Journal of Inherited Metabolic Disease最新文献

Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (−2.65 points), FVC (−9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.

Congenital disorders of glycosylation are genetic defects in the glycoprotein and glycolipid glycan assembly and attachment. Some 200 CDG have been reported since the first clinical description in 1980. Most CDG are enzymatic deficiencies, but 13 (6.5%) are defects in the ER, Golgi apparatus (GA), and plasma membrane transporters. This review provides an update on the clinical, biochemical, genetic, and therapeutic aspects of these disorders and on animal models. Defects in other cellular trafficking mechanisms have been excluded from this update.

GDP-mannose pyrophosphorylase B (GMPPB) deficiency is a congenital disorder of glycosylation due to pathogenic variants of the GMPPB gene. GMPPB catalyzes GDP-mannose synthesis, an early step in multiple glycosylation pathways, including N-glycosylation, O-mannosylation, C-mannosylation, and glycosylphosphatidylinositol-anchor formation. In fibroblasts (N = 3), myoblasts (N = 4) and in muscle biopsies (N = 4) from a total of 7 GMPPB-deficient patients we found evidence of glycogen accumulation, both in cytosol and in lysosome-like vesicles, presence of heterogeneous storage material, and expansion of the lysosomal compartment. Due to the excess of glycogen in cells and tissues, we investigated acid alpha-glucosidase (GAA) in cultured GMPPB fibroblasts. GAA activity was reduced in GMPPB cells, with an impaired protein maturation and lysosomal localization. Incubation of cells with human recombinant GAA (rhGAA), that is fully glycosylated, showed complete correction of GAA activity, normal processing and lysosomal trafficking, with complete clearance of glycogen storage. These results suggest a secondary impairment of specific lysosomal functions in GMPPB deficiency and add information on the complexity of the pathophysiology of this disorder.

Long-chain fatty acid oxidation disorders (lcFAODs) are genetic disorders of energy metabolism that are associated with a risk of metabolic decompensation, especially during catabolic episodes. With improvement in diagnostics and treatment, more women with lcFAODs now reach child-bearing age. So far, little is known about the risk and outcome of pregnancies, particularly in women with more severe forms of lcFAODs. We performed an international web-based survey among health care professionals involved in the care of individuals with lcFAODs and collected data on 89 pregnancies in 39 women (mild VLCAD deficiency n = 8, severe VLCAD deficiency n = 10, LCHAD deficiency n = 4, CPT2 deficiency n = 14, CPT1 deficiency n = 3). There were 72 live births, 12 spontaneous miscarriages, and one stillbirth at 41 weeks of gestation. Four women were still pregnant at the time of the survey. In 25 women, the diagnosis was known before the first pregnancy, whereas 14 had at least one pregnancy before diagnosis. Most women remained metabolically stable during pregnancy, although 19% of women had at least one metabolic decompensation during pregnancy. Forty-one percent of babies were delivered by spontaneous vaginal delivery, 33% after induced labor, and 19% by an elective Caesarean section. Most deliveries were uncomplicated, with preventive i.v. glucose infusions given in 50%. However, 21% of mothers developed a metabolic decompensation in the postpartum period. No maternal deaths were reported. In conclusion, our data show that the outcome of pregnancies in lcFAOD patients is generally favorable, despite a significant risk of metabolic decompensation during the postpartum period.

The deficiency of mitochondrial complex I (CI), a key regulator of cellular energy homeostasis and metabolic flexibility, is a prevalent driver of cardiovascular pathology in mitochondrial disorders. The Ndufs4 knockout (KO) mouse model of Leigh syndrome (LS), which lacks a critical CI subunit, exhibits severe cardiac abnormalities secondary to encephalomyopathy. However, the metabolic basis of LS-associated cardiac dysfunction remains poorly understood. This study aims to evaluate how whole-body CI deficiency affects cardiac bioenergetics and metabolism in late-stage Ndufs4 KO mice. We assessed respiratory chain enzyme activities and oxygen consumption rates using kinetic spectrophotometric assays and high-resolution respirometry, respectively, in mitochondria isolated from Ndufs4 KO and wild-type mouse hearts. Cardiometabolic profiling was performed on a well-powered cohort, employing untargeted GC-TOFMS, ¹H-NMR and semi-targeted LC-MS/MS. Ndufs4 KO hearts showed a 98.9% reduction in CI activity and a 63.9% decline in CI-driven respiration, halving CI's contribution to combined CI + II respiration and prompting a shift toward CII-driven respiration. Cardiometabolic profiles revealed significant reductions in energy-generating substrates, including long-chain fatty acids, glucose, lactic acid and 3-hydroxybutyric acid, along with lower levels of anaplerotic amino acids and TCA cycle intermediates, particularly succinic acid. Additionally, profound disruptions were observed in dimethylglycine, glutamic acid and lysine metabolism. We conclude that whole-body CI deficiency results in severe cardiac bioenergetic and metabolic dysregulation, characterised by reduced CI-dependent respiration and extensive substrate reduction across multiple metabolic pathways. These findings underscore the metabolic vulnerability of the CI-deficient heart and suggest potential therapeutic targets for managing cardiomyopathy in mitochondrial disease.

Natural-history datasets have become pivotal for drug development and for shaping clinical-practice guidelines in rare diseases, yet many lysosomal storage disorders would benefit from deep phenotyping and modern analytic methods. Our objective was to integrate the past decade of genomic, cellular, treatment-outcome, and regulatory advances into a practical framework for capturing and interpreting natural-history data, using Gaucher disease (GD) as a paradigm. We reviewed more than 300 peer-reviewed articles (2005–2025), FDA guidance documents, and output from large real-world registries. Particular attention was paid to long-read GBA sequencing, biomarkers such as lyso-Gb1, emerging newborn screening programs, and preliminary observational work that points toward multi-state disease modeling. Key observations include: (i) Whole-gene sequencing has expanded genotype–phenotype maps, revealing more than 70 recombinant GBA alleles that confound panel tests; (ii) registry trajectories suggest that formal multi-state models could capture treatment-modified courses and silent endpoints—monoclonal gammopathy, malignancy, Parkinson's disease, pulmonary arterial hypertension—better than current summary statistics; (iii) lyso-Gb1 outperforms legacy biomarkers and now serves as a second-tier newborn-screening marker; (iv) Robust natural-history evidence has already underpinned regulatory approvals across several lysosomal disorders—including olipudase alfa for ASMD, cerliponase alfa for CLN2, vestronidase alfa for MPS VII, and sebelipase alfa for infantile-onset LAL-D—demonstrating that well-curated registries can serve as viable external controls for future LSD submissions. The convergence of deep phenotyping, genotype-aware analytics, and systematic biomarker capture promises to transform natural-history registries from descriptive archives into predictive engines. Gaucher disease offers a working template that, when extended across the LSD spectrum, can accelerate precision care and the development of next-generation therapeutics.

Trial Registration: ClinicalTrials.gov identifier: NCT00358943, NCT03291223.