三頭酵素欠損症

Cardiomyopathy is an important manifestation in patients with fatty acid oxidation disorders and represents a major cause of morbidity and early mortality in mitochondrial trifunctional protein (TFP) deficiency. Although a mouse model carrying the TFP β-subunit p.Met404Lys mutation (βTFP-deficient) has been described, cardiac involvement in this model has not been systematically characterized. Here, we combined cardiac histology and multiparametric cardiac MRI (CMR) to define myocardial structure, function, and tissue characteristics in this mouse model. Histological analysis with automated whole-slide collagen quantification revealed myocardial fibrosis with collagen deposition in mutant hearts, and CMR demonstrated increased myocardial extracellular volume in both male and female homozygous mutants. Homozygous males showed reduced ejection fraction, impaired systolic strain, and increased left ventricular end-systolic volume, indicating systolic dysfunction. Male mice were more severely affected than females and exhibited reduced survival. Together, these findings demonstrate that βTFP-deficient mice develop fibrotic cardiomyopathy with systolic dysfunction, reproducing important cardiac features observed in human TFP deficiency. This work establishes the model as a relevant platform for investigating disease mechanisms and therapeutic strategies for cardiomyopathy in TFP deficiency.

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.

BACKGROUND: Patients with LCHADD/TFPD are counseled to follow a diet low in long-chain fats (LCT) and supplement with medium-chain fats (MCT) with adequate micronutrients, but there is limited data on patient implementation of recommendations. We analyzed diet intake of LCHADD/TFPD participants twice, 2 years apart. METHODS: Participants enrolled in the longitudinal Natural History of LCHAD Retinopathy study completed a 3-day food record and supplement logs at baseline and 2 years later. Differences in %LCT and MCT intake over time, and intra-individual and population variation, were analyzed. Percentage of participants meeting estimated average requirements (EAR) for fat-soluble (A, D, E, K) and water-soluble vitamins (B1, B2, B3, C) were calculated. RESULTS: Forty participants were enrolled, 2-36 years (48% female), 25% G1528C homozygous, 68% G1528C heterozygous, and 7% TFPD. Thirty-five baseline and 38 follow-up diet records were included. Fat intake was consistent over time; baseline 13.7% LCT, 18.8% MCT, follow-up 14.7% LCT, 20.6% MCT. Intra-individual variation ranged from 22% to 32% for MCT and LCT, respectively, but both were less than the overall population variation 49% MCT and 36% LCT. An average of 38.8% of participants took a multivitamin; however, only 51% met the EAR for fat-soluble vitamins compared to 81% for water-soluble vitamins. CONCLUSIONS: LCHADD/TFPD patients are consistently consuming a low-fat diet with appropriate supplementation of MCT. Day-to-day variation in %LCT was comparable to the general population, but absolute amount of fat was lower. A greater proportion of patients are still not meeting EAR for fat-soluble vitamins compared to water-soluble vitamins.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive mitochondrial defect of long-chain fatty acid β-oxidation, caused by biallelic pathogenic variants in HADHA or HADHB. We report a 22-year-old male with an atypically mild presentation of LCHADD who was referred to the Undiagnosed Diseases Network (UDN). Trio genome sequencing identified a maternally inherited HADHA frameshift pathogenic variant and a paternally inherited noncoding rare HADHA variant. The paternal noncoding variant was predicted by in silico splicing analysis to create a cryptic splice donor site. This was experimentally confirmed to partially perturb splicing, leading to partial disruption of normal splicing and the production of both normal and aberrant transcripts. Transcripts derived from the cryptic donor site were subject to nonsense-mediated decay (NMD). As a result, the proband's cells produced three HADHA transcripts: a truncated maternal transcript that was destroyed by NMD, an abnormally spliced paternal transcript also subject to NMD, and a normally spliced paternal transcript. The presence of residual normally spliced HADHA transcripts from the paternal allele likely contributes to partial preservation of LCHAD enzyme function and provides a plausible explanation for the proband's attenuated clinical phenotype.