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.

Targeted genome editing has made significant advancements; however, safety and ethical issues have not been fully elucidated, resulting in strict control of the technique. We tested genome editing tools on gametes from a genetically humanized mouse model using a phenylketonuria (PKU) mouse model to gain insights into genome editing in human embryos. The human PKU mouse model Pah^hR111X mice was generated. The junctional region between exon 3 and intron 3 of Pah was replaced with a 120 bp corresponding human PAH sequence, including the pathogenic common variant c.331C > T in Pah^hR111X mice. Pah^hR111X mice successfully recapitulated the PKU phenotype and showed cognitive dysfunction and depressive-like behavior, which are observed in human patients with PKU. Genome editing was applied to fertilized eggs of Pah^hR111X mice utilizing sgRNA that targets the human sequence. Mice with the corrected allele exhibited normal serum phenylalanine levels. Through genome editing, we validated the utility of sgRNA. The genetically humanized mouse model suggested that germ-line genome editing of the pathogenic variant may be feasible for monogenic disorders by revealing the recovery of the phenotype; however, there are remaining issues with the tool, including its efficiency and accuracy. This genome editing protocol using a genetically humanized mouse model will provide insights for improving current issues and contribute to the establishment of heritable human genome editing protocols.

PMM2-CDG (formerly CDG-1a), the most common type of congenital disorders of glycosylation, is inherited in an autosomal recessive pattern. PMM2-CDG frequently presents in infancy with multisystemic clinical involvement, and it has been diagnosed in over 1000 people worldwide. There have been few natural history studies reporting neurodevelopmental characterization of PMM2-CDG. Thus, a prospective study was conducted that included neurodevelopmental assessments as part of deep phenotyping. This study, Clinical and Basic Investigations into Known and Suspected Congenital Disorders of Glycosylation (NCT02089789), included 14 participants (8 males and 6 females ages 2-33 years) with a confirmed molecular diagnosis of PMM2-CDG. Clinical features of PMM2-CDG in this cohort were neurodevelopmental disorders, faltering growth, hypotonia, cerebellar atrophy, peripheral neuropathy, movement disorders, ophthalmological abnormalities, and auditory function differences. All PMM2-CDG participants met criteria for intellectual disability (or global developmental delay if younger than age 5). The majority never attained certain gross motor and language milestones. Only two participants were ambulatory, and almost all were considered minimally verbal. Overall, individuals with PMM2-CDG present with a complex neurodevelopmental profile characterized by intellectual disability and multisystemic presentations. This systematic quantification of the neurodevelopmental profile of PMM2-CDG expands our understanding of the range in impairments associated with PMM2-CDG and will help guide management strategies.

Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.

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.

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.

Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.

Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common "clinical signature" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ¹-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.