• antiepileptic drugs
• glycine encephalopathy
• hiccup‐like movements
• neonatal nonketotic hyperglycinemia
• prenatal indicators

• Birth prevalence
• Epidemiology
• Meta-analysis
• Pompe disease
• Systematic review

• Humans
• Global Health/statistics & numerical data
• Glycogen Storage Disease Type II/epidemiology
• Prevalence
• Infant, Newborn

• AAV
• gene therapy
• inherited metabolic disorders
• lipid nanoparticles
• liver
• metabolite detoxification

• Humans
• Liver/metabolism
• Genetic Therapy/methods
• Animals
• Inactivation, Metabolic/genetics
• Gene Transfer Techniques
• Metabolic Diseases/genetics
• Metabolic Diseases/metabolism
• Metabolic Diseases/therapy
• Metabolism, Inborn Errors/genetics
• Metabolism, Inborn Errors/metabolism
• Metabolism, Inborn Errors/therapy

• Italian Ministry of University and Research
• European Union
• Fondazione Telethon

• congenital diseases
• inborn errors of metabolism
• neonate
• newborn screening
• tandem mass spectrometry

• Humans
• Heart Diseases/etiology
• Heart Diseases/diagnosis
• Heart Diseases/physiopathology
• Cardiomyopathies/etiology
• Cardiomyopathies/diagnosis
• Cardiomyopathies/physiopathology
• Metabolism, Inborn Errors/diagnosis
• Metabolism, Inborn Errors/complications

• Congenital
• Egypt
• Liver diseases
• Orphan
• Rare

• Humans
• Egypt/epidemiology
• Liver Diseases/epidemiology
• Liver Diseases/diagnosis
• Rare Diseases/epidemiology
• Rare Diseases/diagnosis

• Amino acids
• Dried blood spots
• Inborn Errors of metabolism
• LC-MS/MS
• Newborn screening

• Fabry disease
• Gaucher disease
• Inborn errors of metabolism
• Lysosomal storage diseases
• Rare diseases
• Rheumatic diseases
• Sphingolipidoses
• Sphingolipids

• Humans
• Fabry Disease/complications
• Fabry Disease/diagnosis
• Gaucher Disease/complications
• Gaucher Disease/diagnosis
• Rheumatologists
• Quality of Life
• Lysosomal Storage Diseases/diagnosis
• Eye Diseases

• Mice
• Humans
• Animals
• Homocystinuria/genetics
• Homocystinuria/therapy
• Escherichia coli/genetics
• Probiotics/therapeutic use
• Pyridoxine
• Homocysteine

• Arylsulfatase A
• Birth prevalence
• Epidemiology
• Lysosomal storage disease
• Metachromatic leukodystrophy
• Systematic review

• Adult
• Humans
• Cerebroside-Sulfatase/genetics
• Europe
• Leukodystrophy, Metachromatic/genetics
• Lysosomal Storage Diseases
• Prevalence

• Anemia
• Cytopenia
• Diagnosis
• Hemolysis
• Inherited metabolic diseases
• Macrocytosis
• Neutropenia
• Splenomegaly

• Humans
• Cytopenia
• Metabolic Diseases/genetics
• Neutropenia

• enzyme replacement therapy
• gene therapy
• immunomodulatory drugs
• innate immunity
• mucopolysaccharidosis

• Humans
• Therapies, Investigational
• Mucopolysaccharidoses/genetics
• Mucopolysaccharidoses/therapy
• Osteochondrodysplasias
• Antibodies, Monoclonal
• Glycosaminoglycans
• Inflammation

• R01 HD102545 NICHD NIH HHS
• 1R01HD102545-01A1 NIH HHS

• CKD
• Chronic kidney disease
• Inborn error of metabolism
• Metabolomics
• Pediatric

• Adult
• Adolescent
• Humans
• Child
• Diabetes Mellitus, Type 2
• Kidney/metabolism
• Renal Insufficiency, Chronic/genetics
• Metabolomics
• Biomarkers
• Metabolism, Inborn Errors/genetics

• GSD 1a
• epidemiology
• glycogen storage disease type 1a
• prevalence
• simulation modelling
• systematic literature review

• Infant, Newborn
• Humans
• Pregnancy
• Female
• Glycogen Storage Disease Type I/epidemiology
• Glucose-6-Phosphatase
• Parents
• Parturition

