Anti-N-methyl-d-aspartate receptor encephalitis is a central nervous system inflammatory autoimmune disease affecting adults and children. The use of first- and second-line immunotherapies is ...supported. Recent reports suggest the efficacy of bortezomib in severe anti-N-methyl-d-aspartate encephalitis in adult patients not responsive to second-line treatment; there are no data about pediatric patients.
We describe an eight-year-old child with anti-N-methyl-d-aspartate encephalitis not responsive to first- and second-line treatments who experienced marked clinical improvement after bortezomib administration.
Bortezomib is a selective and reversible inhibitor of the 26S proteasome, which is used to treat oncologic and rare autoimmune disorders in pediatric patients. As observed in adult patients, bortezomib administration induced anti-N-methyl-d-aspartate antibody titer decline and clinical improvement with an acceptable risk profile.
This is the first report of the use of bortezomib in children with anti-N-methyl-d-aspartate encephalitis; it could be a useful therapeutic option in children with refractory anti-N-methyl-d-aspartate encephalitis.
Magnetic resonance-guided laser interstitial thermal therapy (MR-gLiTT) is a novel minimally invasive treatment approach for drug-resistant focal epilepsy and brain tumors. Using thermal ablation ...induced by a laser diode implanted intracranially in a stereotactic manner, the technique is highly effective and safe, reducing the risk associated with more traditional open surgical approaches that could lead to increased neurological morbidity. Indications for MR-gLiTT in pediatric epilepsy surgery include hypothalamic hamartoma, tuberous sclerosis complex, cavernoma-related epilepsy, SEEG-guided seizure onset zone ablation, corpus callosotomy, periventricular nodular heterotopia, mesial temporal lobe epilepsy, and insular epilepsy. We review the available literature on the topic and present our series of patients with drug-resistant epilepsy treated by MR-gLiTT. Our experience, represented by six cases of hypothalamic hamartomas, one case of tuberous sclerosis, and one case of dysembryoplastic neuroepithelial tumor, helps to confirm that MR-gLiTT is a highly safe and effective procedure for several epilepsy conditions in children.
GLUT1 deficiency syndrome is a rare, genetically determined neurological disorder for which Ketogenic Dietary Treatment represents the gold standard and lifelong treatment. Patient registries are ...powerful tools providing insights and real-world data on rare diseases.
To describe the implementation of a national web-based registry for GLUT1-DS.
This is a retrospective and prospective, multicenter, observational registry developed in collaboration with the Italian GLUT1-DS association and based on an innovative, flexible and configurable cloud computing technology platform, structured according to the most rigorous requirements for the management of patient's sensitive data. The Glut1 Registry collects baseline and follow-up data on the patient's demographics, history, symptoms, genotype, clinical, and instrumental evaluations and therapies.
Five Centers in Italy joined the registry, and two more Centers are currently joining. In the first two years of running, data from 67 patients (40 females and 27 males) have been collected. Age at symptom onset was within the first year of life in most (40, 60%) patients. The diagnosis was formulated in infancy in almost half of the cases (34, 51%). Symptoms at onset were mainly paroxysmal (mostly epileptic seizure and paroxysmal ocular movement disorder) or mixed paroxysmal and fixed symptoms (mostly psychomotor delay). Most patients (53, 79%) are currently under Ketogenic dietary treatments.
We describe the principles behind the design, development, and deployment of the web-based nationwide GLUT1-DS registry. It represents a stepping stone towards a more comprehensive understanding of the disease from onset to adulthood. It also represents a virtuous model from a technical, legal, and organizational point of view, thus representing a possible paradigmatic example for other rare disease registry implementation.
Pathogenic variants in the dynamin 1 like gene are related to abnormal mitochondrial dynamics and distributions and are associated to variable clinical phenotypes. A few patients harboring the ...p.Arg403Cys missense variant appears to be different from the classical, more severe phenotypes, showing sudden onset of drug resistant seizures after a previously normal or slightly delayed development.
