Journal of Inherited Metabolic Disease最新文献

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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Adenylosuccinate lyase deficiency (ADSLD) is a rare neurological disorder characterized by psychomotor retardation, autistic behaviors, and seizures, with no specific treatment available. ADSL catalyzes the transformation of succinylaminoimidazole carboxamide ribotide (SAICAr) to AICAR, and succinyl-AMP (S-AMP) to AMP. The pathogenesis of the disease is primarily attributed to the toxicity of elevated SAICAr concentrations. Allopurinol, used primarily for hyperuricemia, inhibits purine synthesis and may reduce SAICAr levels. We hypothesized that administering allopurinol could decrease SAICAr levels and lead to clinical improvement. A Phase II, prospective trial evaluated the efficacy of allopurinol in patients with ADSLD over 12 months. Eight participants (four children, four young adults) with developmental delay and high SAICAr levels received Zyloric (10–20 mg/kg/day, maximum 400 mg/day for children and 900 mg/day for adults). The study assessed changes in adaptive and cognitive functioning, behavior, and urinary levels of SAICAr and succinyl-adenosine (S-Ado). Results showed clinical improvements in younger, less cognitively impaired patients, indicated by better Vineland Adaptive Behavior Scale (VABS II) scores and reduced hyperactivity on the Aberrant Behavior Checklist (ABC) and Conners Rating Scale-Revised (CRSR). These improvements correlated with significant decreases in urinary SAICAr levels and an increased S-Ado/SAICAr ratio. No changes were observed in older or noncompliant patients. Allopurinol had no effect on epilepsy but was well tolerated. Allopurinol showed behavioral and developmental benefits in younger ADSLD patients, suggesting that it may be a viable treatment option.

Hypophosphatasia (HPP) is a rare, inherited monogenic disorder that is typically caused by variants in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Genetic testing for ALPL variant(s) to confirm the diagnosis in patients with suspected HPP is a standard practice based on availability. This review attempts to improve the current understanding of the genetics of HPP as it addresses five key related topics: (1) HPP patterns of inheritance and the relationship between HPP genotype and phenotype, (2) how the disease can manifest (including specific genotypes) in heterozygotes, (3) potential reasons why some patients have persistently low alkaline phosphatase activity yet lack an ALPL variant, (4) the implications of and resources for variants of uncertain significance (VUS), and (5) recent information on genetic testing in fetuses and newborns. We summarize pertinent information applicable in daily clinical practice, with the objective of preventing missed, delayed, or incorrect HPP diagnoses and improving patient care.

Classic isovaleric aciduria (cIVA) is a rare inherited metabolic disorder characterized by recurrent life-threatening metabolic decompensations and neurocognitive impairment in untreated patients. This meta-analysis aims to assess the impact of early diagnosis by newborn screening (NBS) on mortality and neurocognitive outcome. A systematic literature search for articles published until 2022 was conducted following PRISMA protocol guidelines. We investigated effects on clinical outcomes and survival, analyzing outcome parameters using meta-analytical measures and estimating effect sizes with a random-effects model. Overall, 20 studies were included, reporting on 240 individuals with cIVA. Individuals identified by NBS presented with a lower frequency of neurological symptoms (13.0% vs. 44.9%; p = 0.0040) and developmental delay (6.1% vs. 51.2%; p < 0.0001), and had a lower mortality rate (1.1% vs. 10.9%; p = 0.0320). The quality of healthcare systems did not have a measurable impact on neurocognitive outcome and mortality. Despite the beneficial effect of NBS on clinical outcome and mortality, it could not reliably prevent the manifestation of neonatal decompensation in all individuals with cIVA identified by NBS. Early diagnosis through NBS is essential for the timely initiation of therapy and for improving outcomes and survival rates in individuals with cIVA.