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.

Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease.

Background: Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked urea cycle disorder characterized by acute hyperammonemic episodes. Hemizygous males are usually affected by a severe/fatal neonatal-onset form or, less frequently, by a late-onset form with milder disease course, depending on the residual enzymatic activity. Hyperammonemia can occur any time during life and patients could remain non- or mis-diagnosed due to unspecific symptoms.

The impact of liver transplantation on health-related quality of life in (acute) intoxication-type inborn errors of metabolism.

Organic acidurias (OAs), urea-cycle disorders (UCDs), and maple syrup urine disease (MSUD) belong to the category of intoxication-type inborn errors of metabolism (IT-IEM). Liver transplantation (LTx) is increasingly utilized in IT-IEM. However, its impact has been mainly focused on clinical outcome measures and rarely on health-related quality of life (HRQoL).

The diagnostic challenge of mild citrulline elevation at newborn screening.

Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency.

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.

Determination of the valence band edge of Fe oxide nanoparticles dispersed in aqueous solution through resonant photoelectron spectroscopy from a liquid microjet.

We use X-ray photoemission and a near ambient pressure with a liquid microjet setup to investigate the electronic structure of FeOOH nanoparticles dispersed in aqueous solution. In particular, we show that by using X-ray resonant photoemission in dilute solutions, we can overcome the limits of conventional photoemission such as low nanoparticle-to-solvent signal ratio, and local nanoparticle charging and measure the valence band structure of FeOOH nanoparticles in aqueous solution with chemical specificity. The resonant photoemission signal across the Fe 2p absorption edge is measured for 2 wt% aqueous solutions of FeOOH nanoparticles (NPs) and the valence band maximum (VBM) of the hydrated FeOOH nanoparticles is determined.

Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient.

Background: Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death. In 2014, based on the promising results obtained by liver-targeted gene therapy in Ethe1 mouse model, we successfully attempted liver transplantation in a 9-month-old EE girl. Here we report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments.

Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation.

Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome.

Orofacial features and pediatric dentistry in the long-term management of Infantile Pompe Disease children.

Background: Glycogen storage disease type II (GSDII) or Pompe disease is a rare autosomal recessive metabolic disorder that leads to intracellular glycogen storage in many tissues, mainly in skeletal muscle, heart and liver. Facial muscle weakness and altered craniofacial growth are very common in Pompe disease children. In this paper we describe the orofacial features in two children affected by GSDII and illustrate a multidisciplinary approach that involved enzyme replace therapy, non-invasive ventilation (NIV) and pediatric dentistry with 5-year follow-up.

Health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism: Analysis of an international data set.

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and - in acute diseases - metabolic decompensations nevertheless. Research on the subjective burden of IT-IEM remains sparse.

Early visual and neuro-development in preterm infants with and without retinopathy.

Background: Retinopathy of prematurity (ROP) is often associated with visual impairment and multiple developmental disabilities.

Aims: As most of the previous studies include infants with brain lesions, that can determine visual impairment per se, a cohort of low neurological risk preterm infants without ROP and with various degree of severity of ROP was assessed in order to establish visual and neurodevelopmental outcome.

Study Design: Preterm infants born at <31 weeks gestation, without major brain lesions, underwent visual function assessment at 1 year corrected age and neurodevelopmental assessment at 2 years corrected age.

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia.

Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second-tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long-term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation.

Spinal cord demyelination in children: A diagnostic challenge in neuropaediatrics for a good outcome.

Background: Biotinidase deficiency (BTD) is an autosomal recessive inborn error of metabolism provoking progressive biotin depletion, which causes, in turn, multiple carboxylase deficiency. Its infantile onset is characterized by intractable seizures associated with lethargy, psychomotor regression, hypotonia, feeding and respiratory problems, and cutaneous abnormalities.

Case Description: We describe a 52-month-old female whose clinical and neuroradiological pictures were consistent with myelopathy, which is generally more frequent in older patients, as well as with symptoms of an infantile onset of biotinidase deficiency, revealed at 17 months.

A wearable video-oculography based evaluation of saccades and respective clinical correlates in patients with early onset ataxia.

Background: Friedreich Ataxia (FRDA) and other inherited chronic ataxias (CAs) are common causes of early onset ataxias (EOA), a group of conditions still lacking effective therapies and biomarkers. Ocular saccades are considered a reliable paradigm of motor control, useful to track the functioning of underlying neural networks and serving as potential markers for neurological diseases.

New Method: A non-invasive video-oculography device (EyeSeeCam) was used to test saccadic parameters (latency, amplitude, duration, velocity) and peak velocity/amplitude ratio ("main sequence") in pediatric patients with FRDA, CAs and healthy controls, providing correlations with standard clinical scores.

Dravet syndrome: Early electroclinical findings and long-term outcome in adolescents and adults.

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders.

Early neurodevelopmental characterization in children with cobalamin C/defect.

Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy.

Corticospinal tract damage in HHH syndrome: a metabolic cause of hereditary spastic paraplegia.

Background: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare disorder of urea cycle characterized by progressive pyramidal and cerebellar dysfunction, whose pathophysiology is not yet fully understood. Here we describe the spectrum of the long fibers involvement in HHH syndrome, attempting a correlation between clinical, electrophysiological and neuro-radiological data.

Methods: Nine HHH patients were longitudinally evaluated by clinical examination, neurophysiological assessment including motor (MEPs), somato-sensory evoked potentials (PESS) and nerve conduction velocity (NCV), brain and spinal cord MRI RESULTS: All patients had pyramidal dysfunction and 3/9 an overt spastic paraplegia.

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.

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.

Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism.

Objectives: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia.

Study Design: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders.