Journal of Inherited Metabolic Disease最新文献

Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900–1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Acid Sphingomyelinase Deficiency (ASMD) is a rare genetic disease that is caused by biallelic pathogenic variants in the SMPD1 gene, leading to a deficiency in the activity of the lysosomal enzyme acid sphingomyelinase (ASM) that catabolizes sphingomyelin (SPM). SPM is a major component of cell membranes and a principal phospholipid of the myelin sheath. Deficiency of ASM leads to the accumulation of SPM and secondary increases in cholesterol and other metabolically related lipids.¹ Organ systems affected include the central nervous system (CNS), liver, spleen, lymph nodes, adrenal cortex, lung airways, and bone marrow. The estimated prevalence of ASMD is 0.4 to 0.6 per 100 000 live births.^{2, 3}

Clinically, ASMD can be broadly categorized into three subtypes. Type A is an early-onset severe disease that is characterized by failure to thrive, hepatosplenomegaly, interstitial lung disease (ILD), and rapidly progressive neurodegenerative disease. Type B is a later onset, less severe disease characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and an atherogenic lipid profile. No CNS manifestations occur in ASMD Type B. ASMD type A/B, an intermediate form between type A and type B, is characterized by presence of some CNS manifestations, hepatosplenomegaly, ILD, dyslipidemia, osteopenia, and thrombocytopenia.⁴ Patients with ASMD were managed primarily with supportive therapies prior to approval of olipudase alfa-rpcp on August 31, 2022.

Olipudase alfa-rpcp, a recombinant human ASM, is an enzyme replacement therapy indicated for the treatment of non-CNS manifestations of ASMD in pediatric and adult patients. Olipudase alfa-rpcp is not expected to cross the blood–brain barrier to treat the CNS manifestations of ASMD. It is administered as an intravenous infusion every two weeks (Q2W), with a recommended starting dose of 0.1 mg/kg in adults and 0.03 mg/kg in pediatric patients. The dose is gradually escalated to a recommended maintenance dose of 3 mg/kg over 14 and 16 weeks in adult and pediatric patients, respectively. The dose-escalation regimens provide a gradual “debulking” of SPM and gradual release of ceramide to decrease the potential inflammatory response and adverse reactions that were observed following single-dose administration of olipudase alfa-rpcp in ASM knockout mice and in the first-in-human clinical trial.⁵

Substantial evidence of effectiveness for olipudase alfa-rpcp in ASMD patients was established with one adequate and well-controlled trial with confirmatory evidence.^{8, 9} The efficacy of olipudase alfa-rpcp was demonstrated by a statistically significant improvement in DLco in 13 adult patients with ASMD type B on treatment compared to 18 patients on placebo. Efficacy in the pediatric population relied upon partial extrapolati

Pompe disease (PD), also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II, is a rare and serious lysosomal disease caused by autosomal recessive variants in the acid alpha-glucosidase (GAA) gene. The resulting enzyme deficiency of GAA results in intra-lysosomal accumulation of glycogen in various tissues. The two forms of PD present differently: infantile-onset PD (IOPD) is a rapidly progressive disease associated with severe left ventricular hypertrophy and high mortality within the first year of life, whereas late-onset PD (LOPD) is a slower progressive disease associated with motor impairment and respiratory muscle weakness; respiratory failure is the most common cause of death.¹ Currently, the approved therapies for PD are recombinant human acid alpha-glucosidases, alglucosidase alfa and avalglucosidase alfa-ngpt. Although alglucosidase alfa results in stabilization or improvement of symptoms for many patients, some patients continue to decline during treatment. For other patients, the improvement in muscle weakness is not sustained, and thus, patients tend to develop progressive disease, which can lead to respiratory failure.^2-4 Therefore, treatment and cure of PD continue to represent unmet needs.

