Elsevier

Clinica Chimica Acta

Volume 503, April 2020, Pages 218-222
Clinica Chimica Acta

One potential hotspot ACADVL mutation in Chinese patients with very-long-chain acyl-coenzyme A dehydrogenase deficiency

https://doi.org/10.1016/j.cca.2019.11.034Get rights and content

Highlights

  • Eight mutations of the ACADVL gene were identified from six Chinese VLCAD deficiency patients.

  • Three novel mutations [c.563G > A (p.G188D), c.1387G > A (p.G463R) and c.1582_1586del (p.L529Sfs*31)] were found.

  • The mutation p.R450H is firstly regarded as the hotspot mutation in the Chinese population.

Abstract

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency), a rare autosomal recessive disorder, is characterized by hypoketotic hypoglycemia, cardiomyopathy, liver damage, and myopathy. VLCAD deficiency is caused by defects of ACADVL gene, which encodes VLCAD protein. The aim of this study was to determine the clinical, biochemical, prognosis and mutation spectrum of patients with VLCAD deficiency in mainland China. A total of Six families visited us, four patients (2 boys and 2 girls) were admitted in hospital due to liver dysfunction, hypoglycemia, and positive newborn screen result. The parents of the other two patients (2 girls) visited us for genetic consultation after their children's death. All the six patients had elevated level of serum tetradecenoylcarnitine (C14:1-carnitine), four of them showed decreased free carnitine (C0) level, and three had dicarboxylic aciduria. Eight types of mutations of the ACADVL gene were detected, three of them are novel, including c.563G > A (p.G188D) c.1387G > A (p.G463R) and c.1582_1586del (p.L529Sfs*31). The p.R450H mutation accounts for 9/52 alleles (5/40 in previous study of 20 unrelated patients, and 4/12 in this study) of genetically diagnosed Chinese VLCAD deficiency cases. The four alive patients (Patient 1–4) responded well to diet prevention and drug therapy with stable hepatic dysfunction condition. In conclusion, we describe three novel mutations of the ACADVL gene among six unrelated families with VLCAD deficiency. Moreover, we suggest that the p.R450H may be a potential hotspot mutation in the Chinese population.

Introduction

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency; MIM# 201475), a rare autosomal recessive disorder that affects mitochondrial fatty acid β-oxidation, is caused by defects in the acyl-CoA dehydrogenase very long chain (ACADVL) gene (MIM# 609575). VLCAD deficiency is a severe form of fatty acid oxidation defects (FAODs) that are responsible for 5% of all sudden and unexpected deaths in infants [1], [2].

The ACADVL gene encodes very long-chain acyl-coenzyme A dehydrogenase (VLCAD, 140 kDa, EC 1.3.99.13), the first enzyme involved in fatty acid β oxidation. This enzyme is located on the inner mitochondrial membrane and is responsible for β oxidation of 14–20 carbon fatty acids [3]. Accumulation of toxic long chain acylcarnitine causes organ dysfunction of the heart, skeletal muscle and liver due to fatty acid degeneration and energy production deficit. Further, since long-chain fatty acid serves as the main source of energy in human body, the blockage of VLCAD activity results in energy depletion, specifically hurting organs which have high energy consumption. According to the clinical phenotype, VLCAD deficiency is divided into three subtypes, (1) the severe neonatal-onset myocardial form which is responsible for cardiomyopathy and high mortality rate; (2) the infantile-onset hepatic form manifested with non-ketotic hypoglycemia and liver damage; and (3) the adolescent or adult-onset myopathy form typically characterized by fasting or exercise-induced muscle weakness, pain, spasms and rhabdomyolysis [4].

To the best of our knowledge, 22 genetically diagnosed patients with VLCAD deficiency have been reported in the Chinese population [5], [6], [7], [8], [9]. Datasets on VLCAD deficient patients were retrieved from PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) by searching the keywords: Very long-chain acyl-coenzyme A dehydrogenase deficiency, or VLCAD deficiency; China, or Chinese; and ACADVL. The VLCAD deficiency pathogenic mutations spectrum in Chinese population has not been established.

Here, we report the clinical, biochemical, and potentially causative mutations in six Chinese VLCAD deficiency patients, including three novel mutations and a mutation at a putative hotspot of the ACADVL gene, thus expanding the variant spectrum of the disease.

Section snippets

Patients

Six patients (two boys and four girls) from six unrelated Chinese families were diagnosed between March 2015 and November 2018 at the Department of Pediatrics, Peking University First Hospital, China. The clinical onset of the symptoms was between the age of 2 days and 1 year. The patients were admitted with indications of liver dysfunction and hypoglycemia, and the parents of the other two patients (Patient 5 and 6) visited us for genetic consultation (Table 1). The parents of all patients

Results

The clinical data and results of laboratory examination are presented in Table 1. All patients were born at term. Four patients (Patient 2, 3, 5 and 6) had acute metabolic crisis attack, three patients (Patient 2, 5, and 6) presented with acute metabolic crisis triggered by infection, vomiting and fasting but one patient (Patient 5) did not have obvious trigger events. Elevated plasma tetradecenoylcarnitine (C14:1-carnitine) level, as well as transaminase were detected in all six patients.

Discussion

VLCAD deficiency was first identified in 1993 by Aoyama et al., and was considered to cause the most severe type of FAODs [3]. In this study, we present six Chinese patients with VLCAD deficiency and describe their symptoms, clinical findings, treatment, and response to the treatment. We also describe the mutations in the ACADVL gene, including three novel mutations and one potential population-specific hotspot mutation.

VLCAD deficiency is initially diagnosed based on clinical features,

CRediT authorship contribution statement

Xiyuan Li: Data curation, Formal analysis, Writing - original draft. Rui Ma: Data curation, Formal analysis, Writing - original draft. Yi Liu: Investigation. Lulu Kang: Investigation. Ruxuan He: Investigation. Jinqing Song: Investigation. Jing Ren: Writing - review & editing. Yang Li: Funding acquisition, Writing - review & editing. Min Huang: Investigation. Jianlong Men: Conceptualization, Funding acquisition. Yanling Yang: Conceptualization, Funding acquisition.

Declaration of Competing Interest

None.

Acknowledgments

This work was supported by the grants from National Key Research and Development Program of China (Grant No. 2017YFC1001700), National Natural Science Foundation of China (Grant No. 81801638), and the National Key Research and Development Program of China-Precision Medicine Research Project (Grant No. 2016YFC0905600-2016YFC0905601). We would like to thank all patients, and the contributions from Similan Clinic.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the insti-tutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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