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.

Heterozygous truncating variant of TAOK1 in a boy with periventricular nodular heterotopia: a case report and literature review of TAOK1-related neurodevelopmental disorders.

BACKGROUND: Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility. CASE PRESENTATION: We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia. CONCLUSIONS: To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.

Novel Insights from Clinical Practice: Xia-Gibbs Syndrome with Pes Cavus, Conjunctival Melanosis, and Eye Asymmetry due to a de novo AHDC1 Gene Variant - A Case Report and a Brief Review of the Literature.

Introduction: Xia-Gibbs syndrome (OMIM 615829) is a rare developmental disorder, caused by heterozygous de novo variants in the AHDC1 gene. Hallmark features include global developmental delay, facial dysmorphisms, and behavioral problems. To date, more than 250 individuals have been diagnosed worldwide. Case Report: We report a 13-year-old female who, in association with typical features of Xia-Gibbs syndrome, presented with macrocrania, pes cavus, and conjunctival melanosis. Whole-exome sequencing identified a de novo frameshift variant, which had not been reported in the literature before. Conclusion: We summarized the main clinical and phenotypic features of patients described in the literature, and in addition, we discuss another feature found in our patient and observed in other cases described, eye asymmetry, which has never been highlighted, and suggest that it could be part of the typical clinical presentation of this condition.

Tick-Borne Encephalitis in a 6-Year-Old Patient: A Case Report.

Background: Tick-Borne Encephalitis virus (TBEV) is a positive-sense single-stranded RNA virus belonging to the Flaviviridae family. TBEV transmission typically occurs through infected Ixodes tick bite or by consumption of unpasteurised milk from infected cattle. Case report: We report the clinical, neuroimaging, electroencephalogram (EEG), and laboratory (microbiological tests and spinal tap) data of a 6- year-old boy with Tick-borne encephalitis. Our patient presented with a biphasic course, initially with a myositis-like picture on his first admission to the emergency department, and after a few days with an encephalitic picture, resulting in a second hospitalization. EEG showed focal slow activity, while his brain magnetic resonance imaging (MRI) showed a signal abnormality, which completely resolved on repeat MRI after 3 months. Conclusion: To our knowledge, this is the youngest patient presenting with myositis in the first phase of Tick-borne encephalitis (TBE). In the presence of a biphasic clinical course, with previous myositis, aspecific MRI changes in the thalamic and midbrain regions and an EEG documenting slowed bioelectrical activity should prompt suspicion of TBEV infection.

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.

Lessons from two series by physicians and caregivers' self-reported data in DDX3X-related disorders.

INTRODUCTION AND METHODS: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. RESULTS: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words. DISCUSSION: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated.

Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals.

PURPOSE: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition. METHODS: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature. RESULTS: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled. CONCLUSION: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene.

'A novel TRIP4 Variant Associated with Peripheral Neuropathy: Expanding the Clinical and Genetic Spectrum of ASC1-Related Myopathy'.

Activating Signal Cointegrator 1 complex (ASC-1 complex) is a ribonucleoprotein tetramer participating in transcriptional coactivation and RNA processing, consisting of four subunits: ASCC1-ASCC3 and ASC-1. Pathogenic variants in the TRIP4 and ASCC1 genes, encoding the ASC-1 and ASCC1 subunits, were recently described in congenital myopathic conditions without signs of motor neuron involvement, and Spinal Muscular Atrophy-like (SMA-like) phenotype with prenatal bone fractures. We present a novel pathogenic TRIP4 variant in two siblings with severe phenotype and mixed sensory-motor polyneuropathy. The reviewed phenotypic spectrum is broad, but sensory-motor polyneuropathy is so-far unreported. We thus expand ASC-1 related myopathy phenotype.

Expanding Phenotype of SYT1-Related Neurodevelopmental Disorder: Case Report and Literature Review.

Introduction: Synaptotagmin 1 (SYT1), the predominant SYT isoform in the central nervous system, likely acts by promoting vesicle docking, deforming the plasma membrane via Ca2+-dependent membrane penetration. Case Presentation: Here, we describe a 21-year-old woman harboring a novel variant in the SYT1 gene, who presents with a complex phenotype, featuring severe intellectual disability, absent speech, behavioral abnormalities, motor stereotypies, dystonic posturing of her hands, a hyperkinetic movement disorder in her childhood, infantile hypotonia, sialorrhea, mild dysmorphic features, epilepsy, peculiar EEG findings, and severe scoliosis. Discussion: Based on our case and literature review on the 22 previously described patients, we can confirm a complex neurodevelopmental disorder in which, unlike other synaptopathies, epilepsy is present in a subset of cases (including our patient: 5/23, 22%), although characteristic EEG changes are far more common (10/23, 43.5%). Our patient's age allows us to provide long-term follow-up data and thus better delineate the SYT1-related clinical phenotype.

Tolosa-Hunt syndrome and recurrent painful ophthalmoplegic neuropathy, case reports: what to do and when?

