Journal of Inherited Metabolic Disease最新文献

Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. Disorders of fatty acid and ketone body metabolism had the highest treatability (67%), followed by disorders of vitamin and cofactor metabolism (60%), and disorders of lipoprotein metabolism (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes.

This study presents the longest systematic prospective follow-up of spinal cord disease in adult male ALD patients to date. Standardized yearly quantitative data collection included scoring of the EDSS, SSPROM, 6-min walking test (6MWT), urological and quality of life questionnaires and vibration sense of the hallux. Progression rates were compared between patients with mild (EDSS ≤ 2.5) and moderate to severe (EDSS > 2.5) disability over a period of 7 years. Data from 79 patients was included. EDSS, SSPROM and 6MWT showed significant disease progression over time. The general progression pattern was linear. Stratified by disease severity, the increase in EDSS was 0.1 points per year in the low EDSS group and 0.2 points per year in the higher EDSS group. SSPROM decreased by −0.7 points per year in the low EDSS group and by −1.9 points per year in the higher EDSS group. 6MWT decreased by −9.3 m/year in the low EDSS group and by −18.2 m/year in the higher EDSS group. The rate of progression in patients with relatively severe disability was higher than in patients with mild disability. Clinical trials will therefore observe effects more rapidly in patients with more advanced disease.

Liver transplantation (LTx) is increasingly used in Urea Cycle Defects (UCDs) to prevent recurrent hyperammonemia and related neurological irreversible injury. Among UCDs, argininosuccinate lyase deficiency (ASLD) has a more complex phenotype than other UCDs, with long-term neurocognitive deficits. Therefore, the role of LTx in ASLD is still debated. The impact of LTx on nine patients with early-onset ASLD was assessed through pre- and post-LTx clinical, neuropsychological, MRI and biochemical evaluations. After LTx, no episodes of metabolic decompensations were reported. Neuropsychological evaluations documented significant improvement in cognitive/developmental functioning especially in patients transplanted in early childhood. Improvements were also highlighted in daily living skills and emotional-behavioral problems, with a reduction in attention disturbances and somatic complaints. Movement disorders resolved after LTx in patient transplanted in early childhood. Any patients developed epilepsy with stability of EEG alterations after LTx. A positive effect of LTx on other disease-related outcomes such as growth, diet, medications, hospitalizations, and long-term ASLD-related complications was highlighted. The primary biomarker argininosuccinic acid dramatically reduced in plasma after transplantation with a decreasing trend in CSF at long-term follow-up. Moreover, health-related quality of life improved after LTx, especially when assessed through MetabQoL, a tool designed for intoxication diseases such as ASLD. In conclusion, our study showed a global beneficial impact of LTx in early-onset ASLD patients to avoid episodes of hyperammonemia, and improve neurocognitive outcome, adaptive and behavioral deficits when performed in early childhood with a dramatic benefit in terms of quality of life.

Gyrate atrophy of the choroid and retina (GACR, OMIM #258870) is a rare inherited metabolic disorder characterized by progressive chorioretinal degeneration and hyperornithinemia. Current therapeutic modalities potentially slow disease progression but are not successful in preventing blindness. To allow for trial development, increased knowledge of the clinical phenotype and current therapeutic outcomes is required. In this study, we analyzed 27 patients with GACR. The median age at inclusion was 24 years (range 8–58), with a median age at diagnosis of 14 years (range 0–42). Symptoms began at a mean age of 9 years (range 0–21). Mixed-models analysis showed a significant association between dietary natural protein intake and plasma ornithine levels. Ornithine increased significantly with age, independent of dietary natural protein intake. We found no statistically significant association between ornithine levels and best-corrected visual acuity over time. Patients who started a natural protein-restricted diet below 10 years of age had better VF outcomes compared to patients that started at a later age. MR spectroscopy was used to asses cerebral creatine deficiency, which was present in 15/20 patients, of whom 10 were supplemented with creatine at the time. Finally, using the Michigan Retinal Degeneration Questionnaire, we provided a first insight into the vision-related disability reported by patients with GACR and showed that higher foveal sensitivity was associated with less perceived disability. To conclude, this study provides insights into the phenotype, genotype, biochemistry, and treatment effects of GACR, which can be used for care pathways and clinical trial design.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder leading to deleterious brain effects. While animal models suggested that MPS I severely affects white matter (WM), whole-brain diffusion tensor imaging (DTI) analysis was not performed due to MPS-related morphological abnormalities. 3T DTI data from 28 severe (MPS IH, treated with hematopoietic stem cell transplantation—HSCT), 16 attenuated MPS I patients (MPS IA) enrolled under the study protocol NCT01870375, and 27 healthy controls (HC) were analyzed using the free-water correction (FWC) method to resolve macrostructural partial volume effects and unravel differences in DTI metrics accounting for microstructural abnormalities. FWC analysis in MPS IH compared to HC revealed higher free-water fraction (FWF) in all WM regions with increased radial (RD) and mean diffusivity (MD). Higher RD, MD, and FWF in cingulate and FWF in temporal WM were observed in MPS IA relative to HC. FWF and RD in the corpus callosum (CC) were higher in MPS IH than in MPS IA. Reaction time was correlated with fractional anisotropy (FA) in frontal and parietal WM in MPS IH. FA in temporal and central WM correlated with d-prime in MPS IA. The HSCT age was related to FA in parietal WM and FWF in frontal WM in MPS IH. FWC delineated subtype-specific WM microstructural abnormalities linked to myelination that were more extensive in MPS IH than IA, with CC findings being a key differentiator between subtypes. Earlier age at HSCT was related to preserved WM microstructure in the brain of MPS IH patients. Free water-corrected DTI distinguishes severe and attenuated MPS I patients and reveals a relationship between attention, age at HSCT, and white matter microstructure.

