The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile.

OBJECTIVE: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. METHODS: Clinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro. RESULTS: The six new patients showed the hallmark features of SMA-PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA-PME variants observed in two specific codons of ASAH1. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C > T variant presented in the first decade of life with limb-girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A > C variant. Leukocyte acid ceramidase activity varied from 4.1%-13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9-fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h. INTERPRETATION: This study details the genotype-phenotype correlations observed in SMA-PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.

Development of a High Strength Geopolymer Incorporating Quarry Waste Diabase Mud (DM) and Ground Granulated Blast-Furnace Slag (GGBS).

This study presents the development and experimental assessment of novel, high strength, cementless binders that incorporate alkali-activated local waste. A silica-rich diabase mud (DM), currently considered as waste, was previously investigated for geopolymerization, signifying that the DM lacked the necessary reactivity to provide a stable geopolymer binder alone. Moreover, even after incorporation of small amounts of cement and metakaolin, the DM mixtures still did not yield adequate mechanical properties. In this study, the local DM was instead combined with another industrial byproduct known as Ground Granulated Blast-furnace Slag (GGBS) in varying mixtures. The mixture design trials enabled the development of three high strength cementless geopolymer mixtures with 28-day compressive strengths ranging between 60 and 100 MPa, comparable to conventional concrete compressive strengths. The results indicate that the innovative geopolymer material is very promising for the manufacturing of pavement tiles and other precast construction products. Most importantly, this study presents the first successful development of a construction material of adequate compressive strength that can absorb large quantities of the abundant quarry waste, following a course of 10 years of unsuccessful attempts to valorize the local DM. Although difficulties were encountered due to a high reactivity rate, especially for the mix that included the highest GGBS content, prototype pavement tiles were manufactured and assessed experimentally. The results reveal a promising potential of valorizing the local DM in the development of precast geopolymer products, despite the effects of shrinkage cracking on the experimental evaluation of the material mechanical properties.

Investigation of the Geopolymerization Potential of a Waste Silica-Rich Diabase Mud.

Diabase mud (DM) is a silica-rich residue yielding from aggregate crushing and washing operations in quarries. This work focuses on identifying the geopolymerization potential of a diabase mud through characterization of its mineralogical composition, investigation of its reactivity, and assessment of the early compressive strengths of alkali activated mixtures formulated based on the mud's dissolution results. The findings suggest that considerably low amounts of Al and Si metals were dissolved following the dissolution tests conducted on DM, however, the incorporation of small quantities of CEM I, gypsum, and metakaolin (MK) moderately at a Na2SiO3:NaOH ratio of 50:50 and with a molarity of NaOH of 4 M enhanced the geopolymerization compared to low L/S ratio mixtures cured at different conditions. When M was increasing, the high L/S ratio mixtures exhibited fluctuations in strengths, especially beyond a 10 M NaOH molarity. Maximum strengths of mixtures at equivalent molarity of 10 were achieved when the Na2SiO3:NaOH ratio reached 30:70, regardless of the ambient conditions and the presence of CEM I. The curing conditions, the ratio of Na2SO3:NaOH, and the presence of CEM I in the DM-based mixtures did not appear to significantly affect the mixture when NaOH concentration was between 2 M and 4 M; at higher molarities, however, these enhanced the strengths of the geopolymerized DM.

Effect of Mechanically Treated Recycled Aggregates on the Long Term Mechanical Properties and Durability of Concrete.

The objective of this research was to study the effect of an optimal mechanical treatment method to reduce the mortar adhered on recycled aggregates (RCA) on the long-term mechanical properties and durability of concretes containing RCA at different replacement levels. It was found that concretes incorporating treated RCA exhibited sharper and more significant increase on 90- and 365-day compressive strengths than any other investigated mixture. The same mixtures also benefitted from a 'shrinkage-controlling' effect, where strains and mass losses were reduced by almost 15% and 10%, respectively, compared to the reference concrete. While sulfate resistance and carbonation resistance are predominantly defined by the hydration products available within the cement paste and not to a large extent by the aggregate type and quality, the incorporation of either treated or untreated RCA in concrete did not appear to expose RACs to significant durability threats.

The Complex Interplay of Cortex, Cerebellum, and Age in a Cohort of Pediatric Patients With Tuberous Sclerosis Complex.

