Journal of Inherited Metabolic Disease最新文献

Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre-molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA-based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

Access to affordable chenodeoxycholic acid (CDCA) is essential for patients with cerebrotendinous xanthomatosis (CTX), a rare, inherited metabolic disorder that is likely to require lifelong treatment. CDCA was discovered in the 1970s as a treatment to prevent neurological decline and improve the quality of life of CTX patients. It is therefore essential that it is available at a reasonable price.

In 2021, the Dutch Authority for Consumers and Markets (ACM) fined Leadiant Biosciences nearly €20 million for abusing its dominant market position. After acquiring the rights to CDCA in 2008, Leadiant increased the price from €46 to over €14 000 per 100 capsules by 2017—despite the drug having been available and used off label for decades. The ACM concluded that these price hikes were not justified by innovation or new research and amounted to unfair exploitation of market exclusivity. Leadiant appealed the ruling, but in February 2025, the District Court concluded that ACM's decision was right [1]. Additional fines by other EU member states were imposed on Leadiant. Because the pricing jeopardized access in the Netherlands, a magistral (compound) preparation of CDCA was used by patients instead.

Following the registration of CDCA for treatment of CTX in the EU, it is important that CDCA (chenodiol, brand name Ctexli) is now also approved in the United States, marketed by Mirum Pharmaceuticals [2]. This offers hope for wider access to this crucial treatment. Of interest is that CDCA was historically used to treat gallstones but has already been used for decades to treat CTX, with many reports showing its well-established use. In the EU, retrospective data were sufficient to approve the product. However, in the US, a double-blind study was requested in a small group of patients, which showed that the treatment, not surprisingly, was effective in reducing the characteristic bile acid accumulations in plasma and urine [2]. Long-term clinical outcomes were considered unachievable, as the treatment is, indeed, standard of care. While it is important to support approval with high-quality data, it is interesting to investigate whether the investment in this small-scale study will support the argument for the price of the drug in the US. A recent publication mentions a list price of US$60487 per 100 tablets [3]. This equates to an annual cost for an adult patient of over US$660000. That's even four times higher than in the EU. For the marketing of this type of drug, whose value has in fact long been established, a cost-based price would be more socially justifiable. As healthcare professionals and patients, we want to emphasize that regulatory approval must be followed by ethical pricing to ensure that all patients—regardless of geographic location or socioeconomic status—receive the medicines they need.

This case underscores the crucial role of oversight and advocacy in protecting patien

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.