borderline cases. As to specific cognitive competence, attention, visual motor integration, visual perception as well as executive functions are the most impaired abilities; language appears less involved, with a predominance of phonological defects. CONCLUSIONS: In our cohort the global development of patients appear less affected than in previous studies. Furthermore, our study points out an impairment of several specific cognitive skills even in patients with a developmental quotient apparently in the normal range. Language and other cognitive skill impairment such as attention, visuo-spatial organization, working memory and executive function appear consistent with what is usually found in cerebellar disorders.

Surgery of children with frontal lobe lesional epilepsy: neuropsychological study.

AIM OF THE STUDY: was to provide new data about the evolution of neuropsychological findings in patients with lesional frontal lobe epilepsy (FLE) operated on with lesion excision. PATIENTS AND METHODS: Twelve patients with lesional FLE underwent full clinical examination including neurological, neuropsychological and developmental assessments, high-resolution magnetic resonance imaging (MRI), ictal and interictal prolonged EEG monitoring and evaluation of seizure semeiology before and after surgery. The mean follow-up duration was 2 years and 10 months (range=14 months-7 years). Another group of lesional temporal lobe epilepsy, matched for the age at surgery and side of surgery, was likewise studied in order to compare neuropsychological patterns and to try to find out specific features in frontal lobe epilepsy evolution. RESULTS: All patients resulted seizure free at outcome except one belonging to Engel's class II. Before surgery general intelligence was similar in FLE as well as in TLE group. Executive functions and motor coordination were frequently affected in FLE whereas patients with TLE often presented with deficits in naming, visual memory and visuo-spatial attention. After surgery there was a frequent decline of IQ in FLE group together with a slight deterioration, especially of executive functions in some patients. An improvement of behaviour was often observed in both groups. CONCLUSIONS: As already reported in literature, neuropsychological pre-surgical data confirms the involvement of attention and executive functions in lesional FLE. No significant neuropsychological improvement was produced by surgery that determined in some cases a slight decline of general intelligence and specific frontal abilities. Yet, generally behaviour improved and seizures were controlled.

Early development in Dravet syndrome; visual function impairment precedes cognitive decline.

Aim of the study was to describe prospectively the early neuropsychological evolution including the first pre-cognitive stages of the Severe Myoclonic Epilepsy in Infancy (SMEI) or Dravet syndrome. Five cases, four of whom since before a diagnostic evidence of the Dravet syndrome, were followed up. Full clinical assessment including developmental, visual function and behaviour assessments were serially performed. In four cases, a variable onset age of cognitive decline assessed with developmental scales was preceded some months before by an impairment of visual function; the remaining patient during all the course of follow-up till 51 months of age showed a normal development without visual impairment. A cognitive decline with variable onset was generally confirmed in Dravet syndrome. The previous early impairment of visual function seems to herald the cognitive decline and provides useful prognostic information; furthermore, it possibly suggests some clues for a better understanding of the mechanisms of cognitive deterioration in this syndrome.

Visual and visuoperceptual function in children with Panayiotopoulos syndrome.

PURPOSE: The aim of this study was to assess behavioral aspects of visual function and visuoperceptual abilities in patients with Panayiotopoulos syndrome (PS), and their possible associations with clinical and electroencephalography (EEG) findings in order to establish the possible effect of interictal paroxysmal activity on visual performance. METHODS: The cohort included 28 patients (14 male and 14 female) of ages ranging between 4 and 15 years. All patients underwent serial videopolygraphic studies and a detailed battery of tests assessing visual abilities, including assessment of acuity, stereopsis, visual fields, and visuoperceptual abilities; tests included the Movement Assessment Battery for Children, the Visuo Motor Integration tests, and evaluation of motion and form coherence threshold. RESULTS: On the assessment of visual function, only 4 of the 28 (15%) had abnormal crowding acuity and one had abnormal stereopsis. On the visuoperceptual assessment, one patient had abnormal results on the Visuo Motor Integration tests, and one on the Movement Assessment Battery for Children, whereas 4 (15%) had abnormal results for form coherence threshold and one for motion threshold. DISCUSSION: Our results suggest that, although most of our patients had focal or diffuse EEG abnormalities involving the occipital regions, abnormalities of visual and visuoperceptual function were relatively uncommon. Age at onset of seizure <5 years and EEG activation to eye closure and during sleep can be considered as factors that slightly increased the risk for developing visual abnormalities. Their presence, however, was not always associated with abnormal visual findings.

Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case.

The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1-26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.

Early thalamic injury associated with epilepsy and continuous spike-wave during slow sleep.

PURPOSE: Mechanisms inducing continuous spike-wave during slow sleep (CSWS) in encephalopathy with electrical status epilepticus during sleep are still unclear. Recently, some sporadic cases with early thalamic injury associated with CSWS have been reported. The aim of the study was to investigate in a population of patients with an early thalamic injury the presence of an activation of paroxysmal activities during sleep, their characteristics, and possible relations to neuroimaging and neuropsychological features. METHODS: Thirty-two patients with prenatal or perinatal thalamic injuries, mostly due to a vascular mechanisms, were fully examined, including neuroimaging, EEG monitoring, and cognitive follow-up. RESULTS AND CONCLUSIONS: Twenty-nine of 32 patients showed major sleep EEG activation. Among these 29 patients, two different groups were distinguished: the first included the more or less typical CSWS (12 cases), generally with symmetry of spike and waves (SWs) and often with no spindle at all. The other cases had an usual asymmetry of SWs and presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of SWs. Behavioral disorders were significantly more present in patients with a true CSWS; their improvement (and in one case of the three thoroughly followed the improvement of cognitive competence) paralleled the disappearance of CSWS. The generally predominant injury of the lateral aspect of the thalamus included reticular nucleus and ventral nuclei. An imbalance of gamma-aminobutyric acid (GABA)(B)--versus GABA(A)--mediated receptors may be evoked as a cofactor predisposing to CSWS.

Electroclinical patterns and evolution of epilepsy in the 4p- syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p- syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS. METHODS: Ten patients (five boys and five girls) underwent a detailed clinical assessment and a prolonged EEG study. Six of the 10 also had video-polygraphy. RESULTS: Nine of the 10 patients had seizures; they were generalized or unilateral clonic and tonic-clonic, and atypical absences associated with myoclonic jerks. Age at onset of seizures varied from 1 day to 2.5 years. In all the patients, including the only one without seizures, two stereotyped EEG patterns were observed, consisting of (a) bursts of rhythmic (3-5 Hz), high-voltage slow waves located in the posterior regions and increased by sleep, or bursts of rapid spike-wave complexes in the centroparietal and parietooccipital regions; and (b) repetitive rapid posterior spikes. Sleep organization was constantly absent or very poor. The evolution of epilepsy was frequently good, with four seizure-free cases at the end of follow-up, two of them weaned from antiepileptic drugs (AEDs). CONCLUSIONS: Seizure onset in WHS also can occur at neonatal age. At least two electrical stereotyped patterns of the epileptic disorder are associated with a relevant disorganization of the sleep states. Prognosis of epilepsy is generally good both for the seizure control and for its evolution.

Epileptic negative myoclonus in a newborn with hemimegalencephaly.

PURPOSE: We report the case of a male newborn with Ohtahara syndrome and right hemimegalencephaly who presented epileptic negative myoclonus in the first days of life. METHODS: Prolonged polygraphic studies were performed, as well as MRI and a full clinical examination. RESULTS: EEG showed a constant and nonreactive pattern of burst suppression. There were several kinds of electro-clinical seizures (generalized myoclonia, short atonias, typical spasm and tonic spasms) at the beginning of the EEG's burst. The periods of EMG silence, lasting less than 300 ms, were associated with stereotyped EEG transients. CONCLUSIONS: Epileptic negative myoclonus can be observed also in neonatal age. The short transient impairment of motor function observed in the newborn seems linked to the slow component of spike-wave discharge, but its mechanism is still not clear.