Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

OBJECTIVE: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome. METHODS: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses. RESULTS: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal. CONCLUSIONS: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.

Clinical outcomes of closed-loop vagal nerve stimulation in patients with refractory epilepsy.

PURPOSE: The AspireSR® is a vagal nerve stimulation (VNS) device that operates as a closed-loop system, delivering an automatic stimulation in response to an ictal heart rate increase that serves as a predictor for an imminent seizure. Our purpose is to assess the outcome of the AspireSR® in a patient population managed in a pediatric neurology unit. METHODS: The records of patients who underwent transplantation during 2015-2017 and are continuously followed in one pediatric-epilepsy clinic, were retrospectively analyzed. Collected information included demographics, use of antiepileptic drugs and seizure type, frequency and duration before and after VNS implantation. RESULTS: 46 patients ages 5-31 years (mean 15.7 ± 5.8), mean age at implantation 14 ± 5.8 years, were included. 29 patients (63%) were new insertions and 17 of the patients (37%) underwent a VNS replacement to the AspireSR® model. Mean follow-up was 13 ± 7.5 months (range 2-29 months). The total cohort responder rate (patients with ≥50% reduction in seizure frequency compared to the pre-implantation period) was 60.9%. (62% in the new insertion group; while 59% in the replacement group had additional benefit over their former VNS model, p = 0.981). Epilepsy etiology, age, age at implantation and type of seizures pre-implantation showed no correlation to response-rate. Five patients (10.9%) experienced complete seizure-freedom following implantation (4/5 in the "new insertion" group). Responses were reported at median follow up of 5 ± 1.3 months post-implantation. 67.4% experienced shorter seizure duration post-implantation. CONCLUSION: Our results suggest that the AspireSR® device provides an early and meaningful benefit to drug-resistant epilepsy patients, which is relevant for both patients with new insertions and those with replacements of former VNS devices.

CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

PURPOSE: To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil. METHODS: A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. RESULTS: CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients. CONCLUSIONS: The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.

Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia.

OBJECTIVE: Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals. PATIENTS AND METHODS: AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vß families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs). RESULTS: Thirty-seven AT patients (median age 12.7 years, range 4.2-25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vß repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vß genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients. CONCLUSION: The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis.

Familial pure proximal renal tubular acidosis--a clinical and genetic study.

BACKGROUND: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease. METHODS: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6. RESULTS: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied. CONCLUSIONS: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.

Pediatric refractory partial status epilepticus responsive to topiramate.

Topiramate was safely administered to two young children with refractory partial status epilepticus via nasogastric tube in rapid titration up to a very high total daily dose. An excellent clinical response occurred in both cases. Reaching high daily doses of topiramate within days allowed for safe discontinuation of other antiepileptic drugs in both patients. Given the high efficacy of rapidly titrated topiramate in our patients, this medication may be useful in some cases of pediatric refractory partial status epilepticus. However, more clinical studies on this therapeutic approach are needed to establish the precise role of topiramate in status epilepticus in children.