Clinical, pathological and genetic features and follow-up of 110 patients with late-onset MADD: a single-center retrospective study

Abstract

Background To observe a long-term prognosis in late-onset multiple acyl-coenzyme-A dehydrogenation deficiency(MADD) patients and to determine whether riboflavin should be administrated in the long-term and high-dosage manner. Methods We studied the clinical, pathological and genetic features of 110 patients with late-onset MADD in a single neuromuscular center. The plasma riboflavin levels and a long-term follow-up were performed. Results Fluctuating proximal muscle weakness, exercise intolerance and dramatic responsiveness to riboflavin treatment were essential clinical features for all 110 MADD patients. Among them, we identified 106 cases with ETFDH variants, 1 case with FLAD1 variants and 3 cases without causal variants. On muscle pathology, fibers with cracks, atypical ragged red fibers(aRRFs) and diffuse decrease of SDH activity were the distinctive features of these MADD patients. The plasma riboflavin levels before treatment were significantly decreased in these patients as compared to healthy controls. Among 48 MADD patients with a follow-up of 6.1 years on average, 31 patients were free of muscle weakness recurrence, while 17 patients had episodes of slight muscle weakness upon riboflavin withdrawal, but recovered after retaking a small-dose of riboflavin for a short-term. Multivariate Cox regression analysis showed vegetarian diet and masseter weakness were independent risk factors for muscle weakness recurrence. Conclusion Fibers with cracks, aRRFs and diffuse decreased SDH activity distinguish MADD from other genotypes of lipid storage myopathy. For late-onset MADD, increased fatty acid oxidation and reduced riboflavin levels can induce episodes of muscle symptoms, which can be treated by short-term and small-dose of riboflavin therapy.

Case report: A novel c.1842_1845dup mutation of ETFDH in two Chinese siblings with multiple acyl-CoA dehydrogenase deficiency

“…We also found that the mild clinical presentation of Proband 2 with the same mutation was very different from that of Proband 1. A possible explanation for this could be that the phenotypic presentation of late-onset MADD is highly variable ( 14 , 15 ), and the late-onset form usually has no obvious clinical symptoms ( 2 ). Mild short stature in Proband 2 may be a prodromal symptom of late-onset MADD.…”

Combined isobutyryl‐CoA and multiple acyl‐CoA dehydrogenase deficiency in a boy with altered riboflavin homeostasis

“…54 Altered RFVT2 levels we detected in erythrocytes (Figure 2) might be the consequences of these cellular stress conditions. Indeed, the proposal that mutations of ETF:QO in MADD might, in turn, induce alteration of FAD homeostasis has been launched by others 55,56 ; further research is necessary to establish this relationship at the molecular level, possibly using Caenorhabditis elegans models 57 or better cell models from our patient.…”

A Comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene

“…To date, there were totally 17 MADD/GAII cases from 9 countries caused by FLAD1 variants according to the publications until April, 2022 [9,17,[19][20][21][22][23][24][25][26]. Among those cases, 9 patients were proved with full or partial ribo avin responsiveness.…”

“…We reviewed literature and listed a summary of 18 cases with MADD/GAII caused by FLAD1 variants including the present case (Supplemental material 3), in which 10 patients were proved with full or partial ribo avin responsiveness(Full ribo avin responsiveness: After ribo avin treatment, the symptoms including muscle weakness disappear and the patient returns to a normal life. Partial ribo avin responsiveness: After ribo avin treatment, the symptoms are partially improved, the patient' condition is stable but not normal) [9,17,[19][20][21][22][23]. The comparison between 10 FLAD1-RRMADD (9 cases from literature and the present case) and 106 ETFDH-RRMADD (in our neuromuscular center) was shown in Table 1.…”