Neonatal Lactic Acidosis, Complex I/IV Deficiency, and Fetal Cerebral Disruption

Abstract

Cerebral developmental abnormalities occur in various inborn errors of metabolism including peroxisomal deficiencies, pyruvate dehydrogenase complex deficiency and others. Associations with abnormalities of the respiratory chain are rare. Here we report male and female siblings with microcephaly, a complex neuromigrational disorder including ependymal cysts, leptomeningeal and subcortical heterotopia, polymicrogyria, multifocal cerebral calcifications, agenesis of the corpus callosum, and spongiform changes in brainstem and cerebellum. Intractable lactic acidosis, causing death on the first day of life, was associated with severely reduced activities of complex I and complex IV. The neuropathological and biochemical findings are closely similar to those reported previously by Samsom et al. in 1994. The findings confirm a distinct genetic syndrome of disrupted brain development with TORCH-like calcifications, and a complex neuronal migration disorder associated with a multicomplex disorder of the respiratory chain.

Key words

Cerebral calcifications - respiratory chain defects - corpus callosum agenesis - neuronal heterotopia - leptomeningeal heterotopia - ependymal cysts - microcephaly - congenital infection

References

• 1 Agsteribbe E, Huckriede A, Veenhuis M, Ruiters M HJ, Niezen-Koning K E, Skjeldal O H. et al . A fatal, systemic mitochondrial disease with decreased mitochondrial enzyme activities, abnormal ultrastructure of the mitochondria and deficiency of heat shock protein-60.  Biochem Biophys Res Commun. 1993;  193 146-154
• 2 Barkovich A J, Peck W W. MR of Zellweger syndrome.  Am J Neuroradiol. 1997;  18 1163-1170
• 3 Barth P G, Walter A, van Gelderen I. Aicardi-Goutières syndrome: a genetic microangiopathy?.  Acta Neuropathologica. 1999;  98 212-216
• 4 Bentlage H ACM, Wendel U, Schägger H, Laak ter H J, Janssen A JM, Trijbels J MF. Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts, but with combined complex I and IV deficiencies in muscle.  Neurology. 1996;  47 243-248
• 5 Brown G K. Pyruvate dehydrogenase E1α deficiency.  J Inher Metab Dis. 1992;  15 625-633
• 6 Brown G K, Squier M V. Neuropathology and pathogenesis of mitochondrial diseases.  J Inher Metab Dis. 1996;  19 553-572
• 7 Chow C W, Anderson R McD, Kenny G CT. Neuropathology in cerebral lactic acidosis.  Acta Neuropathol (Berl). 1987;  74 393-396
• 8 DiMauro S, Schon E A. Mitochondrial respiratory-chain diseases.  N Engl J Med. 2003;  348 2656-2668
• 9 Elpeleg O, Mandel H, Saada A. Depletion of the other genome-mitochondrial DNA depletion syndromes in humans.  J Mol Med. 2002;  80 389-396
• 10 Fischer J C, Ruitenbeek W, Trijbels J M, Veerkamp J H, Stadhouders A M, Sengers R C. et al . Estimation of NADH oxidation in human skeletal muscle mitochondria.  Clin Chim Acta. 1986;  155 263-273
• 11 Kelley R I, Robinson D, Puffenberger E G, Strauss K A, Morton D H. Amish lethal microcephaly: a new metabolic disorder with severe congenital microcephaly and 2-ketoglutaric aciduria.  Am J Med Genet. 2002;  112 318-326
• 12 Kerrigan J F, Aleck K A, Tarby T J, Bird C R, Heidenreich R A. Fumaric aciduria: Clinical and imaging features.  Ann Neurol. 2000;  47 583-588
• 13 Knaap van der M S, Jakobs C, Hoffmann G F, Nyhan W L, Renier W O, Smeitink J A. et al . D-2-hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?.  Ann Neurol. 1999;  45 111-119
• 14 Kleist-Retzow von J C, Cormier-Daire V, Viot G, Goldenberg A, Mardach B, Amiel J. et al . Antenatal manifestations of mitochondrial respiratory chain deficiency.  J Pediatr. 2003;  143 208-212
• 15 Koning de T J, Vries de L S, Groenendaal F, Ruitenbeek W, Jansen G H, Poll-The B T. et al . Pontocerebellar hypoplasia associated with respiratory-chain defects.  Neuropediatrics. 1999;  30 93-95
• 16 Korenke G C, Bentlage H ACM, Ruitenbeek W, Sengers R CA, Sperl W, Trijbels J MF. et al . Isolated and combined deficiencies of NADH dehydrogenase (complex I) in muscle tissue of children with mitochondrial myopathies.  Eur J Pediatr. 1990;  150 104-108
• 17 Lincke C R, Bogert van den C, Nijtmans L G, Wanders R J, Tamminga P, Barth P G. Cerebellar hypoplasia in respiratory chain dysfunction.  Neuropediatrics. 1996;  27 216-218
• 18 Munoz A, Mateos F, Simon R, Garcia-Silva M T, Cabello S, Arenas J. Mitochondrial diseases in children: neuroradiological and clinical features in 17 patients.  Neuroradiology. 1999;  41 920-928
• 19 Rademaker K J, de Vries L S, Barth P G. Subependymal pseudocysts: ultrasound diagnosis and findings at follow-up.  Acta Paediatr. 1993;  82 394-399
• 20 Robinson B H, Chow W, Petrova-Benedict R, Clarke J TR, Allen van M I, Becker L E. et al . Fatal combined defects in mitochondrial multienzyme complexes in two siblings.  Eur J Pediatr. 1992;  151 347-352
• 21 Rosenberg M J, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard M S. et al . Mutant deoxynucleotide carrier is associated with congenital microcephaly.  Nat Genet. 2002;  32 175-179
• 22 Samsom J F, Barth P G, Vries de J IP, Menko F H, Ruitenbeek W, Oost van B A. et al . Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications.  Eur J Pediatr. 1994;  153 510-516
• 23 Shoffner J M, Bialer M G, Pavlakis S G, Lott M, Kaufman A, Dixon J. et al . Mitochondrial encephalomyopathy associated with a single nucleotide pair deletion in the mitochondrial tRNALeu(UUR) gene.  Neurology. 1995;  45 286-292
• 24 Sperl W, Sengers R C, Trijbels J M, Veerkamp J H, Stadhouders A M, Sengers R C. et al . Enzyme activities of the mitochondrial energy generating system in skeletal muscle tissue of preterm and fullterm neonates.  Ann Clin Biochem. 1992;  29 638-645
• 25 Sperl W, Ruitenbeek W, Sengers R CA, Trijbels J MF, Bentlage H, Wraith J E. et al . Combined deficiencies of the pyruvate dehydrogenase complex and enzymes of the respiratory chain in mitochondrial myopathies.  Eur J Pediatr. 1992;  151 192-195
• 26 Tanahashi C, Nakayama A, Yoshida M, Ito M, Mori N, Hashizume Y. MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study.  Acta Neuropathol. 2000;  99 31-38