Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C.

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

Influence of seizures on early development in tuberous sclerosis complex.

OBJECTIVE: Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC. METHODS: Analysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency. RESULTS: Data were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome. CONCLUSIONS: Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.

Efficacy and safety of ketogenic dietary theraphies in infancy. A single-center experience in 42 infants less than two years of age.

PURPOSE: Ketogenic dietary therapies (KDT) are high-fat and low-carbohydrate diets that may achieve seizure control and improve cognitive state. We describe our KDT experience in infants (children less than two years of age). RESEARCH METHODS & PROCEDURES: We conducted a retrospective, descriptive and observational study of 42 infants treated with KDT between 2000-2018. RESULTS: The types of KDT started were: classic ketogenic diet ratio 3:1 (40), ratio 4:1 (1) and modified ketogenic diet with medium-chain triglycerides (1). Four patients switched to a modified Atkins diet. During follow-up, 79%, 57%, 38% and 17% of infants remained on KDT at 3, 6, 12 and 24 months, respectively. Seizure reduction ≥50% compared to baseline was achieved in 50%, 45%, 38% and 17% at 3, 6, 12 and 24 months, respectively. Seizure control was excellent (reduction >90%) in 33%, 31%, 26% and 12%, and seizure-free infants were 9, 9, 10 and 4, at different follow-up intervals, respectively. Sixty-three percent of infants with West syndrome were responders to KDT. Mean length of KDT was 390 days (16 days-4.9 years). Ineffectiveness was the reason for withdrawal in 50% of patients. Early adverse effects (during first month) occurred in 40% of infants. The most frequent early side effects were asymptomatic hypoglycemia and gastrointestinal disturbances. Late-onset side effects occurred in 55-14% of infants during therapy, and most frequent were hypercalciuria and dyslipidaemia. CONCLUSION: KDT are useful and effective treatments in infancy. Side effects are frequent but mild and easy to manage.

Dystonia and Contractures are Potential Early Signs of CACNA1E-Related Epileptic Encephalopathy.

Epileptic encephalopathy related to CACNA1E has been described as a severe neurodevelopmental disorder presenting with early-onset refractory seizures, hypotonia, macrocephaly, hyperkinetic movements, and contractures and is associated with an autosomal dominant inheritance pattern. Most pathogenic variants described to date are missense variants with a gain of function effect, and the role of haploinsufficiency has yet to be clarified. We describe 2 cases of CACNA1E encephalopathy. Notable findings include congenital contractures and movement disorders predating onset of epilepsy, particularly dystonia. We further compared the key phenotypic features depending on variant location. In conclusion, the appearance of congenital contractures, areflexia, and movement disorders before the onset of epilepsy may provide key guidance in the diagnosis of epileptic CACNA1E encephalopathy. A genotype-phenotype correlation was found between the presence of movement disorders and severe intellectual disability and the location of the variant in the CACNA1E gene.

Efficacy of Brivaracetam in children with epilepsy.

BACKGROUND AND OBJECTIVES: To determine the efficacy, tolerance, and safety of BRV in children with epilepsy. METHODS: A retrospective study of patients with epilepsy who received treatment with BRV before age 16 years and underwent a minimum follow-up of 3 months. METHOD AND RESULTS: Sixty-six patients were included in the study. Patients received BRV at a mean age of 8.8 years (range 1-16 years). The majority (93.4 %) had refractory epilepsy, 27 with epileptic encephalopathy. The median maximum dose used was 4.3 mg/kg/day. In 30.3 % of the cases, seizure frequency was reduced by over 50 %, and 9 % remained seizure-free. Greater efficacy was observed in those patients who received higher doses and when a direct switch from levetiracetam (LEV) to BRV was performed. The ineffectiveness of LEV was not related to a failure to respond to BRV treatment. Side effects were identified in 24.2 % of the cases, the most frequent being irritability and drowsiness. CONCLUSIONS: BRV appears to be an effective, safe, and well-tolerated AED in children with refractory epilepsy.

Utility of the transcranial doppler in the evaluation and follow-up of children with Sturge-Weber Syndrome.

