MR neurography (MRN) is a modern technique for visualizing peripheral nerves and quantifying microstructural pathology, yet its use in pediatric populations remains largely unexplored. This study evaluates the applicability and diagnostic performance of MRN in children and adolescents with genetically confirmed long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), in which peripheral neuropathy is a known long-term complication. In a prospective cross-sectional study, 15 patients (LCHADD n = 6; MTPD n = 9) and 14 age-matched controls underwent high-resolution mid-thigh MRN of the sciatic nerve to assess (1) T2-based lesion burden for tibial (SNTib) and peroneal (SNPer) fascicles, (2) functional nerve integrity of the tibial fascicles using diffusion tensor metrics, including fractional anisotropy (FA) and radial diffusivity (RD), and (3) tibial fascicle-based T2 relaxometry parameters. In addition, clinical and electrophysiological data were obtained. Age-adjusted linear regression, ROC analyses, and linear discriminant analyses (LDA) quantified group effects and classification performance. Overall, patients showed higher T2 lesion burden compared with controls (SNTib: +2.75%, P = 0.001; SNPer: +1.94%, P = 0.001), reduced tibial fascicle FA (Δ: -0.098, P = 0.001), and increased tibial fascicle RD (Δ: +147.4×10-6 mm2/s, P = 0.011). Subgroup comparisons between LCHADD and MTPD revealed no significant differences. Of the 15 patients, 7 exhibited signs of clinical neuropathy. Neuropathic individuals showed pronounced abnormalities (SNTib: +4.22%, P < 0.001; SNPer: +2.29%, P = 0.002; ΔFA: -0.138, P < 0.001), while even those without clinical neuropathy exhibited elevated SNPer lesion burden (+1.64%; P = 0.018) and reduced tibial fascicle FA (Δ: -0.062, P = 0.03), compared with controls, indicating subclinical involvement. SNTib lesion burden showed excellent discrimination (AUC: 95.2%), and FA performed well (AUC: 81.2%). Multiparametric LDA achieved 93% apparent in-sample accuracy for patients versus controls, 86% for LCHADD versus MTPD, and 90% for classifying neuropathic, non-neuropathic, and control groups. MRN can be readily applied in children and adolescents and sensitively detects both clinically manifest and subclinical peripheral nerve involvement in long-chain fatty acid oxidation disorders. Extending this capability, exploratory LDA suggests that combining multiple MRN metrics may provide complementary diagnostic and phenotypic information beyond individual parameters.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an extremely rare autosomal recessive disorder, with only a few hundred affected individuals worldwide. Since its initial recognition in the 1980s, only a limited number of studies have described its ocular manifestations. The aim of this review was to summarize and organize the available published evidence regarding ocular findings in LCHADD and their classification. A PubMed search was conducted for studies describing ocular findings associated with LCHADD, using combinations of the following keywords: LCHADD, chorioretinopathy, ocular findings, vision, therapy, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The review included studies published within the past 20 years that reported at least six cases. The search identified 11 eligible studies. Findings were grouped into three categories: LCHADD-associated chorioretinopathy, macular neovascularization (MNV), and the effects of dietary therapy on visual function. Chorioretinopathy emerged as the major pathognomonic ocular feature of LCHADD. MNV was reported in approximately 20% of eyes, often bilaterally but not simultaneously. Progressive myopia was observed in most patients. Newborn screening and early initiation of dietary therapy appear critical and may slow the progression of chorioretinopathy. A strong correlation between patient age and chorioretinopathy severity was consistently demonstrated, and visual deterioration occurred even in individuals with good metabolic control. LCHADD is a life- and vision-threatening disorder characterized by a distinctive chorioretinopathy present in nearly all patients. Early detection through newborn screening and regular ophthalmic follow-up is essential for the optimal management of affected individuals.

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a mitochondrial fatty acid oxidation (FAO) disorder, frequently present with cardiomyopathy and can suffer from life-threatening arrhythmias and heart failure. Although these remain the leading causes of death, the pathophysiology remains unknown. We used an LCHADD mouse model to examine the mechanisms of impaired cardiac function. We previously determined that LCHADD mice (Hadha c.1528G>C homozygotes) recapitulate human disease and develop cardiomyopathy. We performed electrophysiological tests on LCHADD and wild-type (WT) mice, followed by cardiac tissue and molecular expression analysis. LCHADD mice showed significantly increased frequency of atrial premature beats, premature ventricular contractions, atrial flutter, atrial fibrillation, and nonsustained ventricular tachycardia (NSVT) after β-agonist stimulation compared with WT mice. Long QRS and long QT intervals were also observed when compared with WT mice. LCHADD heart sections demonstrated increased cardiomyocyte cross-sectional area, increased lipid and collagen deposition, and decreased glycogen deposits. There was global sympathetic denervation in LCHADD hearts compared with WT. Differentially expressed gene analysis showed increased expression of glycolytic and glutathione synthesis enzymes, and decreased expression of tricarboxylic acid (TCA) cycle enzymes, Ca++ signaling, and cardiac muscle contraction proteins. LCHADD cardiomyopathy has a hypertrophic phenotype with diffuse fibrosis, accumulation of lipids, and lower glycogen storage in the absence of obesity. LCHADD cardiomyocyte metabolism suggests a shift from FAO toward glycolysis with chronic oxidative stress. Energy deficiency and lipotoxicity likely influence Ca++ signaling and cardiac contraction. Long QRS and QT intervals with global sympathetic denervation may predispose the heart to repolarization abnormalities susceptible to arrhythmias and increased risk of sudden cardiac arrest and death.NEW & NOTEWORTHY As major cardiac events and heart failure are the leading causes of death among individuals with LCHADD, we are committed to identify better treatment options. To undertake this, we characterized LCHADD cardiomyopathy using a mouse model. We identified a hypertrophic cardiomyopathy with diffuse fibrosis, extensive lipid accumulation, increased oxidative stress, and global sympathetic denervation with long QT intervals and arrhythmia susceptibility likely caused by cardiomyocyte energetic remodeling, altered homeostasis, and cardiac conduction dysregulation.

Mitochondrial long-chain fatty acid β-oxidation supplies energy to the heart, liver, and skeletal muscle. Impairment of this process due to a block at the step catalyzed by long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) leads to bioenergetic failure, manifesting as hypoglycemia, recurrent rhabdomyolysis, cardiomyopathy, and hepatic dysfunction. Accumulation of toxic intermediates-long-chain 3-hydroxyacyl-CoAs and the corresponding 3-hydroxyacylcarnitines-contributes to pigmentary retinopathy and peripheral neuropathy. Early diagnosis and careful dietary management can reduce life-threatening decompensation in childhood and improve survival into adulthood. This review examines the genetics of human LCHAD deficiency, describes its multisystem complications, and outlines nutritional strategies used to bypass the enzymatic block. We also explore nutrigenomic signals elicited by dietary treatment in LCHAD deficiency.

3-hydroxy acylcarnitines (3-OH-ACs) are key biomarkers for screening of long-chain 3-hydroxyacyl-CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3-day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3-OH-ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3-OH-ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long-chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3-OH-ACs or metabolomics. 3-OH-ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3-OH-ACs.