Rhabdomyolysis and Respiratory Insufficiency Due to the Common ETFDH Mutation of c.250G>A in Two Patients with Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency
Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive metabolic disorder characterized by a fluctuating or progressive proximal myopathy, exercise intolerance, and a good response to riboflavin supplementation. The condition is primarily caused by mutations in the ETFDH gene, which encodes electron transfer flavoprotein dehydrogenase, a critical enzyme in fatty acid, amino acid, and choline metabolism. This article presents the clinical, biochemical, and genetic findings of two adult male patients with late-onset MADD who were initially misdiagnosed with polymyositis and subsequently developed severe rhabdomyolysis and respiratory insufficiency following high-dose glucocorticoid treatment. These cases highlight the importance of recognizing MADD in patients presenting with muscle weakness and the potential risks of glucocorticoid therapy in metabolic disorders.
Clinical Presentation and Initial Misdiagnosis
Both patients presented with progressive muscle weakness and exercise intolerance, which are hallmark symptoms of late-onset MADD. Patient 1, a 46-year-old male, experienced difficulty standing up from a squatting position, climbing stairs, and walking long distances. He also reported intermittent abdominal distension, nausea, and vomiting. Over time, he developed severe neck and masticatory muscle weakness, leading to dysphagia and eventually respiratory insufficiency. Patient 2, a 60-year-old male, exhibited similar symptoms, including symmetrical limb weakness, fatigability, myalgia, and head drop syndrome. Both patients were initially misdiagnosed with polymyositis, a condition characterized by muscle inflammation, and were treated with high-dose intravenous glucocorticoids.
Deterioration Following Glucocorticoid Treatment
The administration of glucocorticoids exacerbated the patients’ conditions, leading to severe rhabdomyolysis and respiratory insufficiency. In Patient 1, the plasma creatine kinase (CK) level increased dramatically from 528 IU/L to 23,500 IU/L, accompanied by elevated serum myoglobin (Mb) and urinary myohemoglobin levels. He developed generalized myalgia and pigmenturia, indicative of rhabdomyolysis. Blood gas analysis revealed type II respiratory insufficiency, with elevated partial pressure of carbon dioxide (PCO2) and reduced partial pressure of oxygen (PO2). Similarly, Patient 2 experienced a sharp increase in CK levels to 16,444.6 IU/L, along with elevated CK-MB, lactic acid, and liver enzyme levels. He required emergency hemodialysis for hyperkalemia and hypocalcemia, and oxygen therapy was initiated to improve oxygen saturation.
Biochemical and Metabolic Analysis
Metabolic spectroscopy analysis revealed characteristic abnormalities in both patients. In Patient 1, blood acyl-carnitine analysis showed elevated levels of medium-chain acylcarnitines (C8, C10, C12, and C14), consistent with MADD. Urinary organic acid analysis revealed increased concentrations of 3-hydroxybutyrate acid and 4-hydroxyphenyl-lactic acid. Patient 2 exhibited similar findings, with elevated plasma acylcarnitine levels (C4, C6, C8, and C10) and abnormal urinary organic acid profiles. These results confirmed the diagnosis of late-onset MADD in both patients.
Muscle Imaging and Histopathology
Muscle magnetic resonance imaging (MRI) demonstrated significant abnormalities in both patients. In Patient 1, MRI revealed filamentous high signals in the gluteus maximus and punctate high signals in the sartorius, gracilis, and biceps femoris, indicating muscle atrophy and edema. Patient 2 exhibited similar findings, with high signals in the gluteus maximus, gracilis, and biceps femoris, as well as muscle atrophy in the semi-membranosus and semi-tendinosus. Muscle histopathology in Patient 1 showed numerous vacuoles in muscle fibers, predominantly in type I fibers, which were confirmed to be lipid droplets by Oil Red O (ORO) staining. Patient 2 exhibited additional necrotic muscle fibers, consistent with rhabdomyolysis.
Genetic Analysis and Western Blot
Genetic analysis identified the common ETFDH mutation c.250G>A in both patients. Patient 1 was homozygous for this mutation, while Patient 2 carried a compound heterozygous mutation of c.250G>A and a novel variant c.959C>T. The novel variant was predicted to be functionally disruptive by SIFT and PolyPhen-2 software programs. Western blot analysis confirmed significantly reduced ETFDH protein expression in muscle specimens from both patients, further supporting the diagnosis of MADD.
Treatment and Follow-Up
Following the correct diagnosis, both patients were treated with riboflavin (150 mg/day), L-carnitine (90 mg/day), and coenzyme Q (60 mg/day), leading to significant clinical improvement. Patient 1 was weaned off mechanical ventilation and nasogastric intubation within one week and achieved full recovery of muscle strength and daily living ability within three weeks. Patient 2 recovered to an asymptomatic state and could walk independently within one month. Both patients continued maintenance therapy with riboflavin (30 mg/day) and coenzyme Q to prevent disease recurrence.
Discussion
These cases underscore the importance of considering metabolic disorders in patients presenting with muscle weakness, particularly when symptoms are exacerbated by fasting, infection, or glucocorticoid therapy. The common ETFDH mutation c.250G>A is a major cause of late-onset MADD in China, and its identification is crucial for accurate diagnosis and appropriate treatment. The severe complications of rhabdomyolysis and respiratory insufficiency observed in these patients highlight the potential risks of glucocorticoid therapy in metabolic disorders and the need for caution in its use.
Conclusion
The clinical, biochemical, and genetic findings in these two patients with late-onset MADD due to the common ETFDH mutation c.250G>A expand the phenotypic spectrum of the disorder and emphasize the importance of early diagnosis and appropriate treatment. Riboflavin supplementation is highly effective in managing the condition, and clinicians should be aware of the potential risks of glucocorticoid therapy in patients with metabolic disorders. These cases serve as a reminder of the need for a thorough diagnostic approach in patients presenting with muscle weakness and exercise intolerance.
doi.org/10.1097/CM9.0000000000000288
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