Difficulties in diagnostics of urea synthesis cycle disturbance

Introduction. Hereditary metabolic diseases include a large group of diseases caused by genetic mutations with a high potential risk of transmitting this disorder to future offspring. Manifesting at any age and accompanied by recurrent and progressive clinical symptoms, some of these mutations become incompatible with life, while most lead to gross violations of the normal physiological process of child development. The paper presents a clinical case of hereditary urea synthesis disorder caused by deficiency of ornithine transcarbamylase of mitochondrial matrix in liver (hyperammonemia type 2) as a result of mutation of the OTC gene (MIM 300461). The disease recessive, linked with the X-chromosome and is associated with a high risk of mortality due to accumulation of toxic concentrations of ammonia. Materials and methods. The boy E., born in 2015. Introduction of protein-based complimentary foods and increase in its portion volume is associated with decrease in appetite, regurgitation, nausea, vomiting, flatulence, dyspepsia appear, and sharp weakness progresses. There is a significant increase in the blood concentration of intracellular liver enzymes. Physical development is slowed due to poor weight gain, and neuropsychiatric development lags significantly. Repeatedly examined in the hospital at the place of residence. Results obtained. A total of 47 genes with mutations causing hereditary diseases with predominant liver damage were studied by mass parallel sequencing. Substitution of c.523G>A (p.Asn175Asp) in the OTC gene in hemizygous state was detected. Clinical diagnosis was established: urea cycle metabolism disorder, hyperammonemia, ornithine transcarbamylase deficiency, E 72.2. Dietary recommendations were given. Carbaglu, Recordati, France at the rate of 100 mg/kg/24 h was prescribed on vital signs. Against the background of the therapy and dietary recommendations the condition of the child had a pronounced positive trend. Conclusions. Since the true incidence of this pathology in Russia has not been established (many cases of metabolic disorders of the urea cycle remain undiagnosed), the presented clinical case will allow clinicians, using modern possibilities of structural and functional analysis of the human genome, to make a timely diagnosis and prescribe adequate therapy, thereby not only prolonging the life of a young patient but also significantly improving its quality.

children, clinical case, inherited metabolic diseases, urea, ornithine transcarbamylase

1. Litvitskii P. F., Mal’tseva L. D. Protein, amino acids and nuceic acids metabolism disorders. Current Pediatrics. 2015;14(1):95-107. (In Russ.). doi: 10.15690/vsp.v14i1.1267.@@ Литвицкий П. Ф., Мальцева Л. Д. Нарушения обмена белков, аминокислот, нуклеиновых кислот. Вопросы современной педиатрии. 2015;14(1):95-107. doi: 10.15690/vsp.v14i1.1267.

2. Baranov A. A., Borovik T. E., Bushueva T. V., et al. Violations of the urea formation cycle. Guidelines. Union of Pediatricians of Russia. Moscow. 2022, 69 P. (In Russ.).@@ Баранов А. А., Боровик Т. Э., Бушуева Т. В., Вашакмадзе Н. Д., Вишнева Е. А., Дегтярева А. В., Дегтярев Д. Н., Журкова Н. В. и др. Нарушения цикла образования мочевины. Методические рекомендации. Союз педиатров России. М., 69 с., 2022.

3. Degtyareva A. V., Baibarina E. N., Evteeva N. V., et al. Neonatal manifestation of urea cycle disorders. Obstetrics and gynecology. 2013;(2):96-100. (In Russ.)@@ Дегтярева А. В., Байбарина Е. Н., Евтеева Н. В., Береговая Е. В., Захарова Е. Ю., Байдакова Г. В. Неонатальная манифестация нарушения цикла мочевины. Акушерство и гинекология. 2013;2:96-100.

4. Grechaninа Е. Ya., Gol’dfarb I.G., Zdybskaya Е. P. et al. Нereditary metabolic diseases. Аminoacidopathy. Оrganic acidurias. Hyperammoniemia. Red cell enzymopathy. In: Clinical genetic problems. Ed. by Е. Ya. Grechanina. Мoscow. Kvadrat Publ., 2003:77-111. (In Russ.).@@ Гречанина Е. Я., Гольдфарб И. Г., Здыбская Е. П. и др. Наследственные нарушения метаболизма. Аминоацидопатии. Органические ацидурии. Гипераммониемии. Эритроцитарные энзимопатии. Проблемы клинической генетики. Под ред. Е. Я. Гречаниной. Москва: Квадрат, 2003;77-111.

5. Bagomedova Z. S., Kotov A. S., Borisova M. N., et al. Onrtihine transcarbamylase deficiency - the real cause of “family curse”. A case report.Russian Journal of Child Neurology. 2016;11(1):29-35. (In Russ.) doi: 10.17650/2073-8803-2016-11-1-29-35.@@ Багомедова Ж. Ш., Котов А. С., Борисова М. Н., Пантелеева М. В., Журкова Н. В., Бёме А. А., Коталевская Ю. Ю., Миронова О. С., Ражева И. В. Недостаточность орнитинтранскарбамилазы - истинная причина «родового проклятия». Описание клинического случая. Русский журнал детской неврологии. 2016;11(1):29-35. doi: 10.17650/2073-8803-2016-11-1-29-35.

