ガラクトース-1-リン酸ウリジルトランスフェラーゼ欠損症

INTRODUCTION: Classical galactosemia (CG), caused by galactose-1-phosphate uridylyltransferase (GALT) enzyme deficiency, is associated with premature ovarian insufficiency (POI) and subfertility. The last years, a counseling paradigm shift has been advocated with emphasis on subfertility instead of infertility because spontaneous pregnancy can occur. CASE PRESENTATIONS: We describe two women (aged 26 and 30 years) with genetically confirmed CG and POI, who conceived spontaneously. Both adhered to lifelong galactose-restricted diet and had regular endocrine monitoring. Their pregnancies were uncomplicated and each delivered a healthy infant at term. CONCLUSIONS: These cases are in line with the counseling paradigm shift, with natural conception being possible in CG. Reproductive counselling of girls and women with CG should entail fertility preservation and spontaneous pregnancy. In case of desired pregnancy, a period of two years to attempt conceiving should be advised. AMH is not a reliable prognostic parameter for predicting the reproductive potential in CG.

BACKGROUND AND OBJECTIVE: Congenital and developmental disorders should be detected early to avoid complications such as disability and death. The Philippine clinical practice guidelines (CPG) were developed to guide healthcare professionals on screening for congenital and developmental disorders among apparently healthy neonates and children. METHODS: Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to CPG development recommended by the Department of Health (DOH), the steering committee, composed of clinical geneticists, developmental pediatricians, family and community medicine physicians, and ambulatory and community pediatricians, set the objectives of the CPG and formulated clinical questions in consultation with stakeholders. There were 15 priority guideline questions that covered various disorders including inborn errors of metabolism, critical congenital heart disease, developmental delay, learning disabilities, and autism. Evidence review experts systematically reviewed existing clinical practice guidelines, appraised, and summarized the evidence. A multisectoral panel formulated recommendations through a formal consensus based on the evidence summaries. The CPG was externally reviewed prior to publication. RESULTS: The CPG provides twenty (20) recommendations on fifteen (15) prioritized questions in the screening for certain congenital and developmental disorders. This CPG contains recommendations for the screening for critical congenital heart disease, thalassemia, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, developmental delay, and autism spectrum disorder. Recommendations against routine screening of cystic fibrosis, sickle cell disease, methionine adenosyltransferase deficiency, tyrosinemia, long chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), carnitine palmitoyl transferase types 1 and 2 (CPT1, CPT2) and glutaric aciduria type 2 (GA2), biotidinase deficiency, beta-ketothiolase deficiency, holocarboxylase synthetase deficiency, and isovaleric acidemia were made. CONCLUSION: The consensus panel recommended the screening of certain conditions, based on the available evidence, the burden of disease, the cost of the confirmatory testing, and its applicability to the population. Although this CPG intends to influence the direction of health policies for the general population, it should not be the sole basis for recreating or abolishing practices that aim to improve the health conditions of many Filipinos, particularly those part of the workforce.

Restricted diet therapy is the cornerstone of treatment in many hereditary metabolic disorders. This study evaluated the effects of dietary treatments for affected children on the dietary habits, lifestyle, quality of life, and stress levels of their mothers. The study included 50 mothers of children aged 2 to 18 years with phenylketonuria, organic acidemias, urea cycle defects, or galactosemia, and 32 mothers of healthy children. Mothers completed a demographic and lifestyle questionnaire, the Short Form-36 Quality-of-Life questionnaire, and the Perceived Stress Scale. More than half of the mothers in the patient group reported modifying their own diets to align with their child's restrictions, while some adopted vegetarian or vegan diets. Many reported limiting social activities, and 18% had quit their jobs to manage dietary treatment. Mothers of affected children showed significantly higher stress scores and lower quality-of-life scores than controls.

