Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy.

Background: Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy.

Management of pain in Fabry disease in the UK clinical setting: consensus findings from an expert Delphi panel.

Background: Fabry disease is a rare, X-linked inherited lysosomal storage disorder, that manifests as a heterogeneous disease with renal, cardiac and nervous system involvement. The most common pain experienced by people with Fabry disease are episodes of neuropathic pain reported in up to 80% of classical hemizygous male patients and up to 65% of heterozygous female patients. No clear consensus exists within UK clinical practice for the assessment and management of pain in Fabry disease based on agreed clinical practice and clinical experience.

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report.

Purpose: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3).

Methods: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months.

Results: In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3-avalglucosidase alfa [n = 5], and cohort 3-alglucosidase alfa [n = 6]).

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease.

Background: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life.

Pulmonary Manifestations of Endocrine and Metabolic Diseases in Children.

Advances in technology, methodology, and deep phenotyping are increasingly driving the understanding of the pathologic basis of disease. Improvements in patient identification and treatment are impacting survival. This is true in endocrinology and inborn errors of metabolism, where disease-modifying therapies are developing.

Transition to Adult Care in Children on Long-Term Ventilation.

The number of children on long-term ventilation (LTV) has exponentially increased over the past few decades. Improvements in management of ventilation coupled with improvements in standards of medical care are increasingly allowing young people on LTV to survive into adulthood. The process of transition from the pediatric to the adult healthcare system is challenging and requires special attention.

Improvement in functional gait parameters following corrective thoracolumbar surgery in children affected by Mucopolysaccharidosis 1 (Hurler syndrome).

Objective: Thoracolumbar kyphosis is a common indication for spinal surgery in children with Mucopolysaccharidosis. Functional outcome of spinal surgical intervention has never been published in patients with this rare disease. We present a cohort of patients with Mucopolysaccharidosis 1(Hurler syndrome) who underwent thoraco-lumbar spinal deformity correction and functional outcome assessed by pre-operative and post-operative gait analysis.

Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency.

Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with >75 candidate disease-associated genes having been reported to date.

International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome.

Aim: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening.

Methods: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I.

I-Cell Disease (Mucolipidosis II): A Case Series from a Tertiary Paediatric Centre Reviewing the Airway and Respiratory Consequences of the Disease.

Background: Inclusion cell disease (I-cell) is a rare autosomal recessive metabolic disease involving multiple organ systems, associated with a severely restricted life expectancy. No curative therapy is currently available, with management aimed at symptom palliation.

Methods: We present a retrospective, single-centre, case series of children referred to a tertiary paediatric metabolic service.

Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing.

Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.

Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.

Results: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses.

Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation.

Premature death in untreated children with Hurler syndrome (HS) in the first decade of life is largely due to life-threatening cardiopulmonary complications. We examined the long-term survival and cardiopulmonary outcome in 54 children undergoing haematopoietic stem cell transplantation (HSCT) at the Royal Manchester Children's Hospital from 1985 to 2008. The median age at first HSCT was 15.

Expanding the phenotype in argininosuccinic aciduria: need for new therapies.

Objectives: This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.

Methods: Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs.

The diagnostic journey of patients with mucopolysaccharidosis I: A real-world survey of patient and physician experiences.

Unlabelled: Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease. Affected individuals have disease ranging from attenuated to severe with significant disease burden, disability, and premature death. Early treatment with enzyme replacement therapy and/or stem cell transplantation can reduce disease progression and improve outcomes.

Paediatric single mitochondrial DNA deletion disorders: an overlapping spectrum of disease.

Background: Single large-scale mitochondrial DNA (mtDNA) deletions (SLSMDs) are amongst the most frequently diagnosed mtDNA disorders in childhood, yet their natural history remains poorly understood. We report the natural history of a large multicentre cohort of such children.

Methods: We reviewed case notes from three different UK centres to determine the clinical course of 34 patients (16 female, 18 male) with childhood-onset mitochondrial disease caused by SLSMDs.

TMEM70 deficiency: long-term outcome of 48 patients.

Objectives: TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood.

How to use serum ammonia.

Hyperammonaemia is a potentially extremely important indicator of impairment in intermediate metabolism. However, lack of experience in sample handling and confusion about what level is significant, can lead to its devaluation as a test. The aim of this article is to help the non-metabolic specialist to decide when it is appropriate to investigate for hyperammonaemia, to discuss potential investigatory pitfalls and to help in interpretation of results.