The clinical and genetical heterogeneity of riboflavin ⁃ responsive multiple acyl ⁃ coenzyme A dehydrogenase deficiency

Abstract

Objective To explore the diversity of clinical manifestations and gene mutations of riboflavin⁃responsive multiple acyl⁃coenzyme A dehydrogenase deficiency (MADD). Methods and Results The clinical, blood biochemical, EMG, muscle biopsy and genetic analysis results of 5 patients with riboflavin⁃responsive MADD were collected, to analyze and summarize the clinical characteristics of riboflavin⁃responsive MADD. The onset age of 5 patients was 13-32 years old, with an average age of 20.40 years old. The main manifestation was fluctuating or progressive muscle weakness, involving facial, neck, proximal limb and respiratory muscles and often aggravated after exercise, fatigue, and infection. Serum creatine kinase (CK) increased slightly to moderately in 5 patients, and blood lactic acid increased significantlyafterexercisein2patients. The EMG of 4 patients showed myogenic damage, and the EMG of one patient showed neurogenic damage in the early stage of the disease and mainly myopathic damage in laterstage. Muscle biopsy of 2 patients showed a large amount of lipid droplet deposition in muscle fibers positive for oil red O staining. Genetic analysis revealed that 4 patients showed homozygous or compound heterozygous  mutations in the ETFDH gene(one patient carried homozygous mutations of G250A; 2patients carried compound heterozygous mutations of G250A and G524A; one patient carried compound heterozygous mutations of T1211C and C1454G), the remaining one case carried the G1399C heterozygous mutationin ETFDH geneandthe C725T heterozygousmutationin ETFB gene. Conclusions In mainland of China, riboflavin⁃responsive MADD mainly presents as a lipid deposition disease involving skeletal muscle, with a progressive or fluctuating course. It is easily misdiagnosed as several types of muscular dystrophy, mitochondrial myopathy, glycogen storage disease, myasthenia gravis and peripheral neuropathy. Themutation ETFDH gene is its main cause. Since riboflavin⁃responsive MADD has a good prognosis, the vitamin B2 diagnostic treatment should be given when the patients are suspected of riboflavin⁃responsive MADD, combined with urine organic acid, blood acylcarnitine, muscle biopsy and genetic analysis to confirm the diagnosis.

DOI：10.3969/j.issn.1672⁃6731.2020.06.011