Early-onset dysphagia and severe neurodevelopmental disorder as early signs in a patient with two novel variants in NARS1: a case report and brief review of the literature.

Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.

Genetic Epilepsies and Developmental Epileptic Encephalopathies with Early Onset: A Multicenter Study.

The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children's Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

Severe Neurodevelopmental Disorder in Autosomal Recessive Spinocerebellar Ataxia 13 (SCAR13) Caused by Two Novel Frameshift Variants in GRM1.

Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is a neurological disease characterized by psychomotor delay, mild to profound intellectual disability with poor or absent language, nystagmus, stance ataxia, and, if walking is acquired, gait ataxia. Epilepsy and polyneuropathy have also been documented in some patients. Cerebellar atrophy and/or ventriculomegaly may be present on brain MRI. SCAR13 is caused by pathogenic variants in the GRM1 gene encoding the metabotropic receptor of glutamate type 1 (mGlur1), which is highly expressed in Purkinje cerebellar cells, where it plays a fundamental role in cerebellar development. Here we discuss the case of an 8-year-old patient who presented with a severe neurodevelopmental disorder with balance disturbance, absence of independent walking, absence of language, diffuse hypotonia, mild nystagmus, and mild dysphagia. Whole-exome sequencing revealed a compound heterozygosity for two likely pathogenic variants in the GRM1 gene, responsible for the patient's phenotype, and made it possible to diagnose autosomal recessive spinocerebellar ataxia SCAR13. The detected (novel) variants appear to be causative of a particularly severe picture with regard to neurodevelopment, in the context of the typical neurological signs of spinocerebellar ataxia.

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism.

Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10-15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

Novel CTNNB1 variant leading to neurodevelopmental disorder with spastic diplegia and visual defects plus peripheral neuropathy: A case report.

Pathogenic variants in the ß1-catenin (CTNNB1) gene have been identified in patients with various diseases, including syndromic intellectual disability, autism spectrum disorder, familial exudative vitreoretinopathy, and neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). We report on the clinical, genetic, neuroimaging, and neurophysiological data of a 15-year-old patient with complex hereditary spastic paraplegias with exotropia, dyskinesia, and cerebellar signs and a so-far unreported demyelinating (mainly sensory) polyneuropathy in her lower limbs. She carries the novel, de novo, likely pathogenic heterozygous c.603_605delinsAATA, p.(Met202Ilefs*6) frameshift variant in the CTNNB1 gene. Although peripheral neuropathy was not previously associated with NEDSDV, in light of the role of ß1-catenin as a junction protein in the peripheral as well as in the central nervous system documented in experimental studies, it might represent a causally linked and under-reported finding to be further explored.

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review.

Despite expanding next generation sequencing technologies and increasing clinical interest into complex neurologic phenotypes associating epilepsies and developmental/epileptic encephalopathies (DE/EE) with movement disorders (MD), these monogenic conditions have been less extensively investigated in the neonatal period compared to infancy. We reviewed the medical literature in the study period 2000-2020 to report on monogenic conditions characterized by neonatal onset epilepsy and/or DE/EE and development of an MD, and described their electroclinical, genetic and neuroimaging spectra. In accordance with a PRISMA statement, we created a data collection sheet and a protocol specifying inclusion and exclusion criteria. A total of 28 different genes (from 49 papers) leading to neonatal-onset DE/EE with multiple seizure types, mainly featuring tonic and myoclonic, but also focal motor seizures and a hyperkinetic MD in 89% of conditions, with neonatal onset in 22%, were identified. Neonatal seizure semiology, or MD age of onset, were not always available. The rate of hypokinetic MD was low, and was described from the neonatal period only, with WW domain containing oxidoreductase (WWOX) pathogenic variants. The outcome is characterized by high rates of associated neurodevelopmental disorders and microcephaly. Brain MRI findings are either normal or nonspecific in most conditions, but serial imaging can be necessary in order to detect progressive abnormalities. We found high genetic heterogeneity and low numbers of described patients. Neurological phenotypes are complex, reflecting the involvement of genes necessary for early brain development. Future studies should focus on accurate neonatal epileptic phenotyping, and detailed description of semiology and time-course, of the associated MD, especially for the rarest conditions.

Severe intellectual disability, absence of language, epilepsy, microcephaly and progressive cerebellar atrophy related to the recurrent de novo variant p.(P139L) of the CAMK2B gene: A case report and brief review.

The CAMK2B gene encodes the ß-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p.(P139L). This case report describes a 22-year-old patient with this recurrent variant, who presents with severe intellectual disability, absence of language, hypotonia, microcephaly, dysmorphic features, epilepsy, behavioral abnormalities, motor stereotypies, optic atrophy, and progressive cerebellar atrophy. Notably, this patient is the oldest reported so far and allows us to better delineate the clinical phenotype associated with this variant, adding clinical aspects never described before, such as epilepsy, optic atrophy, scoliosis, and neuroradiological changes characterized by progressive cerebellar atrophy.

EEG Monitoring of the Epileptic Newborn.

PURPOSE OF REVIEW: Although differentiating neonatal-onset epilepsies from acute symptomatic neonatal seizures has been increasingly recognized as crucial, existing guidelines, and recommendations on EEG monitoring are mainly based on acute symptomatic seizures, especially secondary to hypoxic-ischemic encephalopathy. We aimed to narratively review current knowledge on neonatal-onset epilepsies of genetic, metabolic, and structural non-acquired origin, with special emphasis on EEG features and monitoring. RECENT FINDINGS: A wide range of rare conditions are increasingly described, reducing undiagnosed cases. Although distinguishing features are identifiable in some, how to best monitor and detect less described etiologies is still an issue. A comprehensive approach considering onset, seizure evolution, ictal semiology, clinical, laboratory, EEG, and neuroimaging data is key to diagnosis. Phenotypic variability prevents precise recommendations, but a solid, consistent method moving from existing published guidelines helps in correctly assessing these newborns in order to provide better care, especially in view of expanding precision therapies.

Linking acute symptomatic neonatal seizures, brain injury and outcome in preterm infants.

Neonatal seizures (NS) are the most frequent sign of neurological dysfunction in newborn infants. With increased survival of preterm neonates, the current clinical focus has shifted from preventing death to improving long-term neurological outcome. In the context of acute symptomatic NS, the main negative prognostic factors include etiology, and severity of brain injury, but also prolonged seizures and especially status epilepticus. However, the reasons for the detrimental contribution of seizures to outcome are still unclear, and evidence has been collected both in favor of seizures being an epiphenomenon of brain injury and of independently contributing to further damage. In this narrative focused review, we will discuss both hypotheses, with special emphasis on data relating to preterm infants. We will also identify present controversies and possible future lines of research.

Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study.

AIM: To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit. METHOD: We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]). RESULTS: Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes. INTERPRETATION: We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations. WHAT THIS PAPER ADDS: A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

"Minimal" holoprosencephaly in a 14q deletion syndrome patient.

We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the most common forms and the new forms of holoprosencephaly recently described is also discussed and leads us to suggest classifying the interhemispheric fusion of this case as a "minimal" form of holoprosencephaly. This appears to be the first description in a 14q deletion patient.

Reflex Myoclonic Epilepsy of Infancy: Seizures Induced by Tactile Stimulation.

Myoclonic epilepsy with reflex seizures in infancy is an extremely rare condition, in which seizures are provoked mainly by auditory or auditory-tactile stimuli. To increase the awareness of pediatricians regarding this underrecognized condition, we describe a child with seizures provoked only by the tactile stimulation of specific areas of the head and face.

Neonatal Seizures: A Review of Outcomes and Outcome Predictors.

The majority of neonatal seizures are of acute symptomatic origin, and their occurrence is associated with higher mortality and morbidity compared with the general population, even if there is conflicting evidence of a detrimental effect per se. Etiology is considered the main determinant of outcome, but other factors, including gestational age, brain damage severity, neonatal neurological examination, and electroencephalographically (EEG) interictal and ictal characteristics are also related to neurodevelopmental outcome or death. Therefore, accuracy in early prognostication since the neonatal period can be improved by conveniently integrating different clinical and instrumental findings.The aim of this review is first to review the outcome of newborns with seizures (mortality, epilepsy, cerebral palsy, and intellectual disability), second to review the risk factors for adverse outcome after seizures in the newborn period, considering clinical, EEG/amplitude-integrated EEG, and neuroimaging findings associated with adverse outcome and lack of response to treatment, and finally to review published scoring systems for predicting neurologic outcome after neonatal seizures.

Phenobarbital for Neonatal Seizures: Response Rate and Predictors of Refractoriness.

Background Phenobarbital is the first-line choice for neonatal seizures treatment, despite a response rate of approximately 45%. Failure to respond to acute anticonvulsants is associated with poor neurodevelopmental outcome, but knowledge on predictors of refractoriness is limited. Objective To quantify response rate to phenobarbital and to establish variables predictive of its lack of efficacy. Methods We retrospectively evaluated newborns with electrographically confirmed neonatal seizures admitted between January 1999 and December 2012 to the neonatal intensive care unit of Parma University Hospital (Italy), excluding neonates with status epilepticus. Response was categorized as complete (cessation of clinical and electrographic seizures after phenobarbital administration), partial (reduction but not cessation of electrographic seizures with the first bolus, response to the second bolus), or absent (no response after the second bolus). Multivariate analysis was used to identify independent predictors of refractoriness. Results Out of 91 newborns receiving phenobarbital, 57 (62.6%) responded completely, 15 (16.5%) partially, and 19 (20.9%) did not respond. Seizure type (p = 0.02), background electroencephalogram (EEG; p ≤ 0.005), and neurologic examination (p ≤ 0.005) correlated with response to phenobarbital. However, EEG (p ≤ 0.02) and seizure type (p ≤ 0.001) were the only independent predictors. Conclusion Our results suggest a prominent role of neurophysiological variables (background EEG and electrographic-only seizure type) in predicting the absence of response to phenobarbital in high-risk newborns.

Optimizing Detection Rate and Characterization of Subtle Paroxysmal Neonatal Abnormal Facial Movements with Multi-Camera Video-Electroencephalogram Recordings.

Objectives We retrospectively analyze the diagnostic accuracy for paroxysmal abnormal facial movements, comparing one camera versus multi-camera approach. Background Polygraphic video-electroencephalogram (vEEG) recording is the current gold standard for brain monitoring in high-risk newborns, especially when neonatal seizures are suspected. One camera synchronized with the EEG is commonly used. Methods Since mid-June 2012, we have started using multiple cameras, one of which point toward newborns' faces. We evaluated vEEGs recorded in newborns in the study period between mid-June 2012 and the end of September 2014 and compared, for each recording, the diagnostic accuracies obtained with one-camera and multi-camera approaches. Results We recorded 147 vEEGs from 87 newborns and found 73 episodes of paroxysmal facial abnormal movements in 18 vEEGs of 11 newborns with the multi-camera approach. By using the single-camera approach, only 28.8% of these events were identified (21/73). Ten positive vEEGs with multicamera with 52 paroxysmal facial abnormal movements (52/73, 71.2%) would have been considered as negative with the single-camera approach. Conclusions The use of one additional facial camera can significantly increase the diagnostic accuracy of vEEGs in the detection of paroxysmal abnormal facial movements in the newborns.