Journal of Inherited Metabolic Disease最新文献

Palliative care should be an integral part of follow-up for patients with life-limiting/life-threatening conditions, irrespective of age and diagnosis. Many patients with inherited metabolic disorders (IMD) have palliative care needs due to multi-systemic conditions without curative treatment options. To map the organisation and accessibility of palliative care across European IMD expert centres, and to explore the experiences of IMD physicians with palliative care, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) invited physicians from all 103 member institutions to participate in a survey covering various aspects of palliative care. Ninety-two physicians from 63 institutions in 23 countries participated. A national plan or strategy for palliative care had been established in most countries (87%). Both children (91%) and adults (89%) had access to palliative care services. Most paediatric (86%) and many adult IMD physicians (67%) used advance care planning. A total of 284 referrals to palliative care were reported, mostly IMD patients with lysosomal and mitochondrial disorders, and neurological, respiratory, cognitive and gastrointestinal comorbidities. However, during the past 5 years, the majority of physicians (60%) had referred 20% or fewer of their deceased patients to palliative care. Although palliative care is available in most European IMD expert centres, only a small proportion of deceased IMD patients has been referred. The findings of this study indicate both a misconception and underutilisation of modern palliative care services. Addressing existing barriers is essential, and both IMD physicians and patients may need more information about available palliative care services and up-to-date indications for referral.

Inherited metabolic diseases (IMD) represent the largest and still growing group of treatable genetic disorders and are increasingly amenable to targeted interventions that achieve varying degrees of prognostic improvement. Innovative therapies are on the horizon and offer promising opportunities for disease-changing treatment for a variety of IMDs. For the development of clinical trials specifically for IMDs and in the context of trial readiness, a thorough understanding of the natural history of the IMDs is indispensable for an objective evaluation of meaningful improvement of novel treatment options. Patient registries are key instruments in this regard, since they are recognized as powerful instruments for the collection of longitudinal real-world data, elucidating the phenotypic diversity of disease courses, understanding the impact of diagnosis and treatment on clinical outcomes, and investigating prognostic factors. At the same time, they enable the collection of patient-specific outcome parameters (PROMs) that improve the understanding of the natural phenotype in rare diseases by identifying clinically relevant endpoints, disease burden over time, unmet medical needs, and the impact of diseases and prescribed diets and medication on the quality of life of patients and caregivers. Meta-analysis and quantitative retrospective natural history modeling allow the evaluation of the disease course with the help of published aggregate data, where patient registries are not available. Finally, the various data sources provide the theoretical basis for practical applications such as the creation of consensus-based guidelines, pass studies, and mathematical modeling. This review describes the various options for evaluating and understanding the natural history of rare IMDs in detail, with the ultimate aim of achieving adequate trial readiness.

Cerebrotendinous xanthomatosis (CTX) is a rare, metabolic disorder caused by pathogenic variants in CYP27A1. The classic clinical presentation includes infantile-onset chronic diarrhea, juvenile-onset bilateral cataracts, with development of tendon xanthomas and progressive neurological dysfunction. These multisystem clinical features typically appear in different decades of life often confounding diagnosis of CTX. Further complicating diagnosis is the generally held belief that the clinical presentation of CTX varies highly between individuals and even within families. We applied information theory analyses to CTX patient data to quantitatively assess clinical variability in CTX. We conducted a systematic review of the literature to identify all CTX families reported with CYP27A1 genotype (N = 218). Information theory analyses of subject data across 12 clinical features of CTX showed a remarkably consistent clinical presentation within families, with just four out of 83 families demonstrating notable phenotypic variability. Further analysis of subjects with two pathogenic missense variants versus two loss of function variants showed higher clinical burden in loss-of-function group (p = 0.0001). We surmise that the multi-system, progressive nature of CTX developing across decades leads to variable characterizations of the disease and that standardization of terms and comparison of clinical features within age decade reveals a more consistent clinical presentation. The identification of the common, consistent features of CTX may be useful for screening and diagnosis of this treatable disorder. This study illustrates that information theory analyses can be leveraged to detect clinically relevant information even in the absence of large-scale datasets, such as is often the case for rare disease.

Fabry disease (FD) is a lysosomal storage disease due to genetic variants in the GLA gene located on the X chromosome. Males are hemizygous, while many females are genetic mosaics due to the random inactivation of the X chromosome. While most of the identified variants are deleterious for GLA, in some cases, less rare gene variants have been considered responsible for some FD features. GLA variants were selected from the database of 469 thousand genotyped subjects of the UK Biobank database. Pathogenic variants (ALL_P), variants of uncertain significance (ALL_U), and variants with conflicting interpretations of pathogenicity (ALL_C) were grouped, while p.Asp313Tyr, p.Ala143Thr, p.Ser126Gly, p.Arg118Cys, and p.Asn215Ser were evaluated individually. More than 480 thousand subjects not carrying variants in the GLA gene were used as controls in association studies. Clinical and biochemical phenotypes were extracted from the same database, and a FD phenotype score (FASTEX derived Fabry, FDF score) was derived from the FASTEX prognostic to assess the probability of an FD phenotype score. Pathogenic variants and p.Asn215Ser were associated with FDF score, while all other variants were not associated with any FDF feature. Stratification of patients based on a calculated cardiovascular (CV) risk score demonstrated that patients with nonpathogenic variants within the highest CV risk quartile (> 75th percentile) showed characteristic features of FD, whereas those in the lower risk group (< 75th percentile) showed odds ratios indicating inverse association with FD features. In conclusion, the data from UK Biobank suggest that pathogenic variants are always associated with FD features, while variants of uncertain significance and conflicting interpretation acquire an FD phenotype only in the presence of a high CV risk burden.

