極長鎖アシル-CoA 脱水素酵素欠損症

OBJECTIVES: To investigate the incidence, genetic mutation characteristics, and prognosis of fatty acid oxidation disorder (FAOD) in neonates in Qingdao. METHODS: Clinical data of neonates diagnosed with FAOD from 2014 to 2023 at the Qingdao Neonatal Disease Screening Center were collected and analyzed to determine the incidence, genotype, and prognosis. RESULTS: Among 562 225 neonates screened, 42 were diagnosed with FAOD across six types, yielding an overall incidence of 1/13 386. Primary carnitine deficiency was the most common (20 cases, 48%), with one case showing growth retardation during follow-up. Medium-chain acyl-CoA dehydrogenase deficiency was identified in 6 cases, all of whom demonstrated normal development during follow-up. Short-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases, with one case exhibiting skin erythema, papules, scaling, and dryness during follow-up. Very-long-chain acyl-CoA dehydrogenase deficiency was diagnosed in 5 cases; during follow-up, one patient died and another experienced recurrent rhabdomyolysis. Short/branched-chain acyl-CoA dehydrogenase deficiency was found in 4 cases, with one case showing language regression during follow-up. Multiple acyl-CoA dehydrogenase deficiency was detected in 2 cases; during follow-up, one patient died and one exhibited delayed motor development. Genetic testing performed on 37 of the 42 patients with FAOD identified a hotspot mutation, c.1400C>G, in the SLC22A5 gene among those with primary carnitine deficiency, whereas no predominant hotspot mutations were detected in other FAOD subtypes. CONCLUSIONS: In Qingdao, primary carnitine deficiency is the most prevalent subtypes of FAOD in neonates, characterized by the hotspot mutation c.1400C>G in the SLC22A5 gene. Except for very-long-chain acyl-CoA dehydrogenase deficiency and multiple acyl-CoA dehydrogenase deficiency, most children with other FAOD subtypes have a favorable prognosis.

BACKGROUND: Human milk is considered the gold standard for infant nutrition; however, it is often discontinued in chylothorax and severe very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. As an alternative to complete human milk restriction, defatted human milk may be fed, though it may not fully support optimal infant growth and development. This study aimed to assess the micronutrient profile of defatted human milk. METHODS: Human milk was obtained from UCSD Human Milk Research Biorepository (San Diego, CA). Thirty samples representing 10 independent expressions in the morning, afternoon, and evening were pooled for analysis. Fat removal was performed by centrifugation at refrigerated and room temperatures, electric cream separator, and gravity separation. Analyses of macronutrients, micronutrients, fat-soluble vitamins, and water-soluble vitamins were conducted in triplicate. RESULTS: All defatting methods decreased vitamins A and E by >80%. Folate decreased most by nonrefrigerated centrifugation (52.3, SD < 0.01%) and least by cream separator (22.8, SD < 0.01%). Zinc decreased most by both nonrefrigerated centrifugation (43.5 ± 0.06%) and cream separator (43.5 ± 0.12%), and least by refrigerated centrifugation (17.7 ± 0.10%). Iodine decreased most by refrigerated centrifugation (40.0, SD < 0.01%) and least by cream separator (31.2, SD < 0.01%). Total triglycerides decreased most by refrigerated centrifugation (87.0 ± 0.03%). CONCLUSIONS: All defatting methods decreased amounts of vitamin A, vitamin E, folate, zinc, and iodine. Refrigerated centrifuge was most effective in removing total triglycerides. These results can inform fortification and supplementation guidelines of key micronutrients for patients with chylothorax and VLCAD deficiency consuming defatted human milk.

BACKGROUND: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a mitochondrial fatty acid oxidation disorder caused by mutations in the acyl-CoA dehydrogenase very long chain (ACADVL) gene. Hashimoto's thyroiditis is the most common autoimmune thyroid disease. To the best of our knowledge, their coexistence has not been reported. This case highlights a potential mechanistic link between mitochondrial dysfunction, chronic inflammation, and endocrine autoimmunity. CASE PRESENTATION: A 33-year-old woman presented with acute-onset generalized myalgia, fatigue, and dark-colored urine. Laboratory findings confirmed severe rhabdomyolysis. Thyroid tests revealed primary hypothyroidism with elevated anti-TPO and anti-Tg levels, and ultrasonography demonstrated chronic autoimmune thyroiditis. The patient had a history of recurrent unexplained rhabdomyolysis without identifiable external triggers. Therefore, genetic testing was performed to evaluate for an underlying metabolic myopathy. Genetic testing identified a homozygous ACADVL c.1097G>A (p. Arg366His) variant, confirming VLCAD deficiency. Treatment included intravenous hydration, L-carnitine supplementation, a medium-chain triglyceride (MCT)-enriched diet, and levothyroxine. The patient showed marked improvement and remained stable without recurrence for one year. CONCLUSIONS: To the best of our knowledge, this appears to be the first report describing the coexistence of VLCAD deficiency and Hashimoto's thyroiditis. Chronic mitochondrial dysfunction may potentially contribute to systemic inflammation and immune activation associated with autoimmune thyroid disease. Increased awareness of this association may facilitate earlier clinical recognition and encourage comprehensive evaluation.