BACKGROUND: The neurodevelopmental impairment in tuberous sclerosis complex (TSC) has a multifactorial origin. Various factors have been proposed as predictors of neurological outcome such as tuber load, seizure onset, and TSC2 mutation. Cerebellar lesions have been associated with worse neuroradiological phenotype, but their contribution is not well understood. METHODS: A partly retrospective and partly prospective pediatric cohort study was conducted at three hospitals in Greece between 2015 and 2020. Patients aged ≤ 18 years with a confirmed TSC daignosis were included and underwent brain imaging, a semistructured interview (authorized Greek version of the tuberous sclerosis-associated neuropsychiatric disorders, or TAND, checklist), and intellectual ability assessment. RESULTS: The study populations consisted of 45 patients with TSC (22 females, 23 males; mean age 9.53 years). Twenty patients (44.4%) had cerebellar lesions. Cerebellar involvement was the most powerful predictor of tuber load (P = 0.03). Cerebellar lesions were associated with giant cell astrocytomas (SEGAs) (P = 0.01) and severe neurological outcome (P = 0.01). Even though in the univariate analysis early seizure onset, tuber load, and cerebellar involvement were associated with intellectual impairment and neurological severity, none of them was an independent predictor of cognitive outcome and neurological severity. CONCLUSIONS: Cerebellar lesions are common among individuals with TSC. Cerebellar involvement correlates with supratentorial derangement and the development of SEGAs, which is suggestive of a more severe clinical and neuroradiological phenotype. Cerebellar involvement and early seizure onset were not independent predictors of either neurological severity or intellectual disability or neurobehavioral outcome; their role in TSC clinical phenotype should be further investigated.

Longitudinal Data in Patients with Niemann-Pick Type C Disease Under Combined High Intrathecal and Low Intravenous Dose of 2-hydroxylpropyl-ß-cyclodextrin.

Niemann-Pick Type C disease (NPC) is a rare, incurable, autosomal-recessive, lysosomal storage disorder with protean and progressive neurovisceral manifestations characterized by accumulation of intracellular unesterified cholesterol. The investigational use of 2-hydroxypropyl-beta-cyclodextrin (HP-ß-CD) in the treatment of NPC has shown promising results in improving life expectancy and reducing neurological damage in this patient population. This case report describes two children with the neurological form of NPC: a 5-year-old male patient in advanced stage of the disease and an 11-year-old female patient in moderately advanced stage. Despite treatment with the enzyme inhibitor, miglustat, both patients continued to exhibit severe neurodegeneration. High intrathecal (900mg) and low intravenous (350-500mg/kg) doses of HP-ß-CD (Trappsol®Cyclo™) were administrated twice monthly to the patients in addition to miglustat therapy. The patients were monitored clinically as well as by imaging, laboratory, and biomarker (e.g., total tau protein [T-tau]; phosphorylated tau [P-tau]; neurofilament light [NFL], oxysterols) studies over a period of 16 to 22 months. The combination therapy of miglustat and HP-ß-CD resulted in disease stabilization in both patients. The combination therapy demonstrated a good safety profile, and no adverse effects on hearing were observed. Additionally, CSF biomarkers appeared useful in monitoring neuronal damage. Large, randomized studies are needed to confirm these findings.

Effects of measles-containing vaccination in children with severe underlying neurologic disease.

BACKGROUND: Measles outbreaks pose significant risk for those unvaccinated. PATIENTS AND METHODS: Measles-containing vaccine was offered to unvaccinated children with severe neurologic diseases during a measles outbreak. Vaccination adverse events were reported by parents 30 days following vaccination. Long term effects were evaluated 12 months post vaccination. RESULTS: Twenty-seven children were vaccinated (36 doses given). Half of parents (51.8%) reported no adverse events following immunization. Adverse events included afebrile seizures (6/36), fever alone (5/36) and febrile seizures (5/36). Two children required hospitalization. Quadrivalent measles-containing vaccine combined with varicella was associated with febrile seizures (p = 0.04). No child needed adjustment of the anti-epileptic treatment or exhibited developmental regression. CONCLUSION: Ina series of children with prior severe neurologic disease, the safety-tolerability profile ofvaccines containing a measles vaccine component suggests that vaccination is justified. Main side effect was seizure aggravation in children with known epileptic disease.

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation.

PURPOSE: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. METHODS: Retrospective case series of 20 patients. RESULTS: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. CONCLUSION: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population.

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.