グルタル酸血症２型

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.

Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.

BACKGROUND: Recent studies describe an association between sertraline and acquired late-onset multiple acyl coenzyme A dehydrogenase deficiency (MADD), a rare disorder affecting fatty acid metabolism. MADD was previously considered solely a genetic disorder caused by recessive pathogenic variants mainly in the ETFDH gene. METHODS: A nationwide population-based registry search was conducted to identify adult patients with sertraline-associated MADD in Sweden 2014-2024. Patients with muscle biopsy reports of lipid storage myopathy or biochemical investigations showing acylcarnitine profile suggesting MADD were included. Medical records were retrospectively reviewed. RESULTS: We identified 40 (30/10 female/male) patients using sertraline when diagnosed with MADD. Median age at symptom onset was 42 years and muscle weakness was the most common first symptom. All patients reported muscle symptoms during the disease course. Extra-muscular symptoms, including sensory disturbance (29 patients) and fatigue (18 patients), were common. Most had lipid accumulation in muscle fibers, an abnormal acylcarnitine profile, a myopathic electromyography pattern, and elevated creatine kinase. Cyanocobalamin, folic acid, and proton-pump inhibitors were the most frequent other medications at diagnosis. Five patients carried a heterozygous ETFDH variant. All patients were treated with riboflavin. Almost all (38/39) experienced clinical improvement. Acylcarnitine profile improved in all patients (31/31) with available data. The mean incidence was 1.24 patients per 100,000 adults receiving sertraline treatment per year. CONCLUSIONS: Acquired MADD associated with sertraline is the most common type of adult-onset MADD in Sweden. The disease is generally responsive to riboflavin treatment. Patients presenting with muscle symptoms during sertraline therapy should undergo adequate evaluation to exclude MADD.

Riboflavin responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) is an inherited metabolic disorder which is good responsive to riboflavin treatment. The phenotypic spectrum of adult-onset RR-MADD is highly heterogeneous. In this study, we described three patients with adult-onset RR-MADD presented with muscle weakness and spinal cord involvement. These three patients presented with adult-onset limb weakness, dyspnea, along with sensory levels changes (patient 1 below T2 level, patient 2 below T6 level, and patient 3 below T12 level, respectively). All patients displayed elevated acylcarnitine and urinary organic acids. Muscle biopsies in patient 1 and patient 2 revealed the presence of lipid vacuoles and COX-negative fibers. Genetic analysis identified ETFDH mutation (c.524G > A (p.R175H)) in patient 1, and a compound heterozygous ETFDH mutation (c.34G > C (p.A12P)/c.736G > A (p.E246K)) in patient 2. Spinal-cord MRI excluded structural lesions, whereas muscle MRI indicated fatty infiltration. Short-term riboflavin treatment proved effective in alleviating muscle weakness, while long-term administration of riboflavin, coenzyme Q10, and vitamin B12 demonstrated efficacy in alleviating spinal cord involvement. Inconclusion, our findings suggest that spinal cord involvement may manifest in certain patients with adult-onset RR-MADD, which expand the neurological spectrum of adult-onset RR-MADD.