Journal of The Korean Society of Inherited Metabolic disease (대한유전성대사질환학회지)

The Korea Society of Inherited Metabolic Disease (대한유전성대사질환학회)
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A Case of Late-onset Episodic Myopathic Form with Intermittent Rhabdomyolysis of Very-long-chain acyl-coenzyme A Dehydrogenase (VLCAD) Deficiency Diagnosed by Multigene Panel Sequencing

유전자패널 시퀀싱으로 진단된 성인형 very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) 결핍증 증례

  • Sohn, Young Bae (Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine) ;
  • Ahn, Sunhyun (Department of Special Chemistry, Seoul Clinical Laboratories) ;
  • Jang, Ja-Hyun (Green Cross Genome) ;
  • Lee, Sae-Mi (Green Cross Genome)
  • 손영배 (아주대학교병원 아주대학교 의과대학 의학유전학과) ;
  • 안선현 (서울의과학연구소) ;
  • 장자현 (녹십자지놈) ;
  • 이새미 (녹십자지놈)
  • Published : 2019.04.30
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Abstract

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessively inherited metabolic disorder of mitochondrial long-chain fatty acid oxidation. The clinical features of VLCAD deficiency is classified by three clinical forms according to the severity. Here, we report a case of later-onset episodic myopathic form of VLCAD deficiency whose diagnosis was confirmed by plasma acylcarnitine analysis and" multigene panel multigene panel sequencing. A 34-year old female patient visited genetics clinic for genetic evaluation for history of recurrent myopathy with intermittent rhabdomyolysis. She suffered first episode of rhabdomyolysis with acute renal failure requiring hemodialysis at twelve years old. After then, she suffered several times of recurrent rhabdomyolysis provoked by prolonged exercise or fasting. Physical and neurologic exam was normal. Serum AST/ALT and creatinine kinase (CK) levels were mildly elevated. However, according to her previous medical records, her AST/ALT, CK were highly elevated when she had rhabdomyolysis. In suspicion of fatty acid oxidation disorder, multigene panel sequencing and plasma acylcarnitine analysis were performed in non-fasting, asymptomatic condition for the differential diagnosis. Plasma acylcarnitine analysis revealed elevated levels of C14:1 ($1.453{\mu}mol/L$; reference, 0.044-0.285), and C14:2 ($0.323{\mu}mol/L$; 0.032-0.301) and upper normal level of C14 ($0.841{\mu}mol/L$; 0.065 -0.920). Two heterozygous mutation in ACADVL were detected by multigene panel sequencing and confirmed by Sanger sequencing: c.[1202G>A(;) 1349G>A] (p.[(Ser 401Asn)(;)(Arg450His)]). Diagnosis of VLCAD deficiency was confirmed and frequent meal with low-fat diet was educated for preventing acute metabolic derangement. Fatty acid oxidation disorders have diagnostic challenges due to their intermittent clinical and laboratorial presentations, especially in milder late-onset forms. We suggest that multigene panel sequencing could be a useful diagnostic tool for the genetically and clinically heterogeneous fatty acid oxidation disorders.

Very-long-chain acyl-CoA dehydrogenase (VLCAD) 결핍증은 상염색체 열성으로 유전되는 유전성대사질환으로 미토콘드리아에서 장쇄지방산의 산화 장애이다. VLCAD 결핍증의 임상증상은 중증도 및 발현 시기에 따라 심각한 심장 이상을 동반하는 신생아기 발현형, 소아기 발현형, 지발형의 세 가지로 분류할 수 있다. 저자들은 혈장 아실카르니틴 분석과 유전자패널 염기서열분석 방법으로 확진된 성인기 발현형 VLCAD 결핍증 1례를 경험하였기에 보고하고자 한다. 34세 여자가 반복되는 근육통증과 간헐적 횡문근융해증의 병력을 주소로 내원하였다. 환자는 12세에 처음으로 운동 후 횡문근융해증으로 급성 신부전이 발생하여 혈액 투석을 받고 회복하였다. 이후 환자는 장시간의 운동이나 금식 후에 반복적으로 근육통증과 횡문근융해증이 발생하였다. 내원 시 신체 검진과 신경학적 검진은 정상이었다. 내원시 혈장 AST/ALT, Creatinine kinase (CK)는 약간 상승해있었으나, 이전 의무기록에 의하면 횡문근융해증이 있을 당시 AST/ALT, CK는 매우 상승하였다. 환자의 병력을 토대로 지방산대사장애 의심하에 감별진단을 위하여, 유전자 패널 염기서열 분석과 혈장 아실카르니틴 분석을 시행하였다. 혈장 아실카르니틴 분석결과 C14:1 ($1.453{\mu}mol/L$; 참고치, 0.044-0.285)와 C14:2 ($0.323{\mu}mol/L$; 0.032-0.301)가 증가였고, C14 ($0.841{\mu}mol/L$; 0.065-0.920)는 높은 정상이었다. 유전자패널 염기서열분석에서는 ACADVL 유전자에서 두 개의 병원성변이가 이형접합으로 발견되었으며, 이는 Sanger 염기서열 분석으로 확진되었다: c.[1202G>A(;)1349G>A] (p.[(Ser401Asn)(;)(Arg 450His)]). 환자는 생화학적, 유전학적 검사결과를 바탕으로 지발형 VLCAD 결핍증으로 확진되어 저지방식이와 급성 대사장애를 예방하기 위한 영양 교육을 받았다. 경증의 지발형 지방산 대사장애는 임상증상과 생화학적 검사 이상이 간헐적으로 발생하기 때문에 진단이 어렵다. 유전자패널 염기서열 분석은 지방산대사 장애와 같이 임상증상과 원인 유전자 이상이 다양한 대사 이상질환에서 유용한 진단법이 될 수 있다.

Keywords

References

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