Expanding the Clinical Spectrum of UBTF-Related Neurodevelopmental Disorder.

Objectives: UBTF1 gene encodes for Upstream Binding Transcription Factor, an essential protein for RNA metabolism. A recurrent de novo variant (c.628G>A; p.Glu210Lys) has recently been associated with a childhood-onset neurodegenerative disorder characterized by motor and language regression, ataxia, dystonia, and acquired microcephaly. In this study, we report the clinical, metabolic, molecular genetics and neuroimaging findings and histologic, histochemical, and electron microscopy studies in muscle samples of 2 patients from unrelated families with a neurodevelopmental disorder. Methods: Data were retrospectively analyzed by medical charts revision. Results: Patient 1, a 16-year-old boy, presented a childhood-onset slowly progressive neurodegenerative disorder mainly affecting language skills, behavior, and motor coordination. Patient 2, a 22-year-old woman, presented with a severe and rapidly progressive disease with dystonic tetra paresis, acquired microcephaly, and severe cognitive deficit complicated by pseudobulbar syndrome characterized by involuntary and uncontrollable outbursts of laughing, dysphagia requiring tube feeding, and nocturnal hypoventilation treated with noninvasive ventilation. Both patients carried the recurrent previously described UBTF1 de novo variant and had signs of mitochondrial dysfunction at muscle biopsy. The metabolic profile of patient 2 also revealed a decrease in CSF biopterin. Discussion: These case reports add new insights to the UBTF1 disease spectrum instrumental to improving the diagnostic rate in neurodevelopmental disorders.

Telemedicine applied to neuromuscular disorders: focus on the COVID-19 pandemic era.

Neuromuscular diseases are rare and usually chronic progressive disorders that require a multidisciplinary clinical evaluation and functional monitoring. The patient-physician relationship and therapies are also key elements to be provided. The COVID-19 pandemic dramatically changed the way patients' health was managed and national health care services underwent a radical reorganization. Telemedicine, with the use of Information and Communication Technology (ICT) by health professionals, became the main strategy to ensure the continuation of care. However, the experience regarding the use of Telemedicine in neuromuscular disorders is very limited and the scientific literature is extremely scarce. From the first experiences in the '50s, the development of Telemedicine has been supplemented and supported by the implementation of ICT to guarantee the secure and effective transmission of medical data. Italian national guidelines (2010-2020) describe the technical and professional guarantees necessary to provide Telemedicine services. Nevertheless, at the time the pandemic appeared, no guidelines for clinical evaluation or for the administration of functional scales remotely were available for neuromuscular diseases. This has been a critical point when clinical evaluations were mandatory also for the renewal of drug prescriptions. However, the common opinion that telemedicine basic services were important to overcome the change in medical practice due to COVID-19 in neuromuscular diseases, even in pediatric age, emerged. Moreover, alternative digital modalities to evaluate patients at home in a kind of virtual clinic were considered as a field of future development.

Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study.

Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype-phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.

BAG3-related myofibrillar myopathy: a further observation with cardiomyopathy at onset in pediatric age.

Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by degeneration of Z-disk, causing the disintegration of myofibrils. They may be caused by mutations in different genes, among these, the BAG3 gene (Bcl-2 associed-athanogene-3) encodes a multidomain protein that plays an important role in many cellular processes. We report the case of a 16-year-old male who at 4 years of age presented with a hypertrophic obstructive cardiomyopathy, then developed axonal sensory motor polyneuropathy, muscle weakness, rigid spine, severe kyphoscoliosis and respiratory failure. Muscle biopsy showed the typical hallmark of myofibrillar myopathy with abnormal cytoplasmic expression of multiple proteins. Ade novo heterozygous common mutation in the BAG3 gene with a c.626C > T (p.Pro209Leu) was discovered on NGS genetic analysis. Mutations in the BAG3 gene are causes of a severe and progressive condition and natural history data are important to be collected. An early diagnosis is critical for prognostic implications in cardiomyopathy and respiratory failure treatment.

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.

West syndrome in three patients with brain injury and a benign course.

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury.

Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients.

BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is a severe disorder. Several drugs have been administered as prophylaxis for paroxysmal attacks, however, no therapy is completely effective. METHODS: Our aim is to review the pharmacological data related to the prophylactic and acute treatment of a cohort of 30 patients (16M, 14F, age range 5-42years) and to correlate them with the clinical and genetic data collected through the Italian Biobank and Clinical Registry for AHC. RESULTS: Flunarizine was the most commonly used long-term treatment in the cohort; it reduced duration and frequency of attacks in 50% of patients and decreased intensity in 32.1%. In younger patients, flunarizine seemed significantly more effective in reducing intensity. We found no correlation between the effectiveness of flunarizine and genotype, or between developmental outcome and duration of treatment. In particular, 3 of our patients affected by E815K mutation presented rapid neurological deterioration despite ongoing treatment. Among the other administered prophylactic therapies, few proved to be effective (benzodiazepines, niaprazine, acetazolamide, melatonin, olanzapine, ketogenic diet). No clear rationale exists regarding their use, but these therapies may work by reducing the triggering factors. CONCLUSIONS: The presented data are retrospective, but they are aimed at filling a gap given the rarity of the disease and the lack of randomized and controlled studies. Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.

Comparing cortical auditory processing in children with typical and atypical benign epilepsy with centrotemporal spikes: Electrophysiologic evidence of the role of non-rapid eye movement sleep abnormalities.

OBJECTIVE: The mismatch negativity (MMN) is an objective measure of central auditory discrimination. MMN alterations have been shown in children with language and/or developmental disorders. In benign focal epilepsies, neuropsychological disorders are often reported and linked to interictal epileptic discharges (IEDs) during non-rapid eye movement (NREM) sleep. There are few studies reporting MMN in children with benign epilepsy with centrotemporal spikes (BECTS) and sleep IEDs. Moreover, no MMN recording has yet been reported in atypical BECTS children with continuous spike-and-wave during sleep (CSWS). We retrospectively compared MMN in typical and atypical BECTS children, particularly addressing the impact of NREM sleep IEDs on auditory discrimination. Moreover, we attempted a neuropsychological characterization of patients. METHODS: The MMN was recorded in 9 normal controls and 23 patients (14 typical BECTS and 9 atypical BECTS) in an oddball paradigm with syllable stimuli. MMN, sleep electroencephalography (EEG) and neuropsychological evaluation were realized in the same testing session. RESULTS: Measurable MMN responses to speech stimuli were identified in both the control and patient groups. A significant difference between control and atypical BECTS children was found with respect to amplitude (p = 0.0061). Atypical BECTS also showed a lower MMN amplitude with respect to typical BECTS, but this difference did not reach statistical significance (p = 0.0545). Statistical comparisons between groups revealed no differences in latency. Among the neuropsychological variables, academic difficulties were significantly more prominent in the patients with atypical BECTS (p = 0.04). SIGNIFICANCE: CSWS EEG pattern affects auditory discrimination and may have a long-lasting impact on academic skills acquisition, whereas in typical BECTS children with a lower degree of IED NREM sleep, plastic brain reorganization or the preservation of participating networks may prevent such difficulty. Early electrophysiologic identification of auditory discrimination deficits in epileptic children could be used in early rehabilitation, thereby reducing the risk of developing neuropsychological disorders.

Neuropsychological development in children belonging to BECTS spectrum: long-term effect of epileptiform activity.

Benign epilepsy with centrotemporal spikes (BECTS) is an idiopathic focal epileptic syndrome in childhood. It is called "benign" because the seizure and cognitive outcomes are usually favorable, but a significant number of children with BECTS present heterogeneous cognitive deficits correlated to NREM sleep epileptiform discharges. The atypical evolutions of BECTS form a spectrum of conditions suggesting that slow sleep nocturnal interictal epileptiform discharges (IEDs) specifically determine the neuropsychological deficit. Few follow-up studies of neuropsychological outcome in BECTS are available, and very often, slow sleep has not been recorded throughout night sleep. The present study analyzed the long-term effects of IEDs during NREM sleep on neuropsychological development in children with rolandic spikes. Thirty-three children with a diagnosis of BECTS were monitored for at least two years. Results show that these children are at higher risk for residual verbal difficulties, and the abnormal neuropsychological development is significantly correlated with a greater frequency of NREM sleep discharges, school-age epilepsy onset, and a higher number of antiepileptic drugs (AEDs). The findings are discussed in terms of how slow sleep IEDs affect the consolidation of verbal skills during critical epochs of neuropsychological development.