• THTR2 (SLC19A3) gene mutation
• acute encephalopathy
• amino acid metabolism disorders
• enoyl-CoA hydratase short-chain 1
• fatty acid metabolism disorders
• homocystinuria
• inherited metabolic disease
• liver transplantation
• mitochondrial diseases
• urea cycle disorders

• dental pulp stem cells (DPSCs)
• disease modeling
• in vitro models
• induced pluripotent stem cells (iPSCs)
• mucopolysaccharidoses

• EXPL/BTM-SAL/0659/2021 Fundação para a Ciência e Tecnologia
• Bolsa SPDM de apoio à investigação Dr. Aguinaldo Cabral 2018 (2019DGH1629/ SPDM2018I&D) Portuguese Society for Metabolic Disorders (SPDM)
• 2019DGH1656/ SCF2019I&D Sanfilippo Children's Foundation
• UIDB/00211/2020 Centro de Estudos de Ciência Animal/ Center for the Study of Animal Science
• LA/P/0059/2020 Laboratório Associado para Ciência Animal e Veterinária/Associate Laboratory for Animal and Veterinary Sciences

• Humans
• Autistic Disorder/genetics
• Quality of Life
• Autism Spectrum Disorder/diagnosis
• Autism Spectrum Disorder/genetics
• Metabolic Diseases/diagnosis
• Metabolic Diseases/genetics
• Neurodevelopmental Disorders

Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive genetic disorder of abnormal glycine metabolism caused by insufficient activity of the glycine cleavage enzyme system. Glycine is believed to function mainly as an inhibitory neurotransmitter, but it can also act as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor. The accumulation of a large amount of glycine in the brain leads to neuronal and axonal injury via overactivation of NMDA receptors located in the hippocampus, cerebral cortex, olfactory bulb, and cerebellum and to stimulation of the inhibitory function of glycine receptors located in the spinal cord and brain stem, resulting in central apnea, hiccups, and hypotonia in the early stage of the disease.

The child described in this report had typical clinical manifestations of NKH, such as hiccups, disturbance of consciousness, hypotonia, and convulsions, within the first week after birth. Whole-exome genetic testing revealed that the child had a compound heterozygous mutation, namely, c.395C>A (p.S132X) and c.2182G>A (p.G728R), in the GLDC gene, and he was diagnosed with NKH. For treatment, we administered an oral levetiracetam solution and added topiramate and prednisone for epilepsy control, but the epilepsy remained uncontrollable. Ketogenic diet therapy was started at 6 mo of age, his seizures were significantly reduced, and there were no obvious adverse reactions during ketogenic treatment. Furthermore, we found that with the development of the disease, high levels of serum glycine decreased or even disappeared without intervention, and as the disease progressed, the corpus callosum became dysplastic.

This case shows that plasma glycine levels cannot be used to evaluate the prognosis of NKH, that the development of the corpus callosum can be affected by NKH, and that a ketogenic diet may be effective for seizure control in NKH patients.

• Nonketotic hyperglycinemia
• Compound heterozygosity
• GLDC gene
• Case report

Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Here, we report that metabolic dysfunction perturbs neuronal NMDA receptor (NMDAR) homeostasis and that the restoration of NMDAR signaling ameliorates neurodevelopmental and cognitive deficits in IEM model mice that lack aminopeptidase P1. Aminopeptidase P1-deficient (Xpnpep1^–/–) mice, with a disruption of the proline-specific metalloprotease gene Xpnpep1, exhibit hippocampal neurodegeneration, behavioral hyperactivity, and impaired hippocampus-dependent learning. In this study, we found that GluN1 and GluN2A expression, NMDAR activity, and the NMDAR-dependent long-term potentiation (LTP) of excitatory synaptic transmission were markedly enhanced in the hippocampi of Xpnpep1^–/– mice. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. A single administration of memantine reversed hyperactivity in adult Xpnpep1^–/– mice without improving learning and memory. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1^–/– mice. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1^–/– mice were reversed by chronic memantine treatment. These results suggest that the metabolic dysfunction caused by aminopeptidase P1 deficiency leads to synaptic dysfunction with excessive NMDAR activity, and the restoration of synaptic function may be a potential therapeutic strategy for the treatment of neurological complications related to IEMs.

