Metabolic Control and Frequency of Clinical Monitoring Among Canadian Children With Phenylalanine Hydroxylase Deficiency: A Retrospective Cohort Study.

Achieving and maintaining metabolic control is critical for children with phenylalanine hydroxylase (PAH) deficiency. This retrospective longitudinal cohort study investigated metabolic control and monitoring frequency of children with PAH deficiency (≤ 12 years) treated at one of 12 pediatric metabolic centres across Canada. We abstracted data from medical charts and analyzed outcomes by age and diagnostic classification, using mixed effects regression.

Establishing a core outcome set for creatine transporter deficiency and guanidinoacetate methyltransferase deficiency.

Background: Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients with either condition commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements.

Protein requirements in adults with phenylketonuria and bioavailability of glycomacropeptide compared to an l-amino acid-based product.

Background: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase deficiency. Treatment is primarily a low-Phe diet combined with l-amino acid-based products (l-AA). Protein requirements in adults with PKU have not been directly determined.

Health Care Costs After Genome-Wide Sequencing for Children With Rare Diseases in England and Canada.

Importance: Etiologic diagnoses for rare diseases can involve a diagnostic odyssey, with repeated health care interactions and inconclusive diagnostics. Prior studies reported cost savings associated with genome-wide sequencing (GWS) compared with cytogenetic or molecular testing through rapid genetic diagnosis, but there is limited evidence on whether diagnosis from GWS is associated with reduced health care costs.

Objective: To measure changes in health care costs after diagnosis from GWS for Canadian and English children with suspected rare diseases.

Claudin-11 in health and disease: implications for myelin disorders, hearing, and fertility.

Claudin-11 plays a critical role in multiple physiological processes, including myelination, auditory function, and spermatogenesis. Recently, stop-loss mutations in have been identified as a novel cause of hypomyelinating leukodystrophy (HLD22). Understanding the multifaceted roles of claudin-11 and the potential pathogenic mechanisms in HLD22 is crucial for devising targeted therapeutic strategies.

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Background: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits.

Methods: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes.

Real-world diagnostic outcomes and cost-effectiveness of genome-wide sequencing for developmental and seizure disorders: Evidence from Canada.

Purpose: To determine real-world diagnostic rates, cost trajectories, and cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children with developmental and/or seizure disorders in British Columbia, Canada.

Methods: Based on medical records review, we estimated real-world costs and outcomes for 491 patients who underwent standard of care (SOC) diagnostic testing at British Columbia Children's Hospital. Results informed a state-transition Markov model examining cost-effectiveness of 3 competing diagnostic strategies: (1) SOC with last-tier access to ES, (2) streamlined ES access, and (3) first-tier GS.

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.

Determining ideal balance among branched-chain amino acids in medical formula for Propionic Acidemia: A proof of concept study in healthy children.

Background: Propionic Acidemia (PROP) is an inherited metabolic disorder, with defect in the enzyme propionyl-CoA carboxylase (PCC) which catalyzes catabolism of two of the branched-chain amino acids (BCAA), valine, isoleucine. Nutritional management in PROP depends on dietary protein restriction and consumption of medical formula depleted of the offending amino acids. Recently, concerns have been raised about medical formula due to imbalanced content of BCAA (high leucine - another BCAA, and no valine/isoleucine), which negatively impacts plasma concentrations of BCAA, and growth in children with PROP.

Dietary management and growth outcomes in children with propionic acidemia: A natural history study.

Background: Propionic acidemia (PROP) is an autosomal recessive inherited deficiency of propionyl-CoA carboxylase (PCC) which is involved in the catalytic breakdown of the amino acids valine, isoleucine, methionine, and threonine. PROP nutritional management is based on dietary protein restriction and use of special medical formulas which are free of the offending amino acids, but are enriched in leucine. The resulting imbalance among branched-chain amino acids negatively impacts plasma concentrations of valine and isoleucine, which might impact growth in children with PROP.

Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct -related phenotype.

Background: Morquio B disease (MBD) is a distinct -related dysostosis multiplex presenting a mild phenocopy of -related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one allele and exhibit a pure skeletal phenotype (). Only a minority of MBD cases have been described with additional neuronopathic findings ().

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation.

Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app.

Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disability (collectively 'treatable IDs'). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation.

Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021.

Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report.

Background: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers.

Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct -Related Dysostosis Multiplex.

Morquio B disease (MBD) is an autosomal recessive -gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in -related Morquio A disease. MBD may present as pure skeletal phenotype () or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia.

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.

Developments in evidence creation for treatments of inborn errors of metabolism.

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell-and gene-based therapies have become available. Inherent to the rare nature of the single conditions, generating high-quality evidence for these treatments in clinical trials and under real-world conditions has been challenging.

Impact of enteral arginine supplementation on lysine metabolism in humans: A proof-of-concept for lysine-related inborn errors of metabolism.

Patients with lysine-related inborn errors of metabolism (pyridoxine-dependent epilepsy [PDE] and glutaric aciduria type 1 [GA1]), follow a lysine-restricted diet with arginine-fortified lysine-free amino acid formula and additional oral arginine supplementation as a newer therapy for PDE. The rationale of arginine supplementation is based on arginine's ability to compete with lysine transport across cell membranes via shared transporter systems. Adequate doses of arginine required to competitively inhibit enteral lysine uptake has not been studied in humans This proof-of-concept study investigates the effect of incremental enteral arginine doses on whole-body lysine oxidation using an in vivo stable isotope tracer, L-[1- C] lysine, in healthy humans.

Morquio-B disease: Clinical and genetic characteristics of a distinct -related dysostosis multiplex.

Background: Morquio-B disease (MBD) is a distinct -related dysostosis multiplex involving the trabecular parts of long bones and spine, presenting a mild phenocopy of -related Morquio-A disease.

Methods: We analyzed 63 (n = 62 published) cases with MBD to describe their clinical, biochemical and genetic features.

Results: Forty-one of 51 cases with informative clinical data had including progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly, odontoid hypoplasia.