INTRODUCTION: Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome with typical clinical features including seizures, chronic hemiplegia, hemianopsia and intellectual impairment. Progressive clinical decline may be attributable, at least in part, to progressive venous ischemia. Transcranial Doppler (TCD) ultrasonography could be useful to monitor the degree of hemodynamic involvement and its progression. PURPOSE: To determine whether there is an association between the degree of asymmetry in TCD and intensity of clinical and radiological involvement and whether there is a correlation between clinical changes and changes in serial TCD. METHODS: In fourteen SWS pediatric patients and two "possible cases" (infants younger than two years old without previously known brain involvement, but with other typical signs of SWS) mean flow velocity in the middle cerebral arteries (MCA) was measured by TCD in both hemispheres. The percent difference between hemispheres (asymmetry) was calculated. Clinical and radiological severity was scored using scales. The correlation between TCD asymmetry and SWS clinical and radiological scores was analyzed at baseline, as well as the correlation between the changes in the different variables (TCD asymmetry, clinical and radiological cores) during evolution and in relation to the changes due to therapy. RESULTS: The percentage of MCA velocity asymmetry was positively correlated with the clinical severity score (p = 0.04), and with seizure frequency (p = 0.014). Throughout evolution, therapeutic and clinical changes were associated with noticeable changes in transcranial doppler asymmetry in some cases. CONCLUSIONS: TCD may provide a noninvasive method to assess the severity of blood flow abnormalities at baseline and a method to monitor children for progressive changes over time.

Complicaciones neurológicas en casos de bronquiolitis por virus respiratorio sincitial: estado febril y otras manifestaciones neurológicas / Neurological complications in cases of bronchiolitis due to respiratory syncytial virus: febrile status and other neurological manifestations

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Dos nuevos casos de síndrome de Leigh por mutación m.13513G>A en el gen MTND5 / Two new cases of Leigh syndrome caused by mutation m.13513G> A in the MTND5 gene

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Siringomielias en pediatría: estudio retrospectivo de 25 casos / Syringomyelias in paediatrics: a retrospective study of 25 cases

Introducción. Se define siringomielia como una cavidad que contiene líquido cefalorraquídeo dispuesta en el interior de la médula espinal. Objetivo. Describir las características clínicas de una serie de pacientes con siringomielia, su diagnóstico y tratamiento. Pacientes y métodos. Estudio descriptivo retrospectivo realizado mediante la revisión de historias clínicas en nuestro centro. Resultados. Se revisaron 25 pacientes diagnosticados de siringomielia. En cinco el diagnóstico fue casual y ocho presentaban una patología grave previa (tumoral, ósea o vascular). Dos pacientes comenzaron con hidrocefalia y clínica de hipertensión intracraneal y únicamente dos destacaban cefalea como único síntoma. Cuatro presentaron escoliosis progresiva, dos de ellos como queja inicial, y precisaron cirugía con artrodesis y uso de corsé, respectivamente. Destaca la precocidad del diagnóstico. La mayoría presentaba únicamente pérdida de fuerza leve, con potenciales somatosensoriales y electromiograma normales. En todos se hicieron controles con resonancia magnética. Ocho pacientes precisaron craniectomía descompresiva con laminectomía posterior C1-C2, con drenaje de la cavidad siringomiélica en cuatro. Nueve requirieron válvula de derivación y dos precisaron, además, ventriculostomía. Conclusiones. La presencia de siringomielia en pediatría es rara, y se asocia generalmente a malformaciones en la fosa posterior y antecedentes de disrafismo espinal. Destaca la escoliosis progresiva como posible manifestación aislada. Un abordaje multidisciplinar con controles radiológicos seriados y la valoración por servicios de neurología y neurocirugía pediátricos son mandatorios para su seguimiento (AU)

Introduction. Syringomyelia is defined as a cavity containing cerebrospinal fluid inside the spinal cord. Aim. To describe the clinical characteristics of a series of patients with syringomyelia, as well as its diagnosis and treatment. Patients and methods. We conducted a retrospective descriptive study by reviewing the medical records at our centre. Results. We reviewed 25 patients diagnosed with syringomyelia. In five cases, the diagnosis was reached casually, and eight of them presented a previous severe pathology (tumour, bone or vascular). Two patients began with hydrocephalus and clinical signs and symptoms of intracranial hypertension and just two of them reported headaches as the only symptom. Four presented progressive scoliosis, two of them as the initial complaint, and required surgery with arthrodesis and the use of a corset, respectively. A notable feature was the earliness of the diagnosis. Most of them only presented a slight loss of strength, with normal somatosensory potentials and electromyogram. Check-ups were carried out with magnetic resonance. Eight patients required a decompressive craniectomy with posterior C1-C2 laminectomy, with drainage of the syringomyelic cavity in four cases. Nine of them required a bypass valve and a ventriculostomy also had to be performed in two of them. Conclusions. The presence of syringomyelia is rare in paediatric patients, and is generally associated with malformations in the posterior fossa and a medical history of spinal dysrhaphism. Progressive scoliosis stands out as a possible isolated manifestation. A multidisciplinary approach with regular radiological check-ups and evaluation by paediatric neurology and neurosurgery services are mandatory for its follow-up (AU)