Hai-ping Xie, Wei-jia Zeng,3, Li-xun Chen,3, Zhang-xin Xie,3, Xiao-ping Wang,3, Shen Zhao

1 Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China

2 Department of Emergency, Fujian Provincial Hospital, Fuzhou 350001, China

3 Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou 350001, China

4 Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China

Lipid storage myopathy (LSM) is a manifestation of lipid dysmetabolism, presenting with lipid accumulation in muscles. The mechanism includes defects in intracellular triglyceride catabolism, transport of long-chain fatty acids and carnitine, or fatty acid β-oxidation.[1]Among LSMs, the most common type is multiple acyl-coenzyme A dehydrogenase deficiency (MADD), also called glutaric aciduria type II (GA II), with an estimated prevalence of 1 in 20,000 to 1 in 15,000 births in the United States.[2]A cohort study of 90 Chinese patients showed that the most frequent mutations of MADD were c.250G＞A, c.770A＞G, and c.1227A＞C in the electron transfer flavoprotein dehydrogenase (ETFDH) gene.[3]Common symptoms include symmetrical weakness of the proximal upper and/or lower limbs, steatohepatitis, ketoacidosis, and hypoglycemia.[4,5]However, cases with both respiratory and cardiac muscles affected have rarely been reported. Here, we report a case of a girl who presented with increased serum enzyme levels, labored breathing, cardiogenic shock, and eventual cardiac arrest, which is a rare and lethal complication of GA II. Informed consent for publication was obtained from the patient’s family.

A 15-year-old girl was transferred to the intensive care unit (ICU) following initial cardiopulmonary resuscitation (CPR). She had a medical history of chronic pancreatitis for three years, with three to four attacks per year. She was admitted to the gastroenterology ward due to acute recurrent pancreatitis, hepatic injury, and mild weakness of the proximal lower limbs. Then, she rapidly developed muscle weakness with shallow breathing, elevated serum muscle enzyme levels, rhabdomyolysis, and cardiogenic shock, resulting in cardiac arrest. She underwent tracheal intubation and CPR and achieved successful restoration of spontaneous circulation (ROSC) within 10 min. She was hemodynamically unstable, receiving continued norepinephrine (3 μg/[kg·min]) and dobutamine (5 μg/[kg·min]) infusion following ROSC. She was subsequently admitted to the ICU for further treatment.

In the ICU, vasoactive drugs were maintained for over 24 h and then gradually reduced until complete withdrawal. Since the electrical activity of the diaphragm (Edi) was low, mechanical ventilation was maintained for two weeks prior to weaning. She developed cholestatic jaundice and worsening hepatocellular dysfunction. Ultrasound and liver biopsy met the diagnosis of steatohepatitis. Echocardiography showed hypertrophy in the left ventricle and interventricular septum with decreased echo (Figure 1 A). Magnetic resonance imaging showed atrophy and abnormal signals in the neck and lower limb muscles (Figures 1 C and D). Electromyography indicated myogenous damage.

For differential diagnosis, mass spectroscopy of serum samples was performed, revealing a high level of predominantly middle- and long-chain acyl carnitines (Table 1, supplementary Table 1, and supplementary Figure 1). However, urinary organic acids were normal (supplementary Figure 2). Thus, muscle biopsy and genetic testing were performed. Under a light microscope, muscle fibers showed focally mild-to-moderate atrophy, accompanied by myolysis and necrosis with phagocytosis. The muscle also showed mild proliferation of interstitial fibers. Numerous vacuoles of very different sizes were observed in muscle fibers (Figure 2A). Nicotinamide adenine dinucleotide (NADH) staining and adenosine triphosphatase (ATPase) staining showed that these vacuoles mainly existed in type I fibers (Figures 2 B and C); Oil Red O staining demonstrated that the intracellular vacuoles were lipid droplets (Figure 2D). These findings were consistent with those of myogenous damage, indicating lipid storage myopathy with myofiber necrosis. Under an electron microscope, a medium-large number of lipid droplets were observed in muscle fibers (Figure 2 E). Whole exome sequencing of serum samples showed two pathogenic mutations in theETFDHgene, with two heterozygote missense mutations, c.250G＞A (p. Ala84Thr) in exon 3 and c.524G＞A (p. Arg175His) in exon 5, and one suspected pathogenic mutation in the protease serine 1 (PRSS1) gene c.346C＞T (p. Arg116Cys) in exon 3 (supplementary Table 1).

