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Korean J Neuromuscul Disord > Volume 14(2); 2022 > Article
늦은 발병 근육병 형태의 ACADVL 유전자 복합 이형접합 변이가 확인된 Very-Long-Chain Acyl-CoA Dehydrogenase 결핍증
Very-long-chain acyl-CoA dehydrogenase (VLCAD) is an enzyme involved in β-oxidation in mitochondria, catalyzing long-chain fatty acids containing 14 to 20 carbon chains [1]. VLCAD deficiency is an autosomal recessive disease resulting from pathogenic variants in ACADVL [1,2]. Three major phenotypes of VLCAD deficiency are introduced according to the age of onset and related symptoms: a severe infantile form, a milder childhood form, and a late-onset form with rhabdomyolysis and myoglobulinemia [3]. We report a case presenting adolescent-onset, skeletal muscle-involving familial VLCAD deficiency associated with compound heterozygote variants in ACADVL.
A 44-year-old female (III-2 in Fig. 1A) visited our clinic to evaluate repeated attacks of muscle pain and transient muscle weakness since the age of 19. Her symptoms developed especially when she underwent strenuous physical activities. They were relieved spontaneously after a few days of resting. Moreover, dark brown urine was observed when symptoms were present. She did not report other previous medical histories such as hypoglycemia or cardiomyopathy. Her father (II-2) aged 70 years old was healthy without any health problems. Her mother (II-8) passed away in the 6th decade due to liver disease. Her family members reported that her mother did not complain of pain in her lower extremities until she died. However, one of the patient's younger sisters (III-3) presented similar symptoms. The other sibling (III-2) was asymptomatic. In general inspection, normal muscle bulk was seen in the extremities. She did not present any deficits on neurologic examinations. The evaluation focused on dis- Table 1. Acylcarnitine analysis of the patient covering diseases such as metabolic myopathies or channelopathies that might provoke exercise intolerance or muscle pain after vigorous physical activity. Laboratory tests showed normal ranges of electrolytes and thyroid-related hormones. However, creatine kinase level was elevated to 328 U/L. On electromyography (EMG), increased insertional activities and a few fibrillation and positive sharp waves were noted in the resting state of biceps brachii and deltoid muscle. During voluntary contraction, motor unit potentials of those muscles mainly consisted of small amplitude (<0.3 mV), short duration, polyphasic pattern, and early recruitment, compatible with myopathy. Levels of enzymes involved in glycogen metabolism were within their normal ranges. Based on characteristic clinical presentation and electromyographic findings, we analyzed acylcarnitine profiles by liquid chromatography with tandem mass spectrometry to identify the presence of lipid metabolism disorders. In quantitative analysis, elevated levels of C14:1, C14:2, C14, C16:1, and C16 were detected (Table 1). Since symptoms and acylcarnitine characteristics were compatible with the later-onset episodic myopathic form of VLCAD deficiency, identifying pathogenic variants of ACADVL was essential to confirm the diagnosis. Therefore, after obtaining informed consent from the patient, her father, and the younger sister having the same symptoms, three subjects' molecular genetic tests were conducted to screen ACADVL variants. The patient's ACADVL presented two heterozygote variants detected in trans (NM_000018.3:c.[1096C>T]; [1276G>A], p.[R366C];[A426T]), which were not present in general population databases (The Genome Aggregation Database or Korean Reference Genome Database; Fig. 1B). Variants were classified as likely pathogenic variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines [4]. Her symptomatic sister carried two variants, p.R366C and p.A426T. Her father only had one heterozygote p. R366C variant, indicating the two variants of the proband and her sister were located in trans on each allele (Fig. 1B). We conclude that this case is a familial VLCAD presenting late-onset myopathic form by compound heterozygote variants in ACADVL. Her symptoms were relieved by a low-fat diet and avoidance of vigorous activities.
Two ACADVL variants identified in this family have been previously reported in VLCAD deficiency neonates by newborn screening [5,6]. However, two variants coexisting as a compound heterozygous form in late-onset mild phenotype have not been reported yet. Diagnosis of myopathies due to disorders of lipid metabolism presenting recurrent myalgia and exercise intolerance could be challenging since symptoms are vague and heterogeneous. Moreover, laboratory tests during interictal periods frequently show results within normal ranges. Therefore, clinicians should proceed with studies such as acylcarnitine analysis and EMG to establish a precise diagnosis. Furthermore, gene investigation enabling the detection of pathogenic variants responsible for metabolic myopathies would be necessary, extending the possibility of developing treatment options for these diseases shortly.

Acknowledgments

The research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (NRF-2018M3C7A1056512).

Fig. 1.
Family pedigree of the patient (A) and Sanger sequencing chromatograms of the patient and other family members (B). (A) Family members who underwent DNA analysis for segregation data are indicated by red letters for each variant. A solid black denotes affected patients with very-long-chain Acyl-CoA dehydrogenase deficiency (VLCAD). A black-shaded pattern shows patients only presenting VLCAD-associated symptoms without evidence of genetic variants. (B) Two heterozygote variants (NM_000018.3:c.[1096C>T];[1276G>A], p.[R366C];[A426T]) were present in the patient's ACADVL. In addition, her symptomatic sister demonstrated the same variants as the proband, whereas her father carried only one heterozygote p.R366C variant.
kjnmd-2022-14-2-42f1.jpg
Table 1.
Acylcarnitine analysis of the patient
Test Result (μmol/L) Reference range (μmol/L)
C0 22.579 <50.15
C2 3.477 2.00-17.83
C14:1 1.293a <0.24
C14:2 0.451a <0.18
C14 0.341a <0.12
C16:1 0.140a <0.10
C16 0.260a <0.23
C18 0.081 <0.14
C18:1 0.165 <0.39

a Indicate values above reference range.

REFERENCES

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6. Chen T, Tong F, Wu XY, Zhu L, Yi QZ, Zheng J, et al. Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency. J Zhejiang Univ Sci B 2020;21:885-896.
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