Journal of Inherited Metabolic Disease最新文献

Urea cycle disorders (UCDs) are a group of genetic metabolic conditions characterized by enzyme deficiencies responsible for detoxifying ammonia. Hyperammonemia, the accumulation of intermediate metabolites, and a deficiency of essential amino acids—due to a protein-restrictive diet and the use of ammonia scavengers—can increase the risk of infections, particularly during metabolic crises. While the underlying mechanisms of immune suppression are still being fully elucidated, hyperammonemia may impair the function of immune cells, particularly T cells and macrophages, inhibiting the proliferation of T cells and cytokine production. Arginine, which is essential for T-cell activation and function, may also be limited in these patients, and its depletion can increase their vulnerability to infections. Twenty-four UCD patients and 31 healthy donors were recruited for the study. Peripheral lymphocyte subset analysis, intracellular protein and cytokine staining, and proliferation assays were performed by flow cytometry. Amino acid levels were measured using the HPLC method. The UCD patients exhibited low lymphocyte-proliferation capacity in both proximal and distal defects in response to phytohaemagglutinin (PHA) and anti-CD2, anti-CD3, and anti-CD28 (CD-mix), which was lower than healthy controls. Proximal-UCD patients exhibited a significantly higher response for IFN-γ compared to both distal-UCD patients and healthy controls. The different amino acids in the culture medium were changed significantly in the groups. This study highlights significant immune dysfunctions in UCD patients, particularly impaired T-cell proliferation and altered amino acid metabolism. Proximal UCD patients exhibited a higher IFN-γ response, indicating a potential for hyperinflammation. Despite this, infection rates did not significantly differ between proximal UCD and distal UCD patients, although distal UCD patients had higher hospitalization rates. Amino acid analysis revealed distinct metabolic disruptions, emphasizing the complex interplay between metabolism and immune function. These findings suggest that UCDs cause profound immune alterations, necessitating further research to develop targeted therapeutic strategies.

In many intoxication-type inherited metabolic disorders, the accumulation of the toxic chemical can cause acute life-threatening emergencies. Sometimes this is the inevitable consequence of a severe metabolic defect, but it is often triggered by catabolism. In this article, we consider the acute management when these conditions cause encephalopathy, seizures, stroke-like episodes, thromboses, liver failure, cardiac failure, arrhythmias and rhabdomyolysis. Treatment is available for most intoxication-type disorders, though it is seldom entirely satisfactory. The emergency management involves general measures for the immediate problem (such as liver failure, thrombosis or an arrhythmia) and specific treatment for the metabolic disorder. The latter usually aims to reduce the accumulation of the toxic small molecule. Often this involves preventing or reversing catabolism. Sometimes the formation of the toxic chemical can be reduced by removing dietary precursors, by diverting precursors to alternative pathways, or by inhibiting an earlier step in the affected pathway. Another strategy is to remove the toxic chemical by binding it to a drug or by extracorporeal blood purification. Occasionally, the block in the pathway can be ameliorated and some disorders, specific treatment may prevent the consequences of the accumulating chemical. Despite all these treatment strategies, outcomes are often disappointing, particularly if an intoxication disorder first presents as an emergency. Newborn screening has greatly improved the prognosis for some disorders. For others, outcomes can only be improved by earlier recognition and treatment.

The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the GALT gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.

Cosmc, encoded by the X-linked C1GALT1C1, is a molecular chaperone in the endoplasmic reticulum and a master regulator of O-glycosylation of mammalian glycoproteins. Recently, we described a germline mutation in C1GALT1C1 in two male patients, giving rise to a congenital disorder of glycosylation—COSMC-CDG. Here, we have identified a female patient with a de novo mosaic variant in C1GALT1C1 (c.202C>T, p.Arg68*), which results in a truncated and nonfunctional form of Cosmc (Cosmc-R68). The patient is mosaic, as ~27% of her buccal cells carry the mutation. The patient is now a 5-year old who presented with nonimmune hydrops fetalis. As Cosmc is essential for the generation of normal O-glycans through regulating T-synthase activity, thereby enabling the formation of the universal Core 1 O-glycan Galβ1-3GalNAcα1-Ser/Thr (T-antigen), the loss of Cosmc leads to the expression of the unusual precursor O-glycan termed Tn-antigen (CD175) (GalNAcα1-Ser/Thr). Owing to the mutational mosaicism, only a significant minority of cells would exhibit abnormal O-glycosylation. Analysis of red blood cells (RBCs), leukocytes, and serum from this patient indicated reduced expression of Cosmc and T-synthase proteins and lower T-synthase activity. Consistent with these findings, we observed reduced normal O-glycans in serum glycoproteins and RBCs from the patient, along with elevated expression of the Tn-antigen in serum glycoproteins compared to controls. This case represents the first description of a true mosaic loss-of-function variant in C1GALT1C1, that is, one that occurred postzygotically during embryogenesis, and raises interesting questions about the role of O-glycosylation during fetal development and its consequences on the clinical presentation.

Human milk (HM) is the optimal source of nutrition for infants. Yet the suitability of HM macronutrient composition, paired with the challenge of regulating HM intake, may deserve some consideration for infants with inherited metabolic disorders (IMDs) requiring restrictive and controlled dietary management. Except for classic galactosemia, HM feeding is expected to be feasible, allowing infants to maintain metabolic stability, while growing and developing optimally. However, information about HM feeding in nonphenylketonuria (PKU) literature is scarce. In this systematic review, 52 studies were included, representing 861 infants (86% PKU) receiving HM after IMD diagnosis (mean duration 4–10 months depending on the IMD). For non-PKU IMDs (e.g., other amino acidopathies, urea cycle disorders, organic acidemias, fatty acid oxidation disorders), outcomes of HM feeding were available for few infants, except for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (n = 48). In PKU, HM feeding combined with phenylalanine-free formula, led to adequate metabolic control (25 studies), growth (15 studies), and neurodevelopment (10 studies). For other IMDs, more evidence is required, but the limited data suggest that HM feeding is possible, with attentive monitoring and disease-specific formula supplementation where applicable. In MCAD deficiency, ensuring adequate HM intake is essential, as symptoms were more frequently reported in exclusively breastfed infants. No IMD-specific articles were found on the relationship between HM feeding and many other outcomes of interest (e.g., immune status or comorbidity risk later in life). With the exception of galactosemia, HM feeding is expected to benefit infants with IMD. More data should be published for IMDs other than PKU.

Classic galactosemia (CG) is a rare inherited metabolic disease caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. The condition develops as a potentially fatal illness during the newborn period, but its acute clinical manifestations can be alleviated through a galactose restricted diet. Nonetheless, such dietary intervention is inadequate in preventing significant long-term consequences, including neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. At present, no effective therapy exists to stop the progression of these complications, highlighting the urgent need for new treatment approaches to be developed. Supplements have been used in the treatment of other inborn errors of metabolism; however, they are not typically included in the clinical therapeutic regimen for CG. Recently, our research team has demonstrated that two generally recognized as safe supplements (purple weet potato color, PSPC and myo-inositol, MI) have been effective in partially restoring functions in the ovaries of our GalT-KO mouse model. However, the toxicological profile of both PSPC and MI has not been determined. In this study, we investigated the acute (30 days) and chronic (180 days) oral toxicities of PSPC and MI both in WT control and GalT-KO mice. Furthermore, our study aims to evaluate the effectiveness of oral feeding of PSPC and MI in correcting motor-related and behavioral phenotypes in GalT-KO mice. The long-term treatment of MI at a lower dose demonstrated promising improvements in motor deficit and anxiety driven hyperactivity in the mutant mice.