Respiratory Chain Deficiency in Alpers Syndrome

Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on respiratory chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to respiratory chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the respiratory chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for respiratory chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.

Key words

Mitochondrial respiratory chain - Alpers syndrome - Progressive infantile poliodystrophy - Epileptic encephalopathy - Valproate

References

• 1 Alpers B J. Diffuse progressive degeneration of the gray matter of the cerebrum.  Arch Neurol Psychiatry. 1931;  25 469-505
• 2 Chabrol B, Mancini J, Chretien D, Rustin P, Munnich A, Pinsard N. Valproate-induced hepatic failure in a case of cytochrome c oxidase deficiency.  Eur J Pediatr. 1994;  153 133-135
• 3 Cormier-Daire V, Chretien D, Rustin P, Rötig A, Dubuisson C, Jacquemin E. et al . Neonatal and delayed-onset liver involvement in disorders of oxidative phosphorylation.  J Pediatr. 1997;  130 817-822
• 4 Egger J, Harding B N, Boyd S G, Wilson J, Erdohazi M. Progressive neuronal degeneration of childhood (PNDC) with liver disease.  Clin Pediatr. 1987;  26 167-173
• 5 Ford F R, Livingston S, Pryles C V. Familial degeneration of the cerebral gray matter in childhood.  J Pediatr. 1951;  39 33-43
• 6 Huttenlocher P R, Solitare G B, Adams G. Infantile diffuse cerebral degeneration with hepatic cirrhosis.  Arch Neurol. 1976;  33 186-192
• 7 Morris A A, Singh-Kler R, Perry R H, Griffiths P D, Burt A D, Wong C P. et al . Respiratory chain dysfunction in progressive neuronal degeneration of childhood with liver disease.  J Child Neurol. 1996;  11 417-419
• 8 Munnich A, Rötig A, Cormier-Daire V, Chretien C, Rustin P. . Scriver C et al The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York; McGraw-Hill
• 9 Narkewicz M R, Sokol R J, Beckwith B, Sondheimer J, Silverman A. Liver involvement in Alpers disease.  J Pediatr. 1991;  119 260-267
• 10 Prick M, Gabreëls F JM, Reiner W O. Progressive infantile poliodystrophy, association with disturbed pyruvate oxidation in muscle and liver.  Arch Neurol. 1981;  38 767-772
• 11 Prick M, Gabreëls F JM, Reiner W O. Progressive infantile poliodystrophy (Alpers disease) with a defect in citric acid cycle activity in liver and fibroblasts.  Neuropediatrics. 1982;  13 108-111
• 12 Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray J M. et al . Biochemical and molecular investigations in respiratory chain deficiencies.  Clin Chim Acta. 1994;  228 35-51
• 13 Schwabe M J, Dobyns W B, Burke B, Armstrong D L. Valproate-induced liver failure in one of two siblings with Alpers disease.  Pediatr Neurol. 1997;  16 337-343
• 14 Tulinius M H, Holme E, Kristiansson B, Larsson N G, Oldfors A. Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations.  J Pediatr. 1991;  119 242-250
• 15 Tulinius M H, Holme E, Kristiansson B, Larsson N G, Oldfors A. Mitochondrial encephalomyopathies in childhood. II. Clinical manifestations and syndromes.  J Pediatr. 1991;  119 251-259