Lack of SLC2A1 (glucose transporter 1) mutations in 30 Italian patients with alternating hemiplegia of childhood.

Alternating hemiplegia of childhood is a rare, predominantly sporadic disorder. Diagnosis is clinical, and little is known about genetics. Glucose transporter 1 deficiency syndrome shares with alternating hemiplegia of childhood paroxysmal and nonparoxysmal symptoms. The aim of the study was to investigate glucose transporter 1 mutations in 30 Italian patients. Genetic material was analyzed by DNA amplification and glucose transporter 1 region sequencing. Mutational analysis findings of the SLC2A1 gene were negative in all patients. The pattern of movement disorders was reviewed. Interictal dystonia and multiple paroxysmal events were typical of alternating hemiplegia of childhood. In conclusion, alternating hemiplegia of childhood is a heterogeneous clinical condition, and although glucose transporter 1 deficiency can represent an undiagnosed cause of this disorder, mutational analysis is not routinely recommended. Alternatively, a careful clinical analysis and the 3-O-methyl-D-glucose uptake test can allow prompt identification of a subgroup of patients with alternating hemiplegia of childhood treatable with a ketogenic diet.

Alternating hemiplegia of childhood: metabolic studies in the largest European series of patients.

Alternating hemiplegia of childhood (AHC) is a rare disorder with diagnosis based on clinical criteria, as no laboratory, neuroradiological or genetic markers are currently available. The pathogenic mechanisms are still an enigma. Some hypotheses have been proposed such as hemiplegic migraine variant, epileptic mechanism, channelopathy and mitochondrial disorder, but none of these has been confirmed. Our aim was to analyze the results of metabolic studies performed on a series of 157 European patients who fulfilled diagnostic criteria for AHC. We tried to find a common metabolic abnormality, related with AHC. We did not find significant abnormalities in basic metabolic screening, at different ages. Neurotransmitters in cerebrospinal fluid (n = 26) were normal in all of the patients. Mitochondrial respiratory chain enzyme activities were analyzed in 19 muscle biopsies; in 4 cases, different MRC enzyme deficiencies were demonstrated, ranging from mild-unspecific deficiencies to more profound and probably primary defects. Although we did not find specific metabolic markers in our series, some metabolic disorders such as pyruvate dehydrogenase deficiency, MELAS, cerebral glucose transporter defect and neurotransmitter deficiency can exhibit symptoms similar to those of AHC and need to be ruled out before a diagnosis of AHC can be established. Further studies including high-throughput diagnostic technologies seem necessary to elucidate the etiology of this severe and enigmatic disorder.

Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults.

Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials.

No evidence of GABRG2 mutations in severe myoclonic epilepsy of infancy.

Severe myoclonic epilepsy of infancy (SMEI) has been long suspected to have a genetic origin. Recently mutations in the gene encoding a voltage-gated alpha-1 sodium channel subunit-SCN1A-have been identified as a common cause of SMEI. Moreover, a mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor-GABRG2-has been described in a GEFS+ family with a member affected by SMEI. In order to further investigate the role of GABRG2 in the pathogenesis of SMEI, we have screened for mutations 53 SMEI patients who resulted negative for SCN1A mutations. Mutational screening of GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram. Twenty-nine variant chromatograms were identified corresponding to seven different nucleotide variants. None of them leads to an amino acid change or obvious protein dysfunction. No difference in allele frequency was observed for the SMEI patients compared to a control population indicating that these variants are not involved in SMEI. Our study demonstrates that GABRG2 is not a commonly involved in the etiology of SMEI and suggests that other and yet unidentified genes are involved in the syndrome