Epilepsy and paroxysmal conditions

Advanced search


Full Text:


Alpers-Huttenlocher syndrome is a rare mitochondrial disease connected with mutations in the mitochondrial DNA replicase, polymerase gamma (POLG). The reduction of the activity within mitochondrial enzymes is connected with the reduction of replications level within the mitochondrial DNA. The disease manifests itself once the replications level reaches a critical point. We can also observe the debut variability and disease progression even among patients with identical genotypes and normal children onset up to the moment of clinical presentations debut. Seizures, liver degeneration and progressive development regression are the classical clinical triad of the disease. Seizures are usually resistant to treatment and have a status flow.Liver disfunction is one of the manifestations of the disease inevitable in the terminal stages. The disease in steadily progressive and leads to the patient s death within several years. Valproic acid causes toxic fatal hepatitis developing within several months and leading to the loss of the patent. Timely diagnosis of the disease, prescription of maintenance therapy and elimination of medications containing valproic acid from the seizures therapy can certainly increase patient s lifetime.



About the Authors

T. T. Batysheva
Scientific and Practical Center of Pediatric psychoneurology, Moscow
Russian Federation

Batysheva Tat’yana Timofeevna – director, Ph.D., Professor, Honored Doctor of the Russian Federation.

Address: Michurinsky Prospect, 74, Moscow, 119602, Russia. 

V. M. Trepilets
Scientific and Practical Center of Pediatric psychoneurology, Moscow
Russian Federation

Trepilets Viktoriya Mikhailovna – the highest category doctor.

Address: Michurinsky Prospect, 74, Moscow, 119602, Russia. 

L. Ya. Akhadova
Scientific and Practical Center of Pediatric psychoneurology, Moscow
Russian Federation

Akhadova Leila Yadullaevna – MD, neurologist, chief specialist. 

Address: Michurinsky Prospect, 74, Moscow, 119602, Russia. 

G. S. Golosnaya
Scientific and Practical Center of Pediatric psychoneurology, Moscow
Russian Federation

Golosnaya Galina Stanislavovna –City Clinical Hospital N 13 branch N 1, MD, neurologist highest category.

Address: Sharikopodshipnikovskaya str.,Moscow, 115088,Russia.


1. Заваденко Н.Н., Холин А.А. Эпилепсия у детей с митохондриальными заболеваниями: особенности диагностики и лечения. Эпилепсия и пароксизмальные состояния. 2012; 4 (2): 21-27. / Zavadenko N.N., Kholin A.A. Epilepsiya i paroksizmal’nye sostoyaniya. 2012; 4 (2): 21-27.

2. Михайлова С.В., Захарова Е.Ю. Генетически обусловленные митохондриальные болезни. Российский вестник перинатологии и педиатрии. 2012; 4. / Mikhailova S.V., Zakharova E.Yu. Rossiiskii vestnik perinatologii i pediatrii. 2012; 4.

3. Alpers B.J. Diffuse progressive degeneration of the gray matter of the cerebrum. Arch Neurol Psychiatry. 1931; 25: 469-505.

4. Bai H.X., MA M.H. et al. Novel characterization of drag-associated pancreatitis in children. J Pediatr Gastroenterol Nutr. 2011; 53: 423-428.

5. Bicknese A.R. et al. Early childhood hepatocerebral degeneration misdiagnosed as valproate hepatotoxicity. Ann Neurol. 1992; 8: 65-8

6. Bohan T.P., Helton E. et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology. 2001; 56: 1405-1409.

7. Blok M.J., van den Bosch B.J. et al. The unfolding clinical spectrum of POLG mutations. J Med Genet. 2009; 46: 776-785.

8. Cohen B.H., Naviaux R.K. The clinical diagnosis of POLG disease and other mitochondrial DNA depletions disorders. Methods. 2010; 51: 364-373.

9. Davidzon G., Mancuso M. et al. POLG mutations and Alpers syndrome. Ann Neurol. 2005; 57: 921-923.

10. De Vries M.C., Rodenbuburg R.J. et al. Multiple oxidative phosphorylation deficiencies in severe childhood multisystem disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr. 2007; 166: 229-234.

11. Dimmock D., Tang L-Y. et al. Quantitative evalution of the mitochondrial DNA depletion syndrome. Clin.Chem. 2010; 56: 1119-1127.