Table 1. Results of tandem mass spectroscopy in serum sample

Based on these findings, a diagnosis of GA II was made. She was given a high-carbohydrate, low-fat, and low-protein diet with riboflavin (150 mg/day orally), coenzyme Q10 (CoQ10) (300 mg/day orally), and L-carnitine (1,000 mg/ day intravenously) supplementation. Muscle weakness was improved during withdrawal of positive pressure ventilation. Meanwhile, pancreatitis and hepatic injury were cured. She was eventually discharged without any neurological sequelae of cardiac arrest on day 27 of hospitalization. By the oneyear follow-up, she presented with normal muscle strength, cardiac enzymes and echocardiography (Figure 1 B) and no attack of pancreatitis.

Figure 1. Echocardiography and magnetic resonance imaging.Echocardiography findings: images before treatment (A) and one year later (B); magnetic resonance imaging of the neck and lower limbs showed soft tissue edema, atrophy and abnormal signals of muscles: T2 fat suppression imaging of the neck (C), proton fat suppression imaging of the lower limbs (D). Arrow: muscle injury.

Figure 2. Histopathological changes in skeletal muscles. A: hematoxylin and eosin staining (×200); B: nicotinamide adenine dinucleotide (NADH) stain (×200); C: adenosine triphosphatase (ATPase) stain (×200); D: Oil Red O stain (×200); E: electron microscope image (×200).

In this case, the patient presented with progressive muscle weakness, especially involving the respiratory and cardiac muscles, accompanied by severe steatohepatitis and recurrent pancreatitis. In muscle biopsy, lipid accumulation, muscle atrophy, and fiber necrosis were identified. Tandemmass spectroscopy of serum samples revealed elevated levels of middle- and long-chain acyl carnitines, accounting for the diagnosis of LSM. Due to normal levels of organic acids in urine, gene testing was performed, showing two pathogenic mutations in theETFDHgene, further confirming the MADD diagnosis. The diagnoses of steroid myopathy and mitochondrial myopathy were excluded, considering the normal result of mitochondrial genetic testing and the absence of steroid usage.

During the first 2 weeks of her ICU stay, she was supported by mechanical ventilation because of a low Edi value, suggesting damage to the muscles. Combining the results of echocardiography, we assumed the possibility of cardiomyopathy, which has only been reported in few patients.[6,7]We should highlight that patients with rapidly progressive respiratory muscle weakness and cardiomyopathy have a relatively higher risk of cardiac arrest, requiring prompt treatment.

The combination of pancreatitis attacks and a suspected pathogenic mutation in thePRSS1gene, one of the most common pathogenic variations of hereditary pancreatitis,[8-10]should lead to considerations of hereditary pancreatitis. To date, there have been no reports of hereditary pancreatitis associated with LSM. However, pancreatitis may also be a rare complication of LSM, with unknown mechanisms. The first case of acute pancreatitis in MADD was reported in 1997.[11]To date, only one case of recurrent pancreatitis in MADD was reported in 2004, without detecting pancreatic gene mutations.[12]LSM is characterized by lipid accumulation in muscles, including smooth muscles; thus, it is speculated that the Oddi sphincter was affected in this patient. In this case, no recurrence of pancreatitis during the one-year follow-up confirmed that Oddi sphincter dysfunction might be a complication of GA II despite a genetic predisposition. The function of the Oddi sphincter could be tested through quantitative hepatobiliary scintigraphy, secretinstimulated magnetic resonance cholangiopancreatography, or sphincter of Oddi manometry.[13-15]However, the limitation without further detection in our case is due to the critical condition of the patient.

In our case, cardiac arrest resulted from myopathy in cardiac and respiratory muscle. Early biopsy and genetic analysis can contribute to the accurate diagnosis of GA II, especially in patients with ambiguous mass spectroscopy results. Recurrent pancreatitis might be a rare complication owing to lipid accumulation in the Oddi sphincter.

Funding:This study was supported by the Youth Projects of National Natural Science Foundation of China (81601662) and the Medical Innovation Program of Fujian Province of China (2020CXA003).

Ethical approval:Informed consent for publication was obtained from the patient’s family.

Confl icts of interest:None.

Contributors:HPX and WJZ contributed equally to this work as cofirst authors. HPX and WJZ proposed the study and wrote the paper. All authors contributed to the design and interpretation of the study and to further drafts.

All the supplementary files in this paper are available at http://wjem.com.cn.