BACKGROUND: Premature ovarian insufficiency (POI) is a complication that affects 80% of females with classic galactosemia (CG), an autosomal recessive metabolic disorder caused by mutations in the GALT gene. The immune system plays a critical role in normal ovarian physiology and in the development of pathological conditions, including POI. While previous animal studies have shown that accumulation of toxic galactose metabolites trigger cellular stress pathways, and may contribute to the disease's complications, it remains unclear how these influence the ovarian immune landscape in CG patients. METHODS: Here, we performed single-nucleus and spatial transcriptomic analyses on ovary biopsies from pre-pubertal girls with CG and compared with control ovary samples to explore the changes in ovarian immune milieu. We specifically investigated the gene expression profiles and altered signaling pathways in macrophages and endothelial cells. Mouse ovary cultures were treated with 50mM D-galactose for 48 h and immunohistochemical analysis was performed to evaluate the role of oxidative stress and activation of the NLRP3 inflammasome. RESULTS: Our transcriptomic analysis reveals diverse subpopulations of macrophages inside the ovarian stroma. We noticed a marked increase in both monocyte-derived and tissue-resident macrophages, and expression of proinflammatory cytokine genes (TNF, IL1B, CCL2, CXCL10, CXCL8) in the CG ovary. Transcriptomic profiles of endothelial cells reveal upregulation of cell-adhesion molecules (VCAM1, ICAM1, PECAM1, SELP, SELE) and chemokines (CCL21, CX3CL1) which can modulate immune cell extravasation at the site of inflammation in the CG. IHC data revealed increased expression of NLRP3, CASP-1 and TNF-α expression in the ovaries of CG. Furthermore, D-galactose toxicity in mouse ovaries resulted in oxidative stress evident by increased expression of 8-OHdG and 4-HNE, and increased atresia of ovarian follicles indicated by cleaved-CASP3 expression. We found an increased expression of NLRP3, cleaved CASP1, activated GSDMD, cleaved IL-1β and TNF-α in the D-galactose-treated mouse ovaries, suggesting inflammasome-mediated pyroptotic cell-death and inflammation, which can eventually contribute to augmented follicular atresia. CONCLUSIONS: Our findings provide molecular insights into the proinflammatory immune response driven by oxidative stress-induced activation of the NLRP3 inflammasome pathway in the CG ovary. This study elucidates the plausible role of ovarian pyroptotic macrophages in the exacerbating the inflammatory microenvironment, which may explain the early onset of POI in CG patients.

BACKGROUND/OBJECTIVES: Hepatic diseases frequently present with ocular manifestations that aid diagnosis, provide prognostic data, and guide therapy. Despite the clear utility of the liver-eye axis, the literature lacks reviews that categorize these manifestations by etiology. This review evaluates current evidence to identify ocular findings that serve as clinical tools for diagnosis, prognosis, and therapeutic monitoring of hepatic pathologies. METHODS: A narrative review was conducted using PubMed and Google Scholar to identify English-language articles addressing ocular manifestations associated with liver disease. The primary search encompassed publications from 2000 to 2025, with inclusion of select foundational works published prior to 2000 when they represented seminal studies establishing diagnostic criteria, pathophysiological mechanisms, or natural history data not superseded by subsequent research. Search terms included combinations of liver, hepatic, hepatitis, cirrhosis, cholestasis, eye, ocular, retina, cornea, sclera, conjunctiva, ophthalmic manifestations, and specific disease names. All study designs were eligible. Society guidelines, systematic reviews, and studies from high-impact journals were prioritized. The final selection comprised 59 references representing the most authoritative sources across the spectrum of hepatic conditions. RESULTS: A spectrum of ocular findings linked to distinct hepatic conditions was identified. Manifestations with established clinicopathologic associations were categorized into congenital and acquired etiologies. Congenital liver pathologies included metabolic disorders (Wilson disease, galactosemia, lysosomal storage disorders) and syndromic/genetic causes (Alagille syndrome, hereditary hemochromatosis). Acquired liver diseases encompassed infectious (hepatitis B/C), drug-induced and iatrogenic (interferon, immune checkpoint inhibitors), nutritional (vitamin A deficiency), neoplastic (metastatic hepatocellular carcinoma), and cirrhotic causes. CONCLUSIONS: Specific ocular signs raise clinical suspicion for underlying liver disease and warrant targeted hepatic evaluation. Recognizing these associations facilitates earlier diagnosis and improves outcomes. Systematic screening for these signs is supported in at-risk populations, and prospective validation studies should establish their sensitivity and specificity.