Journal of Inherited Metabolic Disease最新文献

The concept of IMDs has evolved over a century from rare deficits in amino acid catabolism diagnosed by the accumulation of biochemical markers such as phenylketonuria (PKU) to diseases affecting organelle metabolism, synthesis of complex molecules, and cellular trafficking. Small-molecule accumulation disorders form the major group of treatable IMDs. Do not miss these metabolic emergencies! IMDs currently number over 1800 and include all medical specialties. The specificity of true “molecular internists,” metabolic specialists, lies in the in-depth knowledge of metabolic pathways and the understanding of the pathophysiology of the deficits underlying the treatments (“precision medicine”). Neurology is massively impacted, but cerebral metabolism remains largely misunderstood. Genetic analyses are becoming increasingly important for diagnosis but must be complemented by biochemical investigations, which sometimes have greater diagnostic specificity and provide functional information at the phenotype level. Biochemical analyses remain essential for monitoring treatment or even for diagnosis. Finally, contrary to early expectations, newborn screening such as that for phenylketonuria, leading to preventive therapy, could be extended to a significant though limited number of IMDs. Currently, there are numerous initiatives that include genetic screening combined with biochemical testing or that extend screening to lysosomal diseases potentially treatable by enzyme or gene therapy.

R. Šáhó, R. Formánková, J. B. Eisengart, et al., “Outcome of Haemopoietic Stem Cell Transplantation in 21 Patients With Alpha-Mannosidosis,” Journal of Inherited Metabolic Disease 48, no. 4 (2025): e70047, https://doi.org/10.1002/jimd.70047.

The authors have added Dr. Chiara Monachesi as a co-author to the paper.

Chiara Monachesi

Division of Pediatrics, Department of Clinical Sciences, Azienda Ospedaliero Universitaria delle Marche, Presidio Salesi, Ancona, Italy

Dr. Monachesi has no conflict of interest.

Dr. Monachesi's contribution: As the majority of co-authors, she was the treating physician and transplant physician performing the HSCT, examinations, and follow-up in the patients.

There are no other changes in the author list or affiliations.

We apologize for this error.

Lysosomal disorders (LSDs) are a group of rare metabolic disorders, with an overall incidence of 1:4800 to 1:8000 live births. LSDs are primarily caused by dysfunctional lysosomal enzymes, which typically lead to the progressive accumulation of substrates within cellular lysosomes. As a result, patients experience a wide array of somatic symptoms such as visceromegaly, cardiopulmonary abnormalities, and respiratory and urinary infections. Additionally, over two-thirds of LSD subtypes have a neurological component, and without treatment, patients experience neurodegeneration, cognitive decline, and life expectancies spanning infancy to adulthood. At present, there is no therapy that rescues the degenerative neuropathology of LSDs, and current developments, such as brain-targeted enzyme replacement therapy, hematopoietic stem cell transplantation, and even gene therapy, can only prevent further neurodegeneration. However, recent advancements involving induced pluripotent stem cells (iPSCs) have demonstrated that stem cells may harbor the potential to both recapitulate the phenotype of neuropathic LSDs in vitro, as well as serve as a vector for regeneration in vivo, by replacing cells and neurons damaged by disease progression. This review reports the current state of iPSC technology in LSD research, and the pathway by which iPSCs are translated from disease modeling to serving as a regenerative therapeutic for neuropathic LSDs in the clinic.

Bile acid synthesis defects (BASDs) comprise a group of rare, often severe, metabolic disorders. Bile acid replacement therapy decreases toxic bile acid intermediates production and improves biochemical profiles, potentially delaying or stabilizing disease progression. An open label, non-randomized trial with cholic acid (CA) supplementation included six patients with α-methylacyl-CoA racemase (AMACR) deficiency and one patient with 3β-hydroxy-Δ⁵-C₂₇-steroid oxidoreductase deficiency. Patients received up to 20 mg/kg/day CA for 3.5 years, adjusted for biochemical response, side effects, and clinical evaluation. Bile acid metabolites, liver enzymes, liver stiffness, and neurological symptoms were evaluated at baseline and during follow-up. CA was well tolerated in children (n = 3), allowing for higher doses. Adults (n = 4) experienced more side effects, primarily diarrhea and other gastrointestinal symptoms. Children's transaminase levels normalized during treatment, while adults' levels remained normal throughout. Elevated C₂₇-bile acid intermediates, C₂₉-dicarboxylic acid, and pristanic acid were observed in all AMACR patients. C₂₇-bile acids and C₂₉-dicarboxylic acid decreased with treatment, while pristanic acid fluctuated and remained elevated. No clinically relevant changes were observed in liver elasticity, fat-soluble vitamin levels, neurological assessment, or growth (in children). One adult developed hepatocellular carcinoma during treatment. CA treatment is generally safe, with acceptable tolerance and a marked biochemical response observed in children, although biomarker levels remained markedly elevated. In adults, however, the balance shifts negatively, with side effects outweighing the (biochemical) benefits. A longer study is necessary to evaluate the impact of CA treatment on the clinical relevance of the observed biochemical response.