BACKGROUND: Pearson syndrome (PS) is a rare multisystem mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions (SLSMDs). It typically presents in infancy with refractory sideroblastic anemia, exocrine pancreatic insufficiency, and failure to thrive. Due to its heterogeneous manifestations and resemblance to other hematological conditions, early diagnosis remains a clinical challenge. CASE PRESENTATION: A south asian male infant presented with persistent pancytopenia, severe anemia unresponsive to intravenous and oral iron and multivitamin supplements, exocrine pancreatic insufficiency, failure to thrive, and metabolic acidosis. Born to consanguineous parents, the child had a significant family history of early infant deaths and hematological abnormalities. Peripheral smear showed marked anisopoikilocytosis with cytoplasmic vacuolization of erythroid precursors. Bone marrow analysis revealed erythroid hyperplasia, dyserythropoiesis, vacuolated precursors in both the erythroid and myeloid lineages, and ringed sideroblasts. Steatorrhea was consistent with exocrine pancreatic insufficiency, a recognized feature of Pearson syndrome. Although HbA1c was marginally elevated, this finding is nonspecific in infancy and does not indicate endocrine pancreatic dysfunction. Endocrine involvement is typically reported later during mitochondrial disorders and was not supported clinically or biochemically in this case. While mitochondrial DNA deletions underlying Pearson syndrome are usually sporadic, the presence of consanguinity and multiple affected siblings in this family raises the possibility of modifying nuclear genetic factors contributing to phenotypic variability. The overall constellation of clinical features, hematological findings, and bone marrow morphology was diagnostic of Pearson syndrome. CONCLUSIONS: This case underscores the importance of considering mitochondrial cytopathies in infants presenting with unexplained pancytopenia, multisystem involvement, and a suggestive family history, even in the presence of parental consanguinity. Early recognition, even in resource-limited settings, is vital for prognostication and family counseling, though definitive treatment remains supportive.

BACKGROUND/OBJECTIVES: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of mitochondrial fatty acid β-oxidation caused by pathogenic variants in ACADVL. The clinical spectrum is highly heterogeneous, ranging from lethal neonatal cardiomyopathy to late-onset myopathy. This study aims to characterize the rare c.215C>T (p.Ser72Phe) variant, identified in compound heterozygosity with the common pathogenic allele c.848T>C (p.Val283Ala) in a male neonate detected by newborn screening (NBS). METHODS: Genetic analysis was performed using Sanger sequencing on the proband and his family members. The pathogenicity of the p.Ser72Phe variant was evaluated through multiple bioinformatic predictors and interpreted according to ACMG/AMP guidelines. To understand the functional impact on the protein, structural modeling was conducted using FoldX 4.0 for energy calculations and UCSF ChimeraX for the visualization of conformational changes and cofactor-binding site perturbations in the VLCAD homodimer. RESULTS: At the end of the first postnatal week, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of dried blood spots of the proband revealed a markedly abnormal acylcarnitine profile, with C14:1 levels (1.837 μmol/L) approximately five times above the reference range. Clinical reports documented hypoketotic hypoglycemia, consistent with VLCADD. Segregation analysis demonstrated transmission of both variants within the family, with additional heterozygous and homozygous carriers identified. Bioinformatic predictions uniformly classified p.Ser72Phe as deleterious. This variant has an extremely low allele frequency and affects a highly conserved residue in the FAD-binding domain. Structural modeling with FoldX yielded a mean ΔΔG of +22.63 ± 5.48 kcal/mol, indicating a significant localized thermodynamic burden. Inspection of the mutant model in ChimeraX showed perturbation of the side-chain orientation and attenuation of the local hydrogen-bonding network at the FAD-binding site, together with increased steric packing around residue 72. Taken together, the clinical, genetic, and structural evidence support reclassification of p. Ser72Phe as likely pathogenic according to ACMG criteria, specifically applying the ClinGen ACADVL VCEP specifications. CONCLUSIONS: This study expands the ACADVL mutational spectrum and underscores the value of integrating sequencing, segregation, and structural bioinformatics in interpreting rare variants detected through NBS.