medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2026.05.19-32medgen-3451Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHДефицит ацил-КоА-дегидрогеназы жирных кислот с очень длинной углеродной цепью в Республике БеларусьVery-long-chain fatty acid acyl-CoA dehydrogenase deficiency in BelarusГусинаА. А.GusinaA. A.

220053, г. Минск, ул. Орловская, д. 66, к.9

66, build 9, Orlovskaya str., Minsk, 220053

asya.gusina@mail.ruЗиновикА. В.ZinovikA. V.

220053, г. Минск, ул. Орловская, д. 66, к.9

66, build 9, Orlovskaya str., Minsk, 220053

СталыбкоА. С.StalybkoA. S.

220053, г. Минск, ул. Орловская, д. 66, к.9

66, build 9, Orlovskaya str., Minsk, 220053

КулакВ. Д.KulakV. D.

220053, г. Минск, ул. Орловская, д. 66, к.9

66, build 9, Orlovskaya str., Minsk, 220053

МотюкИ. Н.MotjukI. N.

230009, г. Гродно, ул. Горького, д. 77

77, Gorky str., Grodno, 230009

РушкевичЮ. Н.RushkevichJu. N.

220114, г. Минск, ул. Ф. Скорины, д. 24

24, F. Skaryny str., Minsk, 220114

МальгинаЕ. В.MalginaE. V.

220114, г. Минск, ул. Ф. Скорины, д. 24

24, F. Skaryny str., Minsk, 220114

МальчукЛ. В.MalchukL. V.

224013, г. Брест, ул. Кирова, д. 62

62, Kirov str., Brest, 224013

ГусинаН. Б.GusinaN. B.

220053, г. Минск, ул. Орловская, д. 66, к.9

Государственное учреждение «Республиканский научно-практический центр «Мать и дитя»БеларусьRepublican Scientific and Practical Center “Mother and child”BelarusУчреждение здравоохранения «Гродненский областной клинический перинатальный центр»БеларусьGrodno Regional Clinical Perinatal CenterBelarusГУ «Республиканский научно-практический центр неврологии и нейрохирургии»БеларусьRepublican Research and Clinical Center of Neurology and NeurosurgeryBelarusУчреждение здравоохранения «Брестский областной родильный домБеларусьBrest Regional Maternity HospitalBelarus2026080620262551932Copyright © Гусина А.А., Зиновик А.В., Сталыбко А.С., Кулак В.Д., Мотюк И.Н., Рушкевич Ю.Н., Мальгина Е.В., Мальчук Л.В., Гусина Н.Б., 20262026Гусина А.А., Зиновик А.В., Сталыбко А.С., Кулак В.Д., Мотюк И.Н., Рушкевич Ю.Н., Мальгина Е.В., Мальчук Л.В., Гусина Н.Б.Gusina A.A., Zinovik A.V., Stalybko A.S., Kulak V.D., Motjuk I.N., Rushkevich J.N., Malgina E.V., Malchuk L.V., Gusina N.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/3451Введение

Введение. Дефицит ацил-КоА-дегидрогеназы жирных кислот с очень длинной углеродной цепью (VLCADD) – редкое наследственное заболевание из группы дефектов митохондриального β–окисления жирных кислот, причиной которого являются мутации в гене ACADVL. Распространенность VLCADD составляет 1:30000 – 1:100000. Различают тяжелую, средней тяжести и легкую формы заболевания.

Цель

Цель: изучить спектр мутаций в гене ACADVL у пациентов с VLCADD в Республике Беларусь.

Методы

Методы. В исследуемую группу были включены пациенты с VLCADD, выявленные при селективном скрининге нарушений митохондриального бета-окисления жирных кислот и других дефектов обмена методом тандемной масс-спектрометрии (ТМС), а также члены их семей (4 пробанда, 2 родителей и ребенок взрослой пациентки). Поиск вариантов в гене ACADVL осуществлен методом высокопроизводительного секвенирования и секвенирования по Сэнгеру.

Результаты

Результаты. Пробанды 1 и 2 обследованы в возрасте 3 месяцев по поводу острой метаболической декомпенсации, кардиомиопатии, гепатомегалии; у пробанда 2 также отмечали прогрессирующую мышечную гипотонию и выраженную гипогликемию. Оба ребенка умерли в возрасте 3,5 и 7 месяцев соответственно. Пробандам 3 и 4 анализ методом ТМС был проведен в 14 месяцев и 25 лет. У пробанда 3 заболевание проявлялось симптомами поражения печени, периодической гипогликемией, кардиомиопатией. В клинической картине болезни у пробанда 4 преобладали симптомы миопатии.