Here we review the historical background and contemporary insights into genetic dominance, focusing on haploinsufficiency (HI), that is, when the function of only one allele of a gene is not enough to ensure a normal phenotype in a diploid organism. A related phenomenon is triplosensitivity, that is, pathogenic effects when there are three instead of two copies of some 'genes'. The importance of gene dosage issues was realized in humans when whole chromosomal abnormalities (aneuploidy) could be linked to clinical phenotypes such as Down, Edwards, and Patau syndromes. Subsequently, subtler chromosomal deletions and duplications have been shown to be responsible for many developmental syndromes. In several cases, a dosage-sensitive gene mapping to the relevant regions has been implicated as causal. We delve into the mechanisms of HI, especially due to direct protein insufficiency and subunit imbalances in the context of multi-subunit complexes. We show how the nonlinearity inherent to the relationship between genotype and phenotype is responsible for the dominance of the underlying genetic variants. We also explore why increased gene dosage can lead to abnormal phenotypes. Examples include trisomy or segmental genomic duplications in humans and oncogene amplification in cancers. Finally, we examine a few cases of genetic synergy, where the combined effect of two or more variants amplifies their individual effects, underlying a distinguishable phenotype. Further research is required to elucidate the dynamics of multicomponent interactions to unravel the mechanistic complexities of genetic dominance, inter-gene interactions, and their implications for disease.

Bone manifestations are one of the most prevalent complications in patients with Gaucher disease (GD). Bone involvement is evaluated by using imaging methods, and there are different scores to assess its severity. However, there are no biomarkers that allow us to predict these manifestations. In recent years, several miRNAs have been associated with bone involvement and postulated as excellent bioavailable biomarkers. This study aims to identify a miRNA expression profile from plasma exosomes and to associate it with the severity of bone involvement in patients with GD. This study included 60 untreated patients with GD with bone involvement, who were classified according to the S-MRI score into three groups: mild disease (MiBD; S-MRI < 5), moderate disease (MoBD; S-MRI: 5–11), or severe disease (SBD; S-MRI > 11). Plasma exosomes were purified, and miRNAs were extracted and identified by next-generation sequencing (NGS) technology. Differentially expressed miRNAs were validated by droplet digital PCR (ddPCR). In the patients' groups classified by S-MRI, the median ages (Q1–Q3) were: MiBD 19.0 (4.00–40.00), MoBD 40.5 (28.25–56.00), and SBD 37.5 (31.25–47.00) years. When comparing groups, we found 12 differentially expressed exosomal miRNAs. After validation, four miRNAs were identified as differentially expressed: hsa-miR-127-3p, hsa-miR-184, hsa-miR-197-3p, and hsa-miR-660-5p. Notably, hsa-miR-127-3p, hsa-miR-660-5p, and hsa-miR-184 were correlated with the presence of infarcts, necrosis, and the degree of infiltration into the spine, pelvis, and femur. These three miRNAs could serve as bioavailable biomarkers to assess bone disease in GD, and further revalidation with a higher number of patients.

The number of inherited metabolic diseases (IMDs) in newborn screening (NBS) programs has increased significantly in the past decades. For some of the IMDs included in NBS (e.g., tyrosinemia type I), there are clear and substantial health benefits of NBS, while for others (e.g., very long chain acyl CoA dehydrogenase deficiency and 3-methylcrotonyl CoA carboxylase 1 deficiency), this is less clear as NBS identifies individuals who are asymptomatic or have milder forms of the disease. Therefore, knowledge of the full disease spectrum (including later onset forms) is needed when setting diagnostic metabolite cut-offs for NBS. Insights into the clinical, genetic and biochemical characteristics of different patient subsets can be used to redefine NBS protocols to identify patients with more severe forms of the disease who are most likely to benefit from identification in the newborn period. These insights require life-long monitoring of individuals identified based on symptoms versus those identified by NBS to determine long-term health outcomes and quantify the benefits of NBS. Adult metabolic specialists should be included in the development of NBS programs to provide data from this long-term monitoring and to contribute specific knowledge about later onset phenotypes of the IMDs included in NBS programs. The goal should be to develop NBS programs that identify newborns that benefit from early disease detection and treatment, without increasing psychological, social and management burden for individuals who may develop disease in adulthood with milder phenotype or potentially even not at all.