Cell trafficking is a tightly regulated biological process for the exchange of signals and metabolites between cell compartments, including four main processes: membrane trafficking (transport of membrane-bound vesicles), autophagy, transport along the cytoskeleton, and membrane contact sites. These processes are cross-sectional to cellular functions, ranging from the transportation of membrane proteins, membranes, and organelles to the elimination of damaged proteins and organelles. In consequence, cell trafficking is crucial for cell survival and homeostasis, serving as a cornerstone for cellular communication and facilitating interactions both with the surrounding environment and between different organelles. Disorders of cell trafficking are clinically and pathophysiological diverse and complex and form the largest group in the recent International Classification of Inherited Metabolic Disorders (ICIMD). In this review, we explore the four categories of cell trafficking and the biological principles that drive these processes. Instead of delving profoundly into each pathway, as comprehensive reviews on those topics already exist, we offer a broad overview of the molecular mechanisms behind cell trafficking, providing a foundational understanding to ease their entry into this subject and enhance comprehension of the other articles featured in this Special Issue.

Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob^−/−) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob^−/− mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob^−/− mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob^−/− mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI.

Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/).

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder resulting from pathogenic variants in the ABCD1 gene that primarily affects the nervous system and is characterized by progressive axonal degeneration in the spinal cord and peripheral nerves and leukodystrophy. Dysfunction of peroxisomal very long-chain fatty acid (VLCFA) degradation has been implicated in ALD pathology, but the impact on astrocytes, which critically support neuronal function, remains poorly understood. Fibroblasts from four ALD patients were reprogrammed to generate human-induced pluripotent stem cells (hiPSC). hiPSC-derived astrocytes were generated to study the impact of ALD on astrocytic fatty acid homeostasis. Our study reveals significant changes in the lipidome of ALD hiPSC-derived astrocytes, characterized by an enrichment of VLCFAs across multiple lipid classes, including triacylglycerols, cholesteryl esters, and phosphatidylcholines. Importantly, ALD hiPSC-derived astrocytes not only exhibit intrinsic lipid dysregulation but also affect the dendritic tree complexity of neurons in co-culture systems. These findings highlight the cell-autonomous effects of pathogenic variants in the ABCD1 protein on astrocytes and their microenvironment, shed light on potential mechanisms underlying ALD neuropathology, and underscore the critical role of astrocytes in neuronal health.

Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by toxic phenylalanine (Phe) concentrations in blood and brain. State-of-the-art analyses of speech detected a dimension of verbal discourse providing insights that extend beyond those captured by existing paradigms to measure performance associated with biochemical markers in PKU. The Cookie Theft Picture Task provided a standardized stimulus for eliciting spontaneous speech from 42 adults with PKU and 41 adults without PKU. Subtests measuring language and memory from the Wechsler Adult Intelligence Scale-Fourth Edition showed no differences between the groups and no correlations with biomarkers in PKU. In contrast, AI analyses of responses to the Cookie Theft Task revealed significant differences between the PKU and non-PKU groups on 23 linguistic features. Using multidimensional scaling (MDS), these features were aggregated into a single quantifiable Dimension 1 that significantly correlated with biomarkers. When extreme examples of Dimension 1 were presented to chatGPT, the differences noted reflected attention to detail, clarity in word choice, expression cohesion, contextual awareness and emotion recognition. We subsequently defined Dimension 1 as Proficiency in Verbal Discourse. This novel measure elucidated discourse styles possibly associated with suboptimal achievement and learning disabilities, often reported in PKU. In summary, AI captured a characteristic associated with metabolic status undetectable through traditional neuropsychological measures. Future studies will expand upon this novel paradigm, leveraging speech AI to quantify meaningful aspects of everyday functioning and possibly provide information for management decisions. Once validated, this measure holds promise for extension to other rare diseases and incorporation into clinical trials.