Cipaglucosidase alfa-atga provides an exogenous source of GAA. Cipaglucosidase alfa-atga has the same amino acid sequence as the endogenous GAA enzyme but contains complex-type N-glycan structures with two mannose-6-phosphate (M6P) moieties on the same glycan which mediates binding to M6P receptors on the cell surface. Miglustat, which is coadministered with cipaglucosidase alfa-atga, is an N-alkylated iminosugar (a synthetic analog of D-glucose) and is the active ingredient in Zavesca, which is approved for the treatment of adult patients with mild/moderate Type 1 Gaucher disease for whom ERT is not a therapeutic option. Miglustat binds with, stabilizes, and reduces the inactivation of cipaglucosidase alfa-atga in the blood after infusion. The bound miglustat is dissociated from cipaglucosidase alfa-atga after it is internalized and transported into lysosomes.

In this article, we provide the summary of FDA's review of the biologics license application (BLA) for cipaglucosidase alfa-atga and the new drug application (NDA) for miglustat, which were approved to be coadministered for the treatment of adult patients with LOPD who are not improving on their current enzyme replacement therapy (ERT).

Substantial evidence of effectiveness for cipaglucosidase alfa-atga coadministered with miglustat in subjects with LOPD was established using data from one adequate and well-controlled trial with confirmatory evidence (CE). A single trial in subjects 18 years of age and older with LOPD showed a clinically meaningful numerical improvement in motor and lung function compared with treatment with a non-US-approved alglucosidase alfa product coa

Gaucher disease (GD) stands as one of the most prevalent lysosomal disorders, yet neuronopathic GD (nGD) is an uncommon subset characterized by a wide array of clinical manifestations that complicate diagnosis, particularly when neurological symptoms are understated. nGD may manifest as the acute neuronopathic type, or GD type 2 (GD2), either prenatally or within the first weeks to months of life, whereas GD type 3 (GD3) symptoms may emerge at any point during childhood or occasionally in adolescence. The clinical presentation encompasses severe systemic involvement to mild visceral disease, often coupled with a spectrum of progressive neurological signs and symptoms such as cognitive impairment, ataxia, seizures, myoclonus, varying degrees of brainstem dysfunction presenting with stridor, apneic episodes, and/or impaired swallowing. This manuscript aims to provide a comprehensive review of the incidence, distinctive presentations, and diverse clinical phenotypes of nGD across various countries and regions. It will explore the natural history of the neurodegenerative process in GD, shedding light on its various manifestations during infancy and childhood, and offer insights into the diagnostic journey, the challenges faced in the clinical management, and current and investigative therapeutic approaches for GD's neurological variants.

Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene–disease lists from gNBS studies, evaluating gene–disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237–889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene–disease pairs, and the total number of exclusive gene–disease pairs was positively correlated with the total number of genes included per study. While most pairs receive “Definitive” or “Strong” ClinGen classifications, some are labeled as “Refuted” (n = 5) or “Disputed” (n = 28), particularly in genetic cardiac diseases. Importantly, 17%–48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene–disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance.

Brain function depends on neuronal connections in circuits, which range in scale from small local neuronal groups to long-distance projections. Neurons can function in more than one circuit and communicate with thousands of other neurons through more than 100 trillion synapses.¹ In the classical synaptic organization, a presynaptic transmitting neuron releases chemical substances (“neurotransmitters”) from vesicles stored in the axon into the synaptic cleft. At the postsynaptic receiving neuron, the neurotransmitter binds to specific receptors and the binding changes the electrical activity of the postsynaptic neuron, which in turn leads to further interneuron communication. The umbrella term “neurotransmitter” encompasses different types of chemical substances involved in synaptic transmission from cell to cell within the central and peripheral nervous system. Neurotransmitters can be grouped according to their chemical structure into amino acid transmitters (glycine, glutamate and γ-aminobutyric acid (GABA)), monoamines/biogenic amine transmitters, (with the subgroup of catecholamines norepinephrine, epinephrine, and dopamine as well as serotonin), and neuropeptides. Atypical neurotransmitters, as the purinergic neurotransmitters adenosine and adenosine triphosphate (ATP), endogenous cannabinoids and opioids, diffusible gases like nitric oxide (NO) or carbon monoxide (CO) and families of neurotrophic factors and cytokines have either unusual chemical properties or are less extensively studied and understood. All neurotransmitters are essential for the unique and highly orchestrated process of synaptic communication.

