A novel ELP1 mutation impairs the function of the Elongator complex and causes a severe neurodevelopmental phenotype.

BACKGROUND: Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders. Pathogenic variants in its largest subunit ELP1 have been previously found in familial dysautonomia and medulloblastoma, with no link to NDDs affecting primarily the central nervous system. METHODS: Clinical investigation included patient history and physical, neurological and magnetic resonance imaging (MRI) examination. A novel homozygous likely pathogenic ELP1 variant was identified by whole-genome sequencing. Functional studies included in silico analysis of the mutated ELP1 in the context of the holo-complex, production and purification of the ELP1 harbouring the identified mutation and in vitro analyses using microscale thermophoresis for tRNA binding assay and acetyl-CoA hydrolysis assay. Patient fibroblasts were harvested for tRNA modification analysis using HPLC coupled to mass spectrometry. RESULTS: We report a novel missense mutation in the ELP1 identified in two siblings with intellectual disability and global developmental delay. We show that the mutation perturbs the ability of ELP123 to bind tRNAs and compromises the function of the Elongator in vitro and in human cells. CONCLUSION: Our study expands the mutational spectrum of ELP1 and its association with different neurodevelopmental conditions and provides a specific target for genetic counselling.

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

Unusual Presentations of Dystrophinopathies in Childhood.

X-linked recessive mutations in the dystrophin gene are one of the most common causes of inherited neuromuscular disorders in humans. Duchenne muscular dystrophy, the most common phenotype, and Becker muscular dystrophy are often recognizable by certain clinical features; however, less frequent presentations require a higher degree of suspicion. In this article, we describe a series of 6 children (4 boys, 2 girls) referred to a tertiary pediatric neuromuscular clinic for isolated elevated creatine kinase levels (range: 720-7000 IU/L) identified on initial assessment for otherwise unexplained transaminase elevations (n = 2), a social communication disorder (n = 3), and exertional myalgia and/or rhabdomyolysis (n = 1). There was no preceding family history of neuromuscular disease. One boy had an additional history of severe cerebral palsy and cyclical vomiting, and 1 girl had a history of maternal hepatitis C. There was no significant weakness at presentation, and the majority remained stable over a prolonged period of follow-up (age range at last follow-up: 9-16 years). All 6 children were found to carry dystrophin gene mutations resulting in milder phenotypes. This series highlights that dystrophinopathies may not uncommonly present with features distinct from the classic Duchenne muscular dystrophy and Becker muscular dystrophy phenotypes in both boys and girls. Pediatricians should be aware of such atypical presentations to initiate a timely and adequate diagnostic process. Establishing the correct genetic diagnosis of a dystrophinopathy is important to allow appropriate genetic counseling, to implement relevant surveillance and management strategies, and to avoid unnecessary investigations in search of an incorrect alternative diagnosis.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Complications of Deep Brain Stimulation (DBS) for dystonia in children - The challenges and 10 year experience in a large paediatric cohort.

Deep brain stimulation (DBS) has been increasingly used for primary and secondary movement disorders in children and young people. Reports of hardware related complications have been sparse for this population and from small cohorts of patients. We report DBS complications from a single large DBS centre with 10 year experience. Data was collected as a prospective audit and additionally from a questionnaire on recharging of the stimulators. 129 patients with a minimum 6 months follow up were identified, mean age10.8 y (range 3.0-18.75), mean follow up 3.3y (range 0.5-10.3), weight 10.4-94.2 kg, 126 new implants (92 Activa RC) and 69 revisions for reasons other than infection. 26 patients were 7y or younger. Surgical site infections (SSI) rates were 10.3% for new implants and revisions, lower 8.6% for new Activa RC and even lower, 4.7%, for new Activa RC in patients under 7y (1/21). SSI occurred within first 6 months and necessitated total system removal in 86% of those infected. Electrode/extension problems were recorded in 18.4% of patients, fracture in 4.6% malfunction in 7.7%, short extension 3.8% and electrode migration in 2.3%. Other complications involved clinically silent intracranial bleed in 1 patient, skin erosions (2.3%), unexpected switching off in 18.7% of Soletra/Kinetra and 3.4% of Activa RC, transient seroma at IPG site in postoperative period (8%). Of the 48 returned recharging questionnaires, 38% of families required recharger replacement and 23% experienced frequent problems maintaining connection during recharging. However, 83% of responders considered recharging not at all or only a little care burden. We identified lower than previously reported DBS infection rates particularly for patients under 7 years, but relatively high incidence of technical problems with electrodes, extensions and in particular recharging. This has to be considered when offering DBS for children with movement disorders.