Increased Sphingomyelin and Free Sialic Acid in Cerebrospinal Fluid of Kearns-Sayre Syndrome: New Findings Using Untargeted Metabolomics.

BACKGROUND: Kearns-Sayre syndrome (KSS) is caused by duplications and/or deletions of mitochondrial DNA (mtDNA) and is typically diagnosed based on a classic triad of symptoms with chronic progressive external ophthalmoplegia (CPEO), retinitis pigmentosa, and onset before age 20 years. The present study aimed to diagnose two patients, on suspicion of KSS. METHODS: One of the patients went through a diagnostic odyssey, with normal results from several mtDNA analyses, both in blood and muscle, before the diagnosis was confirmed genetically. RESULTS: Two patients presented increased tau protein and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid (CSF). Untargeted metabolomics on CSF samples also showed an increase in the levels of free sialic acid and sphingomyelin C16:0 (d18:1/C16:0), compared with four control groups (patients with mitochondrial disorders, nonmitochondrial disorders, low 5-MTHF, or increased tau proteins). CONCLUSIONS: It is the first time that elevated sphingomyelin C16:0 (d18:1/C16:0) and tau protein in KSS are reported. Using an untargeted metabolomics approach and standard laboratory methods, the study could shed new light on metabolism in KSS to better understand its complexity. In addition, the findings may suggest the combination of elevated free sialic acid, sphingomyelin C16:0 (d18:1/C16:0), and tau protein as well as low 5-MTHF as new biomarkers in the diagnostics of KSS.

Clinical guidance for diagnosis and management of suspected Pediatric Acute-onset Neuropsychiatric Syndrome in the Nordic countries.

Pediatric acute-onset neuropsychiatric syndrome is a clinical concept used to describe a subgroup of children with sudden onset of psychiatric and somatic symptoms. The diagnostic term and especially management of children differs depending on the clinical setting to which they present, and the diagnosis and management is controversial. The aim of this paper is to propose a clinical guidance including homogenous diagnostic work-up and management of paediatric acute onset neuropsychiatric syndrome within the Nordic countries. The guidance is authored by a Nordic-UK working group consisting of paediatric neurologist, child psychiatrists and psychologists from Denmark, Norway, Sweden and Great Britain, and is the result of broad consensus. CONCLUSION: Consensus was achieved in the collaboration on work-up and treatment of patients with paediatric acute-onset neuropsychiatric syndrome, which we hope will improve and homogenise patient care and enable future collaborative research in the field.

Effects of nutrition therapy on growth, inflammation and metabolism in immature infants: a study protocol of a double-blind randomized controlled trial (ImNuT).

BACKGROUND: Current nutritional management of infants born very preterm results in significant deficiency of the essential fatty acids (FAs) arachidonic acid (ARA) and docosahexaenoic acid (DHA). The impact of this deficit on brain maturation and inflammation mediated neonatal morbidities are unknown. The aim of this study is to determine whether early supply of ARA and DHA improves brain maturation and neonatal outcomes in infants born before 29 weeks of gestation. METHODS: Infants born at Oslo University Hospital are eligible to participate in this double-blind randomized controlled trial. Study participants are randomized to receive an enteral FA supplement of either 0.4 ml/kg MCT-oil™ (medium chain triglycerides) or 0.4 ml/kg Formulaid™ (100 mg/kg of ARA and 50 mg/kg of DHA). The FA supplement is given from the second day of life to 36 weeks' postmenstrual age (PMA). The primary outcome is brain maturation assessed by Magnetic Resonance Imaging (MRI) at term equivalent age. Secondary outcomes include quality of growth, incidence of neonatal morbidities, cardiovascular health and neuro-development. Target sample size is 120 infants (60 per group), this will provide 80% power to detect a 0.04 difference in mean diffusivity (MD, mm2/sec) in major white matter tracts on MRI. DISCUSSION: Supplementation of ARA and DHA has the potential to improve brain maturation and reduce inflammation related diseases. This study is expected to provide valuable information for future nutritional guidelines for preterm infants. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03555019 . Registered 4 October 2018- Retrospectively registered.

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.