Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

Introduction: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically.

Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment.

Metachromatic leukodystrophy (MLD) is a devastating rare neurodegenerative disease. Typically, loss of motor and cognitive skills precedes early death. The disease is characterised by deficient lysosomal arylsulphatase A (ARSA) activity and an accumulation of undegraded sulphatide due to pathogenic variants in the ARSA gene.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries.

Background: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions.

First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

Background/objectives: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2.

A retrospective cohort study of Libmeldy (atidarsagene autotemcel) for MLD: What we have accomplished and what opportunities lie ahead.

Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa-cel), an autologous haematopoietic stem cell gene therapy (HSC-GT) product, has demonstrated sustained clinical benefits in MLD.

Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children.

Isolated central nervous system (CNS) presentations of haemophagocytic lymphohistiocytosis (HLH), traditionally a systemic inflammatory condition, have been reported in adults and children. We identified nine patients with a diagnosis of isolated CNS familial hemophagocytic lymphohistiocytosis (fHLH) with symptom onset <18 years of age, and one asymptomatic sibling. Children with atypical chronic/recurrent CNS inflammation should be considered for immunological and genetic panel testing for fHLH even in the absence of any systemic inflammatory features.

Expanding the phenotypic spectrum of pathogenic variants in the PRRT2 gene: bilateral papilledema and abducens nerve palsies secondary to pseudotumor cerebri syndrome.

An 8-year-old girl with known pathogenic variant in the PRRT2 gene causing paroxysmal kinesigenic dyskinesia with infantile convulsions presented with bilateral papilledema and abducens nerve palsy, which was subsequently confirmed to be pseudotumor cerebri syndrome (PTCS). She was treated with acetazolamide and recovered baseline vision, with some residual papilledema. PTCS is not confirmed to be associated with pathogenic variants in the PRRT2 gene; however, this case in conjunction with a previously reported case of PTCS and unilateral abducens nerve palsy in a patient with PRRT2 variants, raises the possibility that PTCS is part of the phenotypic spectrum rather than being a coincidental occurrence.

Neurological manifestations of SARS-CoV-2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study.

Background: The spectrum of neurological and psychiatric complications associated with paediatric SARS-CoV-2 infection is poorly understood. We aimed to analyse the range and prevalence of these complications in hospitalised children and adolescents.

Methods: We did a prospective national cohort study in the UK using an online network of secure rapid-response notification portals established by the CoroNerve study group.

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

Objectives: To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS).

Methods: In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records.

Two Paediatric Patients with Encephalopathy and Concurrent COVID-19 Infection: Two Sides of the Same Coin?

There is increasing evidence that SARS-CoV-2 has neurotropic potential. We report on two paediatric patients who presented with encephalopathy during COVID-19 illness. Both patients had ADEM-like changes in their neuroimaging, negative SARS-CoV-2 RNA PCR in CSF, and paucity of PIMS-TS laboratory findings.

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype.

Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study.

Background: The CNS manifestations of COVID-19 in children have primarily been described in case reports, which limit the ability to appreciate the full spectrum of the disease in paediatric patients. We aimed to identify enough cases that could be evaluated in aggregate to better understand the neuroimaging manifestations of COVID-19 in the paediatric population.

Methods: An international call for cases of children with encephalopathy related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and abnormal neuroimaging findings was made.

T2-highlighted U-fibres and rapid parenchymal volume loss in AESD: An under-recognised subtype of paediatric acute encephalopathy syndromes.

Acute Encephalopathy with Reduced Subcortical Diffusion or AED is a unique subtype of acute paediatric encephalopathy which presents with altered mental status, prolonged seizures and developing characteristic radiological signal changes within the subcortical white matter. Reports of such cases have mainly been from Japan (Takanashi, 2009) and this radiological finding has been recognised as a novel feature of AED. We present three paediatric cases from a tertiary paediatric neurosciences centre in Manchester (Royal Manchester Children's hospital) with characteristic subcortical signal change, and furthermore, follow up imaging which in all 3 patients demonstrated a varying degree of cerebral atrophy.

Fifteen-minute consultation: A practical approach to developmental regression in children.

Developmental regression is an important red flag in any child's developmental performance and should be recognised promptly. It is the loss of previously acquired skills and can affect any sphere of childhood development. Presentation and underlying causes are heterogeneous in nature, in turn presenting many clinical challenges.

Retrospective natural history of thymidine kinase 2 deficiency.

Background: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.

Objective: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.

The Genetics of Febrile Seizures.

Investigators from Virginia Commonwealth University, Norwegian Center for Epilepsy and University of Southern Denmark carried out twin studies to analyse the genetic influence of developing epilepsy after febrile seizures.