12. Engelsen B.A., Tzoulis al. POLG1 mutations cause syndromic epilepsy with occipital lobe predilection. Brain. 2008; 131: 818-828.

13. Harding B.N. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): A personal review. J Child Neurol. 1990; 5: 273-287.

14. Hakonen A.H., Heiskanen S. et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005; 77: 430-441.

15. Horvath R., Hudson G. at al. Phenotypic spectrum associated with mutation of the mitochondrial polymerase gamma gene. Brain. 2006; 129: 1674-1684.

16. Huttenlocher P.R., Solitare GB, Adams G. Infantile diffuse cerebral degeneration with hepatic cirrhosis. Arch Neurol. 1976; 33: 186-192.

17. Giordano C., Powell H. Fatal congenital myopathy and gastrointestinal pseudoobstruction due to POLG1 mutations. Neurology. 2009; 72: 11103-1105.

18. Lax N.Z., Whittaker R.G. et al. Sensory neuronopathy in patients harboring recessive polymerase gamma mutation. Brain. 2012; 135: 62-71.

19. Mochel F., Slama A. Respiratory chain defects may present only with hypoglycemia. J Clin Endocrinol Metab. 2005; 90: 3780-3785.

20. Naviaux R.K., Nguyen KV. POLG mutation associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol. 2004; 55: 706-712.

21. Naviaux R.K., Nyhan W.J. Mitochondrial DNA polymerase gamma deficiency and mt DNA depletion in child with Alpers syndrome. Ann Neurol. 1999; 25: 54-58.

22. Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase gamma. Genomics.1996; 35: 449-458.

23. Russell P., Saneto. Alpers-Huttenlocher syndrome. Pediatr. Neurol. 2013; 167-178.

24. Saneto R.P., Friedman S., Shaw DWW. Neuroimaging in mitochondrial disease. Mitochondrion. 2008; 8: 396-413.

25. Simonati A., Filosto M. et al. Features of cell death in brain and liver, the target tissues of progressive neuronal degeneration of childhood with liver disease (AlpersHuttenlocher disease). Acta Neuropathol. 2003; 106: 57-65.

26. Spinazzola A, Zeviani M. Disorders from perturbation of nuclear-mitochondrial intergenomic cross-tolk. J Intern Med. 2009; 2009265: 174-192.

27. Taylor I., Sheffer I.E., Berkovic S.F. Occipital epilepsies: identification of specific and newly recognized syndromes. Brain. 2003; 126: 753769.

28. Tzoulis C., Engelsen B.A. et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutation: a study of 26 cases. Brain. 2006; 129: 1685-1692.

29. Tulinius M.H., Hagne I. EEG findings in children and adolescents with mitochondrial encephalomyopathies: a study of 25cases. Brain and Develop. 1991; 13: 167-173.

30. Uusimaa J., Hinttala R. et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome. Epilepsia. 2008; 49: 1038-1045.

31. Van Goethem G., Luoma P. et al. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology.2004; 63:1251-1257.

32. Wiltshire E., Davidzon G. et al. Juvenile Alpers Disease. Arch Neurol. 2008; 65: 121-124.

33. Winterhun S., Ferrrara G. et al. Autosomal recessive mitochondrial ataxia syndrome due to mitochondrial polymerase gamma mutation. Neurology. 2005; 64: 1204-1208.

34. Wolf N.I., Rahman S. et al. Status epilepticus in children with Alpers disease caused by POLG1 mutations: EEG and MRI finding. Epilepsia. 2009; 50: 1596-1607.

35. Wong L-J.C., Naviaux R.K. et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mut. 2008; 29: E150-E172.

36. Wortmann S.B., Rodenburg R.J.T. Biochemical and genetic analysis of 3-mtehylglutaconic aciduria type IV: а diagnostic strategy. Brain. 2009; 132: 136-146.

37. Van Goethem G., Luoma P. et al. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004; 63: 1251-1257.

For citation:

Batysheva T.T., Trepilets V.M., Akhadova L.Y., Golosnaya G.S. ALPERS-HUTTENLOCHER SYNDROME. Epilepsy and paroxysmal conditions. 2015;7(1):46-55. (In Russ.)

Views: 255

ISSN 2077-8333 (Print)
ISSN 2311-4088 (Online)