BACKGROUND: Tolosa-Hunt syndrome (THS) and recurrent painful ophthalmoplegic neuropathy (RPON) are rare diseases reported within the "Painful lesions of the cranial nerves" section of the International Classification of Headache Disorders-3rd edition (ICHD-3). In case of a first painful attack, differential diagnosis could be challenging and many pitfalls are due to the rarity of the disorders and the lack of information about correct medical management in youngsters. CASE PRESENTATION: Our main purpose was to report a new case of THS and a new case of RPON describing management and diagnostic investigation at the time of the first episode. In both cases of THS (13 years old) and RPON (14 years old) a unilateral periorbital headache associated with acute onset of ipsilateral third cranial nerve paresis, scarcely responding to non-steroidal anti-inflammatory drugs (NSAID), was present at the beginning of the first attack. Brain MRI with "time-of-flight" (TOF) angiography and the need to administer steroids (after 72 h from onset) in order to stop pain were the most important handles allowing us to adopt the correct management both in THS or RPON since onset and to face recurrences in RPON by avoiding useless therapy during follow-up. CONCLUSION: Unilateral periorbital headache associated with third-fourth or sixth cranial nerve paresis should ideally be investigated with a full work-up, comprehensive of brain MRI with TOF angiography since the first attack. In cases with negative brain MRI spontaneous resolution should be considered and watchful waiting might be advisable before starting steroid therapy.

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.

Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.

Case report: Expanding the phenotype of FOXP1-related intellectual disability syndrome and hyperkinetic movement disorder in differential diagnosis with epileptic seizures.

Objective: We aimed to report on previously unappreciated clinical features associated with FOXP1-related intellectual disability (ID) syndrome, a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, and language delay, with or without autistic features. Methods: We performed whole-exome sequencing (WES) to molecularly characterize an individual presenting with ID, epilepsy, autism spectrum disorder, behavioral problems, and facial dysmorphisms as major features. Results: WES allowed us to identify a previously unreported de novo splice site variant, c.1429-1G>T (NM_032682.6), in the FOXP1 gene (OMIM*605515) as the causative event underlying the phenotype. Clinical reassessment of the patient and revision of the literature allowed us to refine the phenotype associated with FOXP1 haploinsufficiency, including hyperkinetic movement disorder and flat angiomas as associated features. Interestingly, the patient also has an asymmetric face and choanal atresia and a novel de novo variant of the CHD7 gene. Conclusion: We suggest that FOXP1-related ID syndrome may also predispose to the development of hyperkinetic movement disorders and flat angiomas. These features could therefore require specific management of this condition.

A Novel Family with Demyelinating Charcot-Marie-Tooth Disease Caused by a Mutation in the PMP2 Gene: A Case Series of Nine Patients and a Brief Review of the Literature.

INTRODUCTION: Charcot-Marie-Tooth (CMT) is a group of inherited peripheral neuropathies characterized by wide genotypic and phenotypic variability. The onset is typically in childhood, and the most frequent clinical manifestations are predominantly distal muscle weakness, hypoesthesia, foot deformity (pes cavus) and areflexia. In the long term, complications such as muscle-tendon retractions, extremity deformities, muscle atrophy and pain may occur. Among CMT1, demyelinating and autosomal dominant forms, CMT1G is determined by mutations in the PMP2 myelin protein. RESULTS: Starting from the index case, we performed a clinical, electrophysiological, neuroradiological and genetic evaluation of all family members for three generations; we identified p.Ile50del in PMP2 in all the nine affected members. They presented a typical clinical phenotype, with childhood-onset variable severity between generations and a chronic demyelinating sensory-motor polyneuropathy on the electrophysiologic examination; the progression was slow to very slow and predominant in the lower limbs. Our study reports a relatively large sample of patients, members of the same family, with CMT1G by PMP2, which is a rare form of demyelinating CMT, highlighting the genetic variability of the CMT family instead of the overlapping clinical phenotypes within demyelinating forms. To date, only supportive and preventive measures for the most severe complications are available; therefore, we believe that early diagnosis (clinical, electrophysiological and genetic) allows access to specialist follow-up and therapies, thereby improving the quality of life of patients.

Cannabidiol use in patients with Dravet syndrome and Lennox-Gastaut syndrome: experts' opinions using a nominal group technique (NGT) approach.

BACKGROUND: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) currently present a therapeutic challenge. A pharmaceutical cannabidiol (CBD) specialty (Epidyolex®) has been approved by the FDA and EMA for the treatment of seizures in these syndromes. However, in Italy, the use of galenic formulations versus the pharmaceutical CBD has not been clearly regulated. AIM: To share and disseminate expert' opinions on how to use and administer pharmaceutical CBD in patients with DS and LGS as well as identifying a possible strategy for the switch from galenic to pharmaceutical specialty. METHODS: A nominal group technique (NGT) was used, involving eight Italian adult and pediatric neurologists. Two questionnaires were consecutively administered and the Clinician' responses were discussed in a final meeting in order to draw the own conclusions. RESULTS: The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose. CONCLUSION: The use of a pharmaceutical CBD in DS and LGS patients is useful for both seizure treatment and quality of life (QoL) improvement. However, further studies are needed to confirm the improvement in QoL and the best strategy for switching from a galenic formulation to pharmaceutical CBD.

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

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.