Addressing neurological symptoms may offer new treatments for inborn errors of metabolism (IEMs) affecting neurodevelopment. In such IEMs, mutation of an enzyme disrupts a metabolic pathway, causing buildup or lack of key molecules, with symptoms including hyperactivity, developmental delay, and intellectual disability. Because the detailed pathological mechanisms of most IEMs are unknown, there are no treatments for resulting neurological issues. Myoung-Hwan Kim at Seoul National University and co-workers investigated whether they could treat the neurological symptoms of the IEM, aminopeptidase P1 (APP1) deficiency. They found that APP1 deficiency in mice caused an increase in the neural receptor NMDAR. Suppressing NMDAR reduced both neurological and behavioral symptoms. These findings suggest potential treatments for APP1 deficiency, and indicate that neurodevelopmental disorders in IEMs may be treated by repairing the neural circuitry instead of the root metabolic cause.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.

• gender distribution
• inborn errors of metabolism
• inherited metabolic disorders
• minimal birth prevalence
• minimal prevalence
• registry study

• Austria/epidemiology
• Child
• Female
• Humans
• Infant
• Male
• Metabolic Diseases/diagnosis
• Metabolic Diseases/epidemiology
• Metabolism, Inborn Errors/diagnosis
• Metabolism, Inborn Errors/epidemiology
• Prevalence
• Registries
• Retrospective Studies

• VSP-A
• adolescents
• structural equation modeling

• Carrier frequency
• Inborn errors of metabolism
• Metabolic diseases
• Rare diseases
• Recessive Mendelian diseases
• Whole exome sequencing

• Diagnostics
• ICU
• Inborn errors of metabolism
• Neonates

This study was done to determine the factors responsible for non-treatment of inherited metabolic disorders (IMDs) requiring food for special medical purposes (FSMPs) in Pakistan.

A descriptive cross-sectional study was conducted by Departments of Pediatrics & Child Health and Pathology & Laboratory Medicine, Aga Khan University. Patients diagnosed with IMDs from January 2013 to December 2016 requiring FSMPs were surveyed after a year of initial diagnosis to collect the details of treatment advised, mortality status, and reasons of non-treatment, including not prescribed by physician, non-acceptance by family, non-availability or non-affordability.

Over four years period, 311 patients were identified with IMDs; Median age of patients was 1.0 yrs (0.0.2-3.65) with 54% (n=168) being male. Of the total 38.2% (n=119) required FSMPs, 9% (n=28) patients were excluded due to unavailability of diagnostics information. Parents of 58 patients requiring FSMPs out of 119 participated in survey. The leading causes of non-treatment were, FSMPs not prescribed by physicians (n= 30, 51.7%) followed by non-affordability (n=23, 39.6%), families’ unacceptance in (n=9, 18%) patients, non-availability of FSMPs (n=2, 3.4%) and early death of patient (n=1, 1.7%).

The main factors responsible for non-treatment of FSMPs requiring IMDs were non-prescription by physician and non-affordability.

• Inherited metabolic disorder
• Pakistan
• Survey
• Treatment
• food for special medical purposes
• non-affordability
• non-prescription

• Child
• Emergency Service, Hospital
• Humans
• Laboratories
• Metabolism, Inborn Errors/diagnosis
• Odds Ratio
• Urea Cycle Disorders, Inborn

• Methylmalonic acidemia
• clinical-suspected
• epidemiology
• meta-analyse
• newborns

• Sanfilippo syndrome
• birth prevalence
• epidemiology
• meta-analysis
• mucopolysaccharidoses
• mucopolysaccharidosis III
• systematic review

• Cystathionine beta-Synthase/genetics
• Cystathionine beta-Synthase/metabolism
• Homocystinuria/drug therapy
• Homocystinuria/therapy
• Humans
• Molecular Chaperones/genetics
• Mutation
• Phenotype

• R01 DK101404 NIDDK NIH HHS

• Expanded newborn screening
• inborn errors of metabolism
• incidence
• tandem mass spectrometry

• Censuses
• China/epidemiology
• Cross-Sectional Studies
• Humans
• Incidence
• Infant, Newborn
• Metabolism, Inborn Errors/diagnosis
• Metabolism, Inborn Errors/epidemiology
• Neonatal Screening
• Tandem Mass Spectrometry

