RICTOR variants are associated with neurodevelopmental disorders.

RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene.

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome.

Purpose: RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.

Methods: Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing.

Association Between Lysine Reduction Therapies and Cognitive Outcomes in Patients With Pyridoxine-Dependent Epilepsy.

Background And Objectives: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies (LRTs) reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with LRTs and cognitive outcomes.

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients.

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking.

Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy.

Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.

Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy.

The enzyme ubiquitin-like modifier activating enzyme 5 (UBA5) plays an important role in activating ubiquitin-fold modifier 1 (UFM1) and its associated cascade. is widely expressed and known to facilitate the post-translational modification of proteins. Variants in and are involved in neurodevelopmental disorders with early-onset epileptic encephalopathy as a frequently seen disease manifestation.

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability.

Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.

Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency.

Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally.

Melatonin in neuropaediatric MRI: a retrospective study of efficacy in a general hospital setting.

Background: Melatonin may offer a safe and cheap alternative to general anaesthesia and sedatives in neuropaediatric MRI. The purpose of our study was to evaluate its efficacy during a daily scanning programme and to assess its financial benefit.

Methods: Neuro-MRI scans, performed in a general hospital setting after administration of melatonin in 64 children aged 10 months-5 years, were retrospectively reassessed by an experienced paediatric neuroradiologist, rating them as diagnostically contributing or as failed.

Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.

Background: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available.

The neurological phenotype of developmental motor patterns during early childhood.

Introduction: During early childhood, typical human motor behavior reveals a gradual transition from automatic motor patterns to acquired motor skills, by the continuous interplay between nature and nurture. During the wiring and shaping of the underlying motor networks, insight into the neurological phenotype of developmental motor patterns is incomplete. In healthy, typically developing children (0-3 years of age), we therefore aimed to investigate the neurological phenotype of developmental motor patterns.

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.).

Construct Validity and Reliability of the SARA Gait and Posture Sub-scale in Early Onset Ataxia.

In children, gait and posture assessment provides a crucial marker for the early characterization, surveillance and treatment evaluation of early onset ataxia (EOA). For reliable data entry of studies targeting at gait and posture improvement, uniform quantitative biomarkers are necessary. Until now, the pediatric test construct of gait and posture scores of the Scale for Assessment and Rating of Ataxia sub-scale (SARA) is still unclear.

Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI.

Molybdenum cofactor deficiency type A (MoCD-A) is an inborn error of metabolism presenting early after birth with severe seizures. Recently, experimental substitution treatment with cyclic pyranopterin monophosphate (cPMP) has become available. Because prenatal data is scarce, we report data of prenatal Magnetic Resonance Imaging (MRI) in two cases with MoCD-A demonstrating signs of possible early brain injury.

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.

Background: Autosomal recessive mutations in , encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants.

Objective: Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for variants.

Methods: To analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed.

Reliability and discriminant validity of ataxia rating scales in early onset ataxia.

Aim: To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA).

Method: In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation coefficient [ICC]) and discriminant validity of ataxia rating scales (International Cooperative Ataxia Rating Scale [ICARS], Scale for Assessment and Rating of Ataxia [SARA], and Brief Ataxia Rating Scale [BARS]). Three paediatric neurologists independently scored ICARS, SARA and BARS performances recorded on video, and also phenotyped the primary and secondary movement disorder features.

Diagnostic value of MRS-quantified brain tissue lactate level in identifying children with mitochondrial disorders.

Objectives: Magnetic resonance spectroscopy (MRS) of children with or without neurometabolic disease is used for the first time for quantitative assessment of brain tissue lactate signals, to elaborate on previous suggestions of MRS-detected lactate as a marker of mitochondrial disease.

Methods: Multivoxel MRS of a transverse plane of brain tissue cranial to the ventricles was performed in 88 children suspected of having neurometabolic disease, divided into 'definite' (n = 17, ≥1 major criteria), 'probable' (n = 10, ≥2 minor criteria), 'possible' (n = 17, 1 minor criterion) and 'unlikely' mitochondrial disease (n = 44, none of the criteria). Lactate levels, expressed in standardized arbitrary units or relative to creatine, were derived from summed signals from all voxels.

The Burke-Fahn-Marsden Dystonia Rating Scale is Age-Dependent in Healthy Children.

Background: The Burke-Fahn-Marsden Dystonia Rating Scale is a universally applied instrument for the quantitative assessment of dystonia in both children and adults. However, immature movements by healthy young children may also show "dystonic characteristics" as a consequence of physiologically incomplete brain maturation. This could implicate that Burke-Fahn-Marsden scale scores are confounded by pediatric age.

Subtle bilirubin-induced neurodevelopmental dysfunction (BIND) in the term and late preterm infant: does it exist?

Subtle bilirubin-induced neurological dysfunction (BIND) is defined as disturbances in sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone in the absence of the classical findings of kernicterus. This review is restricted to the (sensori)motor signs of BIND associated with unconjugated hyperbilirubinemia in term and late preterm neonates. The diagnosis of BIND at follow-up requires validated, age-specific techniques that are designed to identify these disturbances in infancy and later childhood.

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism caused by fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems.

Assessment of speech in early-onset ataxia: a pilot study.

Aim: The aim of the study was to determine whether paediatric ataxia speech subscores are reliably applicable for international early-onset ataxia (EOA) databases. If so, we reasoned that ataxia speech subscores should be associated with ataxia scores and involve high interobserver agreement, including those for internationally applicable Scale for Assessment and Rating of Ataxia (SARA) syllable repetition tasks (SARASRT).

Method: Three independent paediatric neurologists and a speech therapist scored speech in 52 healthy children (mean age 10y, range 4-16y) and 40 individuals with EOA (mean age 15y, range 5-34y).

Neonatal seizures: aetiology by means of a standardized work-up.

Unlabelled: Neonatal seizures are an alarming symptom and are frequent in neonates. It is important to find the cause of neonatal seizures to start a specific treatment and to give a meaningful prognosis. The aim of this study is to investigate the incidence of different aetiologies of neonatal seizures in our hospital by a specific work-up.