6. Biochemistry. E. S. Severin (ed.). Moscow. GEOTAR-med., 2015:768. (In Russ.)@@ Биохимия. Под ред. Е. С. Северина. Москва: ГЭОТАР-мед, 2015;768.

7. McCullough B.A., Yudkoff M., Batshaw M. L., Wilson J. M., Raper S. E., Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000 Aug 14;93(4):313-9. doi: 10.1002/1096-8628(20000814)93:4<313:: aid-ajmg11>3.0.co;2-m.

8. Degtyareva A. V., Sokolova E. V., Zakharova E. Yu., Isaeva M. Kh., Vysokikh M. Yu., Ivanets T. Yu., Degtyarev D. N. Hyperammonemia in Neonatologist Practice. Ros Vestn Perinatol i Pediatr. 2020;65:(6):98-107 (in Russ.) doi: 10.21508/1027-4065-2020-65-6-98-107.@@ Дегтярева А. В., Соколова Е. В., Захарова Е. Ю., Исаева М. Х., Высоких М. Ю., Иванец Т. Ю., Дегтярев Д. Н. Гипераммониемия в практике неонатолога. Российский вестник перинатологии и педиатрии. 2020;65(6):98-107. doi: 10.21508/1027-4065-2020-65-6-98-107.

9. Degtyareva A. V., Kirtbaya A. Z., Sokolova E. V., et al. Neonatal hyperammonemia transient condition or marker of inborn errors of metabolism? Neonatologia. Novosti, mnenia, obucenie. 2018;7(1):96-102. (In Russ.) doi: 10.24411/2308-2402-2018-00013.@@ Дегтярева А. В., Киртбая А. З., Соколова Е. В., Балашова Е. Н., Ионов Е. Ю., Байдакова О. В., Высоких М. Ю., Никитина И. В., Зубков В. В. Неонатальная гипераммонемия - транзиторное состояние или маркер наследственных болезней обмена веществ / Неонатология: новости, мнения, обучение: 2018;7(1): 96-102. doi: 10.24411/2308-2402-2018-00013.

10. Wilnai Y., Blumenfeld Y. J., Cusmano K., Hintc S. R. et al. Prenatal treatment of ornithine transcarbamylase deficience. Mol Genet Metab. 2018 Mar;123(3);297-300. doi: 10.1016/j.ymgme.2018.01.004.

11. Kolchina A.N., Yatsyshina E. E., Malysheva L. V., Ledentsova E. E., Lidyaeva E. E., Khaletskaya O. V. Diagnostics of Inherited Metabolic Diseases in Newborns with the Hyperammonemia Syndrome at the Onset of Disease (Pilot Study). Sovremennye tehnologii v medicine. 2021;13(1):59-65 (In Russ.) doi: 10.1769/stm 2021.13.1.07.@@ Колчина А. Н., Яцышина Е. Е., Малышева Л. В., Леденцова Е. Е.,. Лидяева Е.Е, Халецкая О. В. Диагностика наследственных болезней обмена веществ у новорожденных с синдромом гипераммониемии в дебюте заболевания (пилотное исследование). Современные технологии в медицине. 2021;13(1):59-65. doi: 10.1769/stm 2021.13.1.07.

12. Alexandrovich Yu.S., Pshenisnov K. V., Felker E. Yu., Abramova N. N., Gabrusskaya T. V. Urea Cycle Defects Causing Acute Cerebral Failure in Children: Case Report.Intensive Care Herald. 2017;1;74-80 (In Russ.) doi: 10.21320/1818-474X-2017-1-74-80.@@ Александрович Ю. С., Пшениснов К. В., Фелькер Е. Ю., Абрамова Н. Н., Габрусская Т. В. Нарушение цикла синтеза мочевины как причина острой церебральной недостаточности у детей: случай из практики. Вестник интенсивной терапии. Клинические наблюдения. 2017;1:74-80. doi: 10.21320/1818-474X-2017-1-74-80.

13. Brossier D., Goyer I., Ziani L., Marquis C., Mitchell G., Ozanne B., Jouvet P. Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive careunit. J Inherit Metab Dis. 2019;42(1):77-85. doi: 10.1002/jimd.12029.

14. Pechatnikova N.L., Bryukhanova N. O., Potekhin O. E., Vitkovskaya I. P., Petryaykina E. E., Koltunov I. E. Selective screening for hereditary metabolic diseases. Guidelines. Moscow, Moscow Department of Health, 2017:24. (In Russ.).@@ Печатникова Н. Л., Брюханова Н. О., Потехин О. Е., Витковская И. П., Петряйкина Е. Е., Колтунов И. Е. Селективный скрининг на наследственные болезни обмена веществ. Методические рекомендации. Департамент здравоохранения г. Москвы;. Москва, 2017;24.