グルタル酸血症２型

PURPOSE OF REVIEW: To summarize recent advances in adult-onset disorders of muscle lipid metabolism, with particular emphasis on fatty acid β-oxidation disorders (FAODs), multiple acyl-CoA dehydrogenase deficiency (MADD) and MADD-like disorders, and neutral lipid storage disease with myopathy (NLSDM). RECENT FINDINGS: Recent studies in FAODs have provided new insights into long-term outcomes, exercise physiology, prognostic biomarkers, and the impact of newborn screening (NBS) on disease management. In MADD, growth differentiation factor 15 (GDF15) has emerged as a potential biomarker. Major advances have occurred in MADD-like disorders, including the identification of COASY as a novel disease gene and the recognition of sertraline-associated acquired MADD-like disorder, challenging the traditional view of FAODs as exclusively genetic diseases. In NLSDM, recent cohort studies have expanded the phenotypic spectrum, highlighted cardiomyopathy as a major determinant of morbidity and mortality, and revealed a critical role of adipose triglyceride lipase (ATGL) in maintaining mitochondrial network integrity and function. SUMMARY: Advances in clinical phenotyping, metabolic biomarkers, molecular genetics, and NBS have substantially improved the diagnosis and understanding of adult-onset disorders of muscle lipid metabolism. The recognition of sertraline-associated MADD-like disorder has established that lipid storage myopathies can also arise through acquired toxic mechanisms. Collectively, these developments are expected to facilitate earlier diagnosis, improve disease classification, and support the development of targeted therapeutic strategies for these rare but often treatable disorders.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an autosomal recessive disorder; yet, recent findings suggest up to 10% of cases may result from heterozygous electron transfer flavoprotein dehydrogenase (ETFDH) variants exhibiting dominant or dominant-like effects. Here, a novel heterozygous ETFDH variant (c.1798A>C, p.Asn600His) was identified within a three-generation family. The grandfather presented with muscular weakness at age 35, and the father developed similar symptoms at 19 following a tonsillectomy. Both were diagnosed with MADD based on muscle biopsies revealing neutral lipid accumulation and acylcarnitine profiles and responded fully to riboflavin therapy (150 mg/day). The two siblings, aged 8 and 10, carry the same mutation and show increased acyl-carnitine levels but remain asymptomatic due to early riboflavin treatment. Skin fibroblasts from affected individuals were immortalized and subjected to normal and reduced riboflavin levels. Gene expression analysis demonstrated unchanged ETFDH RNA but reduced protein levels in mutant cells, particularly under low riboflavin. Structural modelling suggested the Asn600His substitution destabilizes the protein, diminishing its mitochondrial function. Proximity ligation assays indicated a decreased interaction with mitochondrial complex III, while oxygen consumption via fatty acid oxidation was impaired, especially at reduced riboflavin. The novel ETFDH variant found in this family gives a possible dominant pattern of inheritance for MADD, where a single mutant allele impairs the mitochondrial metabolism, particularly under riboflavin-deficient conditions, and highlights the importance of early riboflavin supplementation in preventing clinical symptoms.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare inherited disorder that disrupts fatty acid metabolism. We report a case of a patient who presented with confusion, undifferentiated shock, and rapidly worsening lactic acidosis and hyperammonemia, unexplained in severity by primary liver dysfunction. Metabolic investigations suggested the probable cause was late-onset MADD, likely triggered by pneumonia and exacerbated by early administration of fatty acid-containing sedatives. Early recognition of MADD and other metabolic disorders, whether inherited or acquired, is crucial for timely diagnosis and management. Unexplained hyperammonemia and other metabolic abnormalities should prompt clinicians to consider these rare conditions.

BACKGROUND: Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) is an autosomal recessive disorder of fatty acid oxidation predominantly caused by variants in the ETFDH gene. However, approximately 10% of patients carry a single heterozygous variant. We hypothesize that ETFDH haploinsufficiency may contribute to the development of RR-MADD, especially under certain environmental stressors. METHODS: Skin fibroblasts derived from one RR-MADD patient carrying a heterozygous variant in ETFDH and his asymptomatic father carrying the same variant were cultured. Under varying concentrations of riboflavin, ETFDH gene expression profiles, intracellular free fatty acid (FFA) levels, mitochondrial function, cellular viability, and accumulation of reactive oxygen species (ROS) and lipid droplets were assessed and compared between the two cell lines. These phenotypic comparisons were subsequently extended to HEK293 cell models engineered to carry either heterozygous or homozygous c.917G > A variants in ETFDH. Etfdh knock-in mice carrying c.250G > A (p.A84T) variants were used to evaluate the contribution of single heterozygous variants to disease susceptibility at the organismal level. RESULTS: Under identical culture conditions, fibroblasts from the RR-MADD patient and his father exhibited comparable levels of ETFDH gene expression and FFA, along with similar mitochondrial function, cellular viability, ROS production, and accumulation of lipid droplets. This finding suggests that environmental factors rather than genotype cause phenotypic differences between the two individuals. Moreover, exposure to severe riboflavin deficiency induced a similar RR-MADD phenotype in HEK293 cells regardless of whether they carried heterozygous or homozygous variants. Mice harboring the heterozygous Etfdh c.250G > A variant exhibited a classic RR-MADD phenotype and pathological changes following combined dietary interventions consisting of riboflavin deficiency and high-fat diet. CONCLUSIONS: This study demonstrates that single heterozygous ETFDH variants confer increased susceptibility to RR-MADD in the presence of specific environmental stressors, offering new genetic insights into the inheritance pattern of the disease.

BACKGROUND: Multiple acyl-Coenzyme A dehydrogenase deficiency (MADD) is an inborn error of metabolism affecting fatty acid, amino acid and choline oxidation and is included in newborn screening in Australia. Recent reports describe adults with clinical and biochemical features of MADD, but negative genetic findings, associated with sertraline use. AIM: To describe a well newborn found to have a transient MADD-like biochemical pattern on newborn screen analysis, attributed to maternal sertraline use. RESULTS: The newborn was delivered via semi elective C-section at term and was well at delivery, with age-appropriate growth percentiles. The mother had been taking sertraline throughout pregnancy and at delivery. Newborn screen analysis on day 2 showed elevation in multiple acylcarnitines (C5DC, C6, C8, C10 and C14:1), suggestive of MADD. The neonate remained well post-delivery and blood glucose and lactate levels at 1 and 4 h of age were normal.Repeat acylcarnitine profile on day 5 of life showed improving values. Urine organic acids showed mild elevation of 2-hydroxyglutarate, supporting the MADD-like biochemical pattern. By day 12 of life, the acylcarnitines had normalised. Extensive gene panel analysis, including ETFA, ETFB, and ETFDH, identified no variants of clinical significance. CONCLUSION: Maternal sertraline use is a potential cause of a transient neonatal MADD-like biochemical pattern. Such medication-related effects should be considered when reviewing the possible aetiology of newborn screen results suggestive of MADD.