Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease.

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

Correlation between the Mandibular Lingula Position and Some Anatomical Landmarks in Cone Beam CT.

BACKGROUND: the position of the mandibular lingula (Li) affects the success rate of the inferior alveolar nerve block (IANB) and ramus osteotomies. This study evaluated the position of the Li, to investigate the anatomical relationship between the Li and some anatomical measurements using cone beam computed tomography (CBCT). METHODS: 201 hemimandibular CBCTs of 111 patients (43 males and 68 females; 18 to 88 years old) were retrospectively evaluated. The Li location was determined from the lingula tip to: the occlusal plane, the anterior and posterior borders of the mandibular ramus, the lower border of the mandible, the distal surface of the mandibular second molar, and the mandibular notch. We evaluated the correlations between the Li and the anteroposterior diameter of the mandibular ramus; the vertical distance between condyle and mandibular angle; the mesial-distal diameter of the first, second, and third mandibular molar, the intercanine distance, the intermolar distances among the first, second, and third mandibular molars; the distance between the intermolar line of the first molar and midline, and the length of the mandibular body. RESULTS: the vertical distance of the Li from the occlusal plane was 11.22 ± 4.27 mm. Some parameters significantly correlated with the anatomical measurements taken into consideration. CONCLUSIONS: the present study provides new information concerning the Li and mandibular anatomy in the Italian population. Moreover, by correlating some anatomic measurements to the Li position, the localization of the Li is made possible, indirectly through the measurement of some distances between anatomical landmarks.

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

The urinary organic acids profile in single large-scale mitochondrial DNA deletion disorders.

Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class. In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS. PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3-methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype. Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias.

Trigonal and Peritrigonal Lesions of the Lateral Ventricle: Presurgical Tractographic Planning and Clinic Outcome Evaluation.

BACKGROUND: Surgery of lesions within the atrium of the lateral ventricle remains a challenging procedure because of the deep location and the relationship to vascular structures. The aim of this study was to determine the usefulness of tractography to evaluate the position of white matter tracts located along the course of the surgical access to trigonal and peritrigonal lesions. METHODS: Diffusion tensor imaging (DTI) was acquired in 19 patients. All patients underwent surgical resection of brain tumors. Pre- and postoperative clinical conditions were evaluated by a neurosurgeon, using the Karnofsky Performance Status Scale. The corticospinal tract, optic radiation, and arcuate fasciculum were reconstructed because of their location close to the trigonal region. Two neurosurgeons were asked to assess the surgical approach with and without tractography. RESULTS: According to the tractographic reconstructions, the surgical access was chosen from the middle temporal gyrus in 12 patients (63%) and the posterior parietal gyrus in 7 patients (37%), leading to an a priori change in the surgical approach in 14 patients (73%). Six patients (31%) showed new postsurgical transient symptoms, whereas in 2 patients (10%) the deficits were permanent. After 30 days, the Karnofsky Performance Status Scale evaluation showed an improvement or a substantial stability of symptoms in 90% of cases. In 2 patients, a worsening of 30% of clinical performance was appreciable. CONCLUSIONS: The use of DTI in preoperative planning of trigonal and peritrigonal lesions may help in description of the best surgical approach for patient; this technique allows to reach the tumors, saving the white matter tracts, when it is possible.

In Situ Solid-Gas Reactivity of Nanoscaled Metal Borides from Molten Salt Synthesis.

Metal borides have mostly been studied as bulk materials. The nanoscale provides new opportunities to investigate the properties of these materials, e.g., nanoscale hardening and surface reactivity. Metal borides are often considered stable solids because of their covalent character, but little is known on their behavior under a reactive atmosphere, especially reductive gases. We use molten salt synthesis at 750 °C to provide cobalt monoboride (CoB) nanocrystals embedded in an amorphous layer of cobalt(II) and partially oxidized boron as a model platform to study morphological, chemical, and structural evolutions of the boride and the superficial layer exposed to argon, dihydrogen (H2), and a mixture of H2 and carbon dioxide (CO2) through a multiscale in situ approach: environmental transmission electron microscopy, synchrotron-based near-ambient-pressure X-ray photoelectron spectroscopy, and near-edge X-ray absorption spectroscopy. Although the material is stable under argon, H2 triggers at 400 °C decomposition of CoB, leading to cobalt(0) nanoparticles. We then show that H2 activates CoB for the catalysis of CO2 methanation. A similar decomposition process is also observed on NiB nanocrystals under oxidizing conditions at 300 °C. Our work highlights the instability under reactive atmospheres of nanocrystalline cobalt and nickel borides obtained from molten salt synthesis. Therefore, we question the general stability of metal borides with distinct compositions under such conditions. These results shed light on the actual species in metal boride catalysis and provide the framework for future applications of metal borides in their stability domains.