We report on a boy with abrupt onset of focal status and coma at the age of 13, initially treated as autoimmune encephalitis, with final diagnosis of de novo missense p.Arg403Cys variant in the DNM1L gene.
We compare his clinical, electrophysiological, biochemical, neuroradiological and histopathological picture to the rare cases reported to date and provide diagnostic clues that can help clinicians in differentiate p.Arg403Cys-related phenotype from that of immune-mediated encephalopathies.
The clinical picture related to p.Arg403Cys mutations should be considered alongside acquired pathologies in the differential diagnosis of young patients with focal refractory epilepsy and encephalopathy, also occurring during late childhood or adolescence. Prompt genetic testing allows to avoid unnecessary treatments and procedures and to better define the prognosis and management strategies.
Heterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 ...protein, an essential subunit of the DNA-dependent RNA polymerase II.
We investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks.
This case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.
Abstract
Background
Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) ...is a neurodegenerative condition caused by biallelic
TPP1
variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies.
Methods
This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age.
Results
The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in
TPP1
was identified, leading to a CLN2 diagnosis. Three pathogenic variants in
MECP2
were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects.
Conclusions
Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.
Pallister-Killian syndrome (PKS) is a rare genetic disorder with multi-organ involvement caused by mosaic tetrasomy of chromosome 12p. Although many caregivers report the presence of impaired sleep ...in their children, there are no clear data in the literature on this issue and no systematic study has ever been performed. With this study, we aimed to characterize the features of sleep in Pallister-Killian syndrome and identify the possible influence of clinical and demographic features. Moreover, our aim was to verify the effectiveness of conventional screening questionnaires in this particular group of patients.
We prospectively enrolled 14 patients aged 1-17 years in collaboration with PKS Kids Italia ONLUS. The Sleep Disturbance Scale for Children (SDSC) questionnaire was administered to caregivers. Then, video polysomnography (VPSG) of at least 24 h was performed and results were compared with a same-aged control group.
A total of 92% of patients had abnormal SDSC scores, extremely high in the "disorder of initiating and maintaining sleep" (DIMS) and "sleep breathing disorders" (SBD) subscales. VPSG showed a significantly impaired macrostructure in PKS patients, with a higher Arousal Index (
< 0.00001) and percentage of time spent in N3 (
< 0.00001), and reduced Sleep Efficiency (
= 0.0006). After dividing both PKS and controls into two groups based on median age, some peculiarities emerged: the younger group had higher Awakenings Index (
= 0.0207) and percentage of time spent in N1 (
= 0.015) while the older group showed higher time in bed (TIB) (
= 0.0485), compared with controls. Due to poor compliance, the Apnea-Hypopnea Index (AHI) was evaluated only for 10 PKS children, being significantly increased (
= 0.0427) compared with controls. SBD subscale scores in SDSC were significantly related to AHI values in VPSG (
= 0.0099).
This study constitutes the first attempt to describe the sleep pattern in PKS. Despite small numbers due to the rarity of the syndrome, our VPSG results confirm the high prevalence of sleep disorders (SDs) in these patients. It is therefore essential to investigate and treat them. The SDSC scale is a good screening tool for early detection also in these patients, with particular sensitivity in detecting breathing disorders.
Developmental delay and intellectual disability are two pivotal elements of the phenotype of Pallister-Killian Syndrome (PKS). Our study aims to define the cognitive, adaptive, behavioral, and ...sensory profile of these patients and to evaluate possible correlations between the different aspects investigated and with the main clinical and demographic variables.
Individuals of any age with genetically confirmed PKS were recruited. Those ≤ 42 months were administered the Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III), and those > 42 months the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II). Stereotyped behaviors (Stereotypy Severity Scale, SSS) and aggressive behaviors (Behavior Problems Inventory-Short Version, BPIs) were assessed in all subjects > 1 year; sensory profile (Child Sensory Profile 2, C-SP2) in all aged 2-18 years.