Phosphomannomutase deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation, characterized by variable early-onset neurological (hypotonia, cerebellar syndrome, developmental delay) and multi-organ manifestations. Although several clinical trials are ongoing, current biomarkers lack prognostic or monitoring utility. Emerging transcriptomic studies suggest dysregulated pathways in PMM2-CDG, but miRNAs, key gene expression regulators, remain unexplored. This cross-sectional study aims to investigate a circulating miRNA signature that may distinguish PMM2-CDG patients from unaffected controls, providing an initial framework for future studies on potential predictive and monitoring tools. Differential gene expression analysis was used to identify significant differentially expressed (DE) miRNAs, while machine learning models (LASSO, XGBoost) were applied to create an miRNA predictive signature. Dysregulated miRNA pathways analysis provided insights into affected tissues and cellular mechanisms. An optimized protocol addressing challenges in pediatric blood samples was implemented. miRNA profiles from blood samples of 28 PMM2-CDG patients and 67 unaffected controls were analyzed, identifying six DE miRNAs. Regarding machine learning models, XGBoost achieved the best performance (AUC 0.917). Biological analysis revealed that DE miRNAs influence neurological, endocrinological, immunological, and cellular pathways related to the PMM2-CDG phenotype. Notably, miR-122-5p emerged as a highly predictive marker, indicating liver and neurological involvement. Circulating miRNAs represent a promising, minimally invasive avenue for further investigation. While preliminary evidence of their potential diagnostic utility is provided, additional validation in larger and more diverse populations is required to determine their relevance for clinical stratification or monitoring in PMM2-CDG, contributing to future biomarker-driven personalized medicine efforts in this disease.

Classic galactosemia is a rare metabolic disorder resulting from galactose-1-phosphate uridylyltransferase deficiency, which disrupts normal galactose metabolism, leading to toxic accumulation of galactose-1-phosphate and galactitol. Despite early dietary intervention, patients remain at risk for long-term neurological impairments, including cognitive deficits, motor speech disorders, and psychiatric conditions. The mechanisms driving these persistent abnormalities remain unclear. This study investigated brain metabolic and structural alterations in adults with classic galactosemia using advanced multiparametric MRI. Six patients (3 males, 3 females; mean age 34.0 ± 7.3 years) adhering to lifelong galactose-restricted diets and six age- and sex-matched controls underwent 3T and 7T MRI, including T1-weighted imaging, pseudo-continuous arterial spin labeling, and high-resolution MR spectroscopic imaging. Patients exhibited significantly lower myo-inositol (mIns) concentrations in cerebellum (p = 0.007), putamen (p = 0.023), and cerebral white matter (p = 0.001), reflecting a chronic mIns deficiency despite dietary management. Structural analyses revealed reduced volumes of white matter (p < 0.001), bilateral putamen (p < 0.038), and left thalamus (p = 0.044); alongside increased cortical thickness and reduced cortical surface area, indicating abnormal cortical maturation, particularly in regions associated with motor and cognitive processing. Additionally, cerebral blood flow was elevated in emotion-processing regions, including bilateral amygdala (p < 0.022) and thalamus (p < 0.038). These preliminary findings highlight persistent neurological alterations in classic galactosemia despite dietary management and suggest that chronic mIns deficiency may contribute to the pathophysiology. They underscore the need for larger, longitudinal studies to confirm these results, investigate potential correlations with clinical severity and biochemical markers, and explore therapeutic strategies aimed at modulating mIns metabolism.

Liver transplantation (LTx) has become, over the years, an increasingly used therapeutic option in patients with inherited metabolic diseases (IMD). Initially performed for Tyrosinemia Type I and ornithine transcarbamylase deficiency, it now accounts as the second indication for pediatric transplants worldwide. The use of LTx has been extended to systemic metabolic disorders, in which a genetically normal liver can correct the defect by providing an enzyme replacement therapy that improves metabolic control and disease burden, reducing the risk of metabolic crises and neurological damage, allowing for the withdrawal, in most diseases, of dietary restrictions and specific medications. The temporal changes, mainly reflecting improved LTx management through a multidisciplinary approach, have provided excellent outcomes and long-term patient survival, shifting the paradigm from a lifesaving procedure to a life-improving treatment. However, challenges still exist, particularly, in systemic IMD due to the persistence of the underlying defect in extra-hepatic tissues. Immunosuppression, especially in organic acidurias, may lead to new, drug-related, neurotoxic risks. The new indications for transplantation should target endpoints that are not exclusively clinical, addressing major attention to the improvement of health-related quality of life issues. Protocols for managing LTx in IMD need to be harmonized, and future joint multicenter actions will fill these gaps and provide a uniform vision of this evolving scenario.

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 medical writing of the article was supported by Chiesi Farmaceutici S.p.A. This information was unintentionally omitted from the published article.

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