Mitochondrial DNA depletion syndrome 13. A case report

The etiology of cerebral palsy in children with intrauterine hypotrophy at birth and developmental delay is often explained by chronic intrauterine hypoxia. However, children with muscle hypotonia and developmental delay require genetic examination.
The aim of this study is to report a case of mitochondrial disease caused by FBXL4 gene mutations and to identify main diagnostic criteria for mitochondrial DNA (mtDNA) depletion syndromes (MDS) in early childhood.
Mitochondrial DNA depletion syndrome-13 is associated with FBXL4 gene mutations located in the 6q16.1–q16.27 locus. This disorder was first described in 2013 by P.E. Bonnen and X. Gai independently. MDS are a clinically and genetically heterogeneous group of diseases inherited by an autosomal recessive type and caused by mutations in genes that support the biogenesis and integrity of mtDNA.
Encephalomyopathic mtDNA depletion syndrome-13 (MTDPS13) (OMIM: 615471) is an exceedingly rare autosomal recessive disease caused by biallelic mutations in the FBXL4 gene (MIM: 605654) with an estimated prevalence of 1 case per 100,000– 400,000 newborns. The disease onset is usually observed in the neonatal period; 75 % of patients develop symptoms by the age of 3 months. In the majority of cases, mtDNA depletion syndrome-13 manifests itself in the early neonatal period; however, in some patients, the disease onset was registered by the age of 24 months. The disease is characterized by encephalopathy, hypotension, lactic acidosis, severe developmental delay, and changes in the area of basal ganglia revealed by magnetic resonance imaging of the brain. FBXL4-related encephalomyopathy is a multisystem disease primarily affecting the central nervous system, heart, and liver. It is characterized by different clinical manifestations such as lactic acidosis, developmental delay, generalized hypotension, nutritional disorders, and growth retardation. Some patients demonstrate specific facial features, including prominent forehead, sinus-shaped folds, thick eyebrows, long eyelashes, epicanthus, short eye slits, hypertelorism, wide and depressed nose bridge, long and smooth labial groove, thin upper lip, and low-set ears.
The disease prognosis is extremely poor; most children die before the age of 4 years. Approximately half of the patients suffer from microcephaly and hyperammonemia. The outcome varies; death was reported in 30 % of cases. Mean time to death was 3 years (median – 2 years).
The diagnosis is crucial for medical and genetic counseling and possible prenatal diagnosis.

1. Degtyareva A.V., Stepanova E.V., Itkis Yu.S. et al. Mitochondrial DNA depletion syndrome: a case report. Rossiyskiy vestnik perinatologii i pediatrii = Russian Bulletin of Perinatology and Pediatrics 2017;62(5):55–62. (In Russ.).

2. Malakhov O.A., Morozov A.K., Ogarev E.V., Kosova I.A. Hip joint development in children and adolescents (experimental anatomical and X-ray examination). Vestnik travmatologii i ortopedii im. N.N. Priorova = N.N. Pirogov Bulletin of Traumatology and Orthopedics 2002;9(3):70–5. (In Russ.).

3. Marks V.O. Orthopedic diagnostics (tutorial). Minsk: Science and technology, 1978. 512 p. (In Russ.).

4. Mikhaylova S.V., Zakharova E.Yu., Tsygankova P.G., Abrukova A.V. Clinical polymorphism of mitochondrial encephalomyopathies caused by POLG mutations. Rossiyskiy vestnik perinatologii i pediatrii = Russian Bulletin of Perinatology and Pediatrics 2012;57(4–2):54–61. (In Russ.).

5. Nikolaeva E.A. Diagnosis and prevention of nuclear-encoded mitochondrial diseases in children. Rossiyskiy vestnik perinatologii i pediatrii = Russian Bulletin of Perinatology and Pediatrics 2014;59(2):19–28. (In Russ.).

6. Studenikin V.M., Globa O.V. Mitochondrial pathology in children. Lechashchiy vrach = Physician 2016;(1):32–5. (In Russ.).