• IMDs
• Inherited metabolic diseases
• Psychological support
• Rare diseases
• Social services

• Adult
• Caregivers
• Child
• Germany
• Humans
• Parents
• Rare Diseases
• Surveys and Questionnaires

• Third Health Programme

• Agenesis of Corpus Callosum
• Amino Acid Oxidoreductases/genetics
• Female
• Genotype
• Glycine/metabolism
• Humans
• Hyperglycinemia, Nonketotic/genetics
• Infant
• Infant, Newborn
• Magnetic Resonance Imaging
• Male
• Multienzyme Complexes/genetics
• Mutation/genetics
• Retrospective Studies
• Seizures/etiology
• Seizures/genetics
• Transferases/genetics

• GLDC variants
• Middle East population
• ethnic population
• glycine encephalopathy
• nonketotic hyperglycinemia

• Newborn screening
• cost–benefit
• cost–utility
• inherited metabolic disorders
• outcome

• NAFLD progression
• PNPLA3
• endocrine disruptors
• inborn errors associated with NAFLD
• intestinal failure-associated liver disease
• nutrition-associated
• secondary NAFLD
• toxicant-associated

• cell transplantation
• cellular therapy
• liver regeneration
• placenta
• stem cell transplantation

• Amnion/cytology
• Epithelial Cells/transplantation
• Female
• Humans
• Maple Syrup Urine Disease/therapy
• Placenta
• Pregnancy

Mucopolysaccharidoses (MPS) are rare, inherited lysosomal storage disorders characterized by progressive multiorgan involvement. Previous studies on incidence and prevalence of MPS mainly focused on countries other than the United States (US), showing considerable variation by country. This study aimed to identify MPS incidence and prevalence in the US at a national and state level to guide clinicians and policy makers.

This retrospective study examined all diagnosed cases of MPS from 1995 to 2015 in the US using the National MPS Society database records. Data included year of birth, patient geographic location, and MPS variant type. US population information was obtained from the National Center for Health Statistics. The incidence and prevalence rates were calculated for each disease. Incidence rates were calculated for each state.

We obtained information from 789 MPS patients during a 20-year period. Incidence of MPS in the US was found to be 0.98 per 100,000 live births. Prevalence was found to be 2.67 per 1 million. MPS I, II, and III had the highest incidence rate at birth (0.26/100,000) and prevalence rates of 0.70–0.71 per million. Birth incidences of MPS IV, VI, and VII were 0.14, 0.04 and 0.027 per 100,000 live births.

This is the most comprehensive review of MPS incidence and prevalence rates in the US. Due to the large US population and state fragmentation, US incidence and prevalence were found to be lower than other countries. Nonetheless, state-level studies in the US supported these figures. Efforts should be focused in the establishment of a national rare disease registry with mandated reporting from every state as well as newborn screening of MPS.

• Incidence
• Newborn screening
• Prevalence
• Rare disease registry

• Clinical and genetic analysis
• Hunter syndrome
• Mucopolysaccharidosis
• Social adaptation

• Humans
• Mucopolysaccharidosis II/genetics
• Male
• Female
• Child
• Child, Preschool
• Adolescent
• Adult
• Russia
• Enzyme Replacement Therapy
• Glycosaminoglycans/urine
• Infant
• Iduronate Sulfatase/therapeutic use
• Iduronate Sulfatase/genetics
• Young Adult
• Phenotype

• АААА-А18-118051790107-2 Russian Ministry of Health

• biochemistry
• epidemiology
• metabolic
• neonatology

• Apnea/diagnosis
• Apnea/epidemiology
• Chromatography, Ion Exchange/methods
• Coma/diagnosis
• Coma/epidemiology
• Consanguinity
• Glycine/blood
• Glycine/cerebrospinal fluid
• Humans
• Hyperglycinemia, Nonketotic/diagnosis
• Hyperglycinemia, Nonketotic/epidemiology
• Hyperglycinemia, Nonketotic/genetics
• Hyperglycinemia, Nonketotic/mortality
• Incidence
• Live Birth/epidemiology
• Muscle Hypotonia/diagnosis
• Muscle Hypotonia/epidemiology
• Mutation/genetics
• Phenotype
• Seizures/diagnosis
• Seizures/epidemiology
• Severity of Illness Index
• Tunisia/epidemiology