У пробанда 1 выявлена гомозиготная делеция p.Leu201TrpfsTer39 (NM_000018.4 (ACADVL): c.532delC) в экзоне 7 гена ACADVL. Пробанд 2 являлась компаундным гетерозиготным носителем миссенс-мутации p.Gly253Val (NM_000018.4 (ACADVL): c.758G>T) в экзоне 9 и мутации со сдвигом рамки p.Pro296ArgfsTer17 (NM_000018.4 (ACADVL):c.887_888delCT) в  экзоне 11. У пробанда 3 обнаружены замена p.Arg366Cys (NM_000018.4 (ACADVL): c.1096C>T, rs771874163) в экзоне 11 и нонсенс-мутация p.Arg615Ter (NM_000018.4 (ACADVL):c.1843C>T, rs1057520507) в экзоне 20. У пробанда 4 идентифицированы два вероятно патогенных варианта в интроне 8 и экзоне 15: NM_000018.4 (ACADVL): c.752+2delC и p.Lys507Glu (NM_000018.4 (ACADVL): c.1519A>G, rs1217344032). У отца и сына пациентки установлено носительство мутации c.752+2delC, а у матери – p.Lys507Glu в гетерозиготном состоянии.

Заключение

Заключение. VLCADD – относительно редкий наследственный дефект обмена веществ в Беларуси. Заболевание характеризуется выраженным клиническим полиморфизмом, значительной генетической гетерогенностью и наличием очевидных корреляций генотип-фенотип. В результате проведенного исследования установлен спектр мутаций в гене ACADVL у пациентов с VLCADD в Республике Беларусь, обнаружены новые патогенные и вероятно патогенные варианты (p.Leu201TrpfsTer39, p.Gly253Val, p.Pro296ArgfsTer17 и c.752+2delC), не зарегистрированные в открытых базах данных и не описанные ранее в доступных опубликованных работах, посвященных VLCADD.

Introduction

Introduction. Very-long-chain fatty acid acyl-CoA dehydrogenase deficiency (VLCADD) is a rare inherited disorder of fatty acid oxidation caused by mutations in the ACADVL gene. The prevalence of VLCADD is 1:30,000 – 1:100,000. The severe form of the disease presents in the neonatal period or within the first months of life and is characterized by cardiomyopathy, hydropericardium, arrhythmia, hypotension, hepatomegaly and hypoglycemia. Moderate VLCADD manifests in the first year of life or in early childhood, its symptoms include hepatomegaly and episodes of hypoketotic hypoglycemia. In mild cases, the first signs of the disease such as muscle pain, exercise intolerance, episodes of rhabdomyolysis appear in adolescence or later.

Purpose

Purpose. To study the spectrum of mutations in the ACADVL gene in patients with VLCADD in the Republic of Belarus

Patients and methods

Patients and methods. The study group included patients with VLCADD identified during selective screening for mitochondrial betaoxidation of fatty acids and other metabolic defects by tandem mass spectrometry (TMS), and their family members (4 probands, 2 parents, and a child of an adult patient). Genetic testing was performed via high-throughput sequencing combined with Sanger sequencing.

Results and discussion

Results and discussion. Probands 1 and 2 suffered from acute metabolic decompensation, cardiomyopathy, hepatomegaly at the age of 3 months; the proband 2 also had progressive muscle hypotonia and severe hypoglycemia. Both children died at the age of 3.5 and 7 months, respectively. Probands 3 and 4 underwent TMS at 14 months and 25 years. In proband 3, the disease manifested with liver damage, episodes of hypoglycemia, cardiomyopathy. Symptoms of myopathy predominated in patient 4. Proband 1 was found to have a homozygous deletion p.Leu201TrpfsTer39 (NM_000018.4 (ACADVL): c.532delC) in exon 7 of the ACADVL gene. Proband 2 had missense mutation p.Gly253Val (NM_000018.4 (ACADVL): c.758G>T) in exon 9 and the frameshift mutation p.Pro296ArgfsTer17 (NM_000018.4 (ACADVL): c.887_888delCT) in exon 11. In Proband 3 we found p.Arg366Cys substitution (NM_000018.4 (ACADVL): c.1096C>T, rs771874163) in exon 11 and nonsense mutation p.Arg615Ter (NM_000018.4 (ACADVL): c.1843C>T, rs1057520507) in exon 20. Proband 4 had two likely pathogenic variants in intron 8 and exon 15: NM_000018.4 (ACADVL): c.752+2delC and p.Lys507Glu (NM_000018.4 (ACADVL): c.1519A>G, rs1217344032). The patient’s father and son were found to be carriers c.752+2delC mutation, and the mother had p.Lys507Glu in a heterozygous state.

Conclusion

Conclusion. VLCADD is a relatively rare hereditary metabolic defect in Belarus. The disease is characterized by pronounced clinical polymorphism, significant genetic heterogeneity, and the presence of evident genotype-phenotype correlations. As a result of the study, a spectrum of mutations in the ACADVL gene was established in patients with VLCADD in the Republic of Belarus, new pathogenic and likely pathogenic variants (p.Leu201TrpfsTer39, p.Gly253Val, p.Pro296ArgfsTer17 and c.752+2delC) were discovered. These variants were not registered in open databases and not previously described in available published works on VLCADD.

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The authors declare that there are no conflicts of interest present.