Mitochondrial Encephalomyopathy Associated with Pyruvate Dehydrogenase Complex Deficiency: Eight Clinical Cases

Background. Defects in pyruvate dehydrogenase complex (PDC), involved in the glycolysis products integration into the cells' energy metabolism, are one of the reasons of mitochondrial pathology development. The diagnosis of this condition can be pretty complicated also due to the lack of description of such patients with encephalomyopathy associated with PDC deficiency in Russian population. Clinical Cases Description. We have performed the analysis of clinical manifestations polymorphism of progressive mitochondrial encephalomyopathy caused by pathogenic variants in nuclear X linked gene, PDHA1 (encodes alpha subunit of pyruvate dehydrogenase), in 8 boys aged from 1 to 8 years. The adverse perinatal period was mentioned in all cases. The major features of symptom complex by the time of hospital examination were psychomotor retardation, ataxy, myopathic manifestations. Dystonic attacks were observed in 2 sibs. All patients had changes on brain magnetic resonance imaging: in basal ganglia in 6 children and ventriculomegaly in 2 children. All children had lactic acidosis. Clinical examination has shown that 4 patients had severe damage of nervous system, other 4 patients had moderate damage. Missense mutations in the PDHA1 gene were revealed in 6 children, insertions and duplications including 6 and 16 base pairs — in 2 children. The moderate positive dynamics was noticed as a result of complex treatment of children: stabilization of the overall condition, no metabolic crises, decrease in frequency of dystonic attacks. Conclusion. The clinical polymorphism of mitochondrial encephalomyopathy associated with PDC deficiency is described. The differences in manifestations of severe and moderate forms of disease are shown. The presented description may be useful for medico-genetic counseling and providing medico-genetic care for families.

1. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;26(348):2656-2668. doi: 10.1056/NEJMra022567

2. Haas RH, Parikh S, Falk MJ, et al. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics. 2007; 120(6):1326-1333. doi: 10.1542/peds.2007-0391

3. Poole OV, Hanna MG, Pitceathly RD. Mitochondrial disorders: disease mechanisms and therapeutic approaches. Discov Med. 2015;20(111):325-331.

4. Lissens W, De Meirleir L, Seneca S, et al. Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 2000;15(3):209-219. doi: 10.1002/(SICI)1098-1004(200003)15:3<209::AID-HUMU1>3.0.CO;2-K

5. Sperl W, Fleuren L, Freisinger P, et al. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. J Inherit Metab Dis. 2015;38(3):391-403. doi: 10.1007/s10545-014-9787-3

6. Ciara E, Rokicki D, Halat P, et al. Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing. Mol Genet Metab Rep. 2016;7:70-76. doi: 10.1016/j.ymgmr.2016.03.004

7. Patel KP., O'Brien TW, Subramony SH, et al. The Spectrum of Pyruvate Dehydrogenase Complex Deficiency: Clinical, Biochemical and Genetic Features in 371 Patients. Mol Genet Metab. 2012; 105(1):34-43. doi: 10.1016/j.ymgme.2011.09.032

8. Horga A, Woodward CE, Mills A, et al. Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair. Hum Genet. 2019;138(11):1313-1322. doi: 10.1007/s00439-019-02075-9

9. Gupta N, Rutledge C. Pyruvate Dehydrogenase Complex Deficiency: An Unusual Cause of Recurrent Lactic Acidosis in a Paediatric Critical Care Unit. J Crit Care Med. 2019;5(2):71-75. doi: 10.2478/jccm-2019-0012

10. Blass JP, Avigan J, Uhlendorf BW. A defect in pyruvate decarboxylase in a child with an intermittent movement disorder. J Clin Invest. 1970;49:423-432. doi: 10.1172/JCI106251

11. Blass JP, Kark RAP, Engel WK. Clinical studies of a patient with pyruvate dehydrogenase deficiency. Arch Neurol. 1971;25:449-460.

12. Singhi P, De Meirleir L, Lissens W, et al. Pyruvate dehydroge-nase-e1a deficiency presenting as recurrent demyelination: an unusual presentation and a novel mutation. JIMD Rep. 2013; 10:107-111. doi: 10.1007/8904_2012_211

13. Natarajan N, Tully HM, Chapman T. Prenatal presentation of pyruvate dehydrogenase complex deficiency. Pediatr Radiol. 2016; 46(9):1354-1357. doi: 10.1007/s00247-016-3585-z

14. Sofou K, Dahlin M, Hallbook T, et al. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis. 2017;40(2):237-245. doi: 10.1007/s10545-016-0011-5

15. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi: 10.1038/gim.2015.30

16. Volgina SYa, Khaliullina ChD, Nikolaeva EA, et al. Pyruvate dehydrogenase complex deficiency — a rare mitochondrial disease in a 4-year-old boy. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2020;65(2):86-91. (In Russ). doi: 10.21508/1027-4065-2020-65-2-86-91

17. Nikolaeva EA, Mamedov IS. Diagnostics and treatment of hereditary defects in fatty acid metabolism in children. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2009;54(2):51-65. (In Russ).

18. Janeiro P, Jotta R, Ramos R, et al. Follow-up of fatty acid в-oxidation disorders in expanded newborn screening era. Eur J Pediatr. 2019; 178(3): 387-394. doi: 10.1007/s00431-018-03315-2.

19. Haas RH, Parikh S, Falk MJ, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab. 2008; 94(1):16-37. doi: 10.1016/j.ymgme.2007.11.018

20. Hui J, Kirby DM, Thorburn DR, Boneh A. Decreased activities of mitochondrial respiratory chain complexes in non-mitochondrial respiratory chain diseases. Dev Med Child Neurol. 2006;48(2): 132-136. doi: 10.1017/S0012162206000284

21. Lieber DS, Calvo SE, Shanahan K, et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology. 2013; 80(19):1762-1770. doi: 10.1212/WNL.0b013e3182918c40

22. Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018;3(2):175-192. doi: 10.1002/epi4.12225