Communication was also the main goal of the conference “Rare-neurotransmitter-related diseases—Research to treatment (RNTD-R2T)” which took place in the city of Belgrade, Serbia, with 184 participants from 24 countries. With funding from the European Joint Programme Rare Diseases (EJPRD) and with the aim of fostering involvement of and exchange between all stakeholders, the conference brought together experienced clinical scientists and basic researchers with Early Career Researchers and patient advocacy organizations. This special issue of the Journal of Inherited Metabolic Disease discusses conference highlights from all three perspectives.

The patient organizations were active contributors to the discussion and, led by Lil' Brave One and SSADH-Defizit e.V., identified unique challenges associated with the diagnostic odyssey for rare neurotransmitter diseases, assessed the factors contributing to diagnostic delay, and proposed strategies to improve the diagnostic process.² They further recognized four main gaps between patients, clinicians and scientists.³

Several scientists and clinicians contributed original research and review articles on the topic of neurotransmitter-related disorders. The review focused on a metabolomic perspec

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies.

N-acetylglutamate synthase (NAGS) makes acetylglutamate, the essential activator of the first, regulatory enzyme of the urea cycle, carbamoyl phosphate synthetase 1 (CPS1). NAGS deficiency (NAGSD) and CPS1 deficiency (CPS1D) present identical phenotypes. However, they must be distinguished, because NAGSD is cured by substitutive therapy with the N-acetyl-L-glutamate analogue N-carbamyl-L-glutamate, while curative therapy of CPS1D requires liver transplantation. Since their differentiation is done genetically, it is important to ascertain the disease-causing potential of CPS1 and NAGS genetic variants. With this goal, we previously carried out site-directed mutagenesis studies with pure recombinant human CPS1. We could not do the same with human NAGS (HuNAGS) because of enzyme instability, leading to our prior utilization of a bacterial NAGS as an imperfect surrogate of HuNAGS. We now use genuine HuNAGS, stabilized as a chimera of its conserved domain (cHuNAGS) with the maltose binding protein (MBP), and produced in Escherichia coli. MBP-cHuNAGS linker cleavage allowed assessment of the enzymatic properties and thermal stability of cHuNAGS, either wild-type or hosting each one of 23 nonsynonymous single-base changes found in NAGSD patients. For all but one change, disease causation was accounted by the enzymatic alterations identified, including, depending on the variant, loss of arginine activation, increased K_m^Glutamate, active site inactivation, decreased thermal stability, and protein misfolding. Our present approach outperforms experimental in vitro use of bacterial NAGS or in silico utilization of prediction servers (including AlphaMissense), illustrating with HuNAGS the value for UCDs of using recombinant enzymes for assessing disease-causation and molecular pathogenesis, and for therapeutic guidance.

Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.

Humans derive fatty acids (FA) from exogenous dietary sources and/or endogenous synthesis from acetyl-CoA, although some FA are solely derived from exogenous sources (“essential FA”). Once inside cells, FA may undergo a wide variety of different modifications, which include their activation to their corresponding CoA ester, the introduction of double bonds, the 2- and ω-hydroxylation and chain elongation, thereby generating a cellular FA pool which can be used for the synthesis of more complex lipids. The biological properties of complex lipids are very much determined by their molecular composition in terms of the FA incorporated into these lipid species. This immediately explains the existence of a range of genetic diseases in man, often with severe clinical consequences caused by variants in one of the many genes coding for enzymes responsible for these FA modifications. It is the purpose of this review to describe the current state of knowledge about FA homeostasis and the genetic diseases involved. This includes the disorders of FA activation, desaturation, 2- and ω-hydroxylation, and chain elongation, but also the disorders of FA breakdown, including disorders of peroxisomal and mitochondrial α- and β-oxidation.