Twenty-two subjects were enrolled (11 F/11 M; age 9 months to 28 years). All subjects ≤ 42 months had psychomotor developmental delay. Of the subjects > 42 months, 15 had low IQ deviation, and 1 in the normal range. Stereotypies were frequent (median SSS-total score 25/68). Lower Vineland-II values corresponded to greater intensity and frequency of stereotypies (
= 0.004 and
= 0.003), and self-injurious behaviors (
= 0.002 and
= 0.002). Patients with severe low vision had greater interference of stereotypies (
= 0.027), and frequency and severity of aggressive behaviors (
= 0.026;
= 0.032). The C-SP2, while not homogeneous across subjects, showed prevalence of low registration and sensory seeking profiles and hypersensitivity to tactile and auditory stimuli. Lower Vineland-II scores correlated with higher Registration scores (
= 0.041), while stereotypies were more frequent and severe in case of high auditory sensitivity (
= 0.019;
= 0.007). Finally, greater sleep impairment correlated with stereotypies and self-injurious behaviors, and lower Vineland-II scores.
The present study provides a further step in the investigation of the etiopathogenesis of the syndrome. Furthermore, these aspects could guide rehabilitation therapy through the identification of targeted protocols.
Schimke Immuno-Osseous Dysplasia (SIOD) is an autosomal recessive multisystem disorder caused by pathogenic variants in the gene SMARCAL1. The clinical picture is characterized by spondyloepiphyseal ...dysplasia resulting in growth failure, nephropathy and T-cell deficiency. Neurologic manifestations include microcephaly, cognitive impairment, migraine-like headaches and cerebrovascular manifestations such as cerebral atherosclerotic vascular disease and reversible cerebral vasoconstriction. The role of SMARCAL1 deficiency in non-vascular neurological complications is still under debate. Epilepsy has been reported in a few patients, even in the absence of brain abnormalities. Data regarding electroencephalographic (EEG) patterns in SIOD are scarce
We describe the clinical, neuroradiological and EEG findings in two unrelated patients with SIOD showing a peculiar pseudo-periodic EEG pattern apparently not related to the cerebrovascular complications, since it was recognized both before and after cerebrovascular events
Our observations support the hypothesis that SMARCAL1plays an important role in neurodevelopment and brain function and expand the spectrum of neurological abnormalities related to SIOD.
Epilepsy with continuous spike-waves during slow sleep syndrome (CSWSS) is characterized by various seizure types, a characteristic EEG pattern and neuropsychological disorders. The main purpose of ...this study was to evaluate the long-term outcome of CSWSS occurred in childhood and to evaluate the variables that could influence the quality of social adaptation and the personality profile.
This is a prospective study on 24 young adults with previous CSWSS (median age 24.5 yrs) who were enrolled between January and July 2011 at the G. Gaslini Children’s Hospital, Genoa, Italy. Patients were divided into two groups: twelve with previous spike-wave index (SWI > 85%) defined as typical CSWSS (T-CSWSS) and twelve with previous SWI = 50–85% defined as atypical CSWSS (A-CSWSS). All the subjects were submitted to Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Psychological General Well-Being Index (PGWBI), and to a structured interview.
A correlation was observed with the severity of EEG abnormalities expressed by the SWI and outcome. The T-CSWSS group showed a significantly lower perceived well-being. Similarly in the T-CSWSS group the percentage of MMPI-2 clinical scales with T-scores ≥65 was higher than in the A-CSWSS group. Finally, a significant lower schooling in the T-CSWSS group was observed.
There seem to be two forms of the same disease, with similar onset and clinical evolution but a different outcome regarding the social and psychological conditions. The outcome of the social adaptation and of the personality consciousness was related with the severity of the EEG abnormalities: more favorable in patients with less intense SWI activity (A-CSWSS) compared those with a more severe EEG impairment (T-CSWSS).
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