7. Antoun G., McBride S., Vanstone J. et al. Detailed biochemical and bioenergetic characterization of FBXL4-related encephalomyopathic mitochondrial DNA depletion. JIMD Rep 2016;27:1–9. DOI: 10.1007/8904_2015_491

8. Bannwarth S., Procaccio V., Lebre A.S. et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 2013;50:704–14. DOI: 10.1136/jmedgenet-2013-101604

9. Barоy T., Pedurupillay C., Bliksrud Y. et al. A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13. Eur J Med Genet 2016;59:342–6. DOI: 10.1016/j.ejmg.2016.05.005

10. Bonnen P.E., Yarham J.W., Besse A. et al. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am J Hum Genet 2013;93:471–81. DOI: 10.1016/j.ajhg.2013.07.017

11. Chinnery P.F., Elliott H.R., Hudson G. et al. Epigenetics, epidemiology and mitochondrial DNA diseases. Int J Epidemiol 2012;41(1):177–87. DOI: 10.1093/ije/dyr232

12. Davis R., Liang C., Edema-Hildebrand F. et al. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Am Acad Neurol 2013;81:1819–26. DOI: 10.1212/01.wnl.0000436068.43384.ef

13. Debray F.G., Lambert M., Mitchell G.A. Disorders of mitochondrial function. Curr Opin Pediatr 208;20:471–82. DOI: 10.1097/MOP.0b013e328306ebb6

14. El-Hattab A.W., Craigen W.J., Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta 2017;1863(6):1539–55. DOI: 10.1016/j.bbadis.2017.02.017

15. El-Hattab Ayman W., Fernando Scaglia. Mitochondrial DNA depletion syndromes: Review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 2013;10(2):186–98. DOI: 10.1007/s13311-013-0177-6

16. Gai X., Ghezzi D., Johnson M.A. et al. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. Am J Hum Genet 2013;93:482–95.

17. Gold D.R., Cohen B.H. Treatment of mitochondrial cytopathies. Semin Neurol 2001;21:309–25. DOI: 10.1055/s-2001-17948

18. Honzik T., Tesarova M., Magner M. et al. Neonatal onset of mitochondrial disorders in 129 patients: Clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis 2012;35:749–59.

19. Huemer M., Karall D., Schossig A., Abdenur J.E. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. J Inherit Metab Dis 2015;38(5):905–14. DOI: 10.1007/s10545-015-9836-6

20. Koene S., Smeitink J. Mitochondrial Medicine. A Clinical Guideline. 1st edn. Khondrion, Nijmegen, 2011. 135 p.

21. Liang C., Ahmad K., Sue C.M. The broadening spectrum of mitochondrial disease: Shifts in the diagnostic paradigm. Biochim Biophys Acta 2014;1840(4):1360–7. DOI: 10.1016/j.bbagen.2013.10.040

22. Maypek E. Inborn Errors of Metabolism – Early Detection, Key Symptoms and Therapeutic Options. Bremen: UNI-MED, 2008. 128 p.

23. Pagliarini D.J., Calvo S.E., Chang B. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008;134(1):112–23.

24. Pfeffer G., Majamaa K., Turnbull D.M. et al. Treatment for mitochondrial disorders. Cochrane Database Syst Rev 2012;4:1–42. DOI: 10.1002/14651858.CD004426.pub3

25. Reimers J. The stability of the hip in children: A radiological study of the results of muscle surgery in cerebral palsy. Acta Orthop Scand 1980;184:1–100. DOI: 10.3109/ort.1980.51.suppl-184.01

26. Schaefer A.M., Taylor R.W., Turnbull D.M., Chinnery P.F. The epidemiology of mitochondrial disorders – past, present and future. Biochim Biophys Acta 2004;1659:115–20. DOI: 10.1016/j.bbabio.2004.09.005

27. Spinazzola A. Mitochondrial DNA mutations and depletion in pediatric medicine. Semin Fetal Neonatal Med 2011;16:190–6.

28. Suomalainen A., Isohanni P. Mitochondrial DNA depletion syndromes – many genes, common mechanisms. Neuromuscul Disord 2010;20:429–37. DOI: 10.1016/j.nmd.2010.03.017

29. Thompson N., Baker R., Cosgrove A. et al. Relevance of the popliteal angle to hamstring length in cerebral palsy crouch gait. J Pediatr Orthop 2001;21:383–7. DOI: 10.1097/01241398-200105000-00023

30. Van Rij M.C., Jansen F.A.R., Hellebrekers D.M.E.I. et al. Polyhydramnios and cerebellar atrophy: A prenatal presentation of mitochondrial encephalomyopathy caused by mutations in the FBXL4 gene. Clin Case Rep 2016;4(4):425–8.