Mitochondriopathien im Kindes- und Jugendalter

Fazit

Mitochondriopathien sind angeborene Erkrankungen des Energiestoffwechsels mit einer sehr großen klinischen wie genetischen Heterogenität. Eine frühzeitige Diagnose ist wichtig für die prognostische Einordnung, die genetische Beratung der Familien und ggf. für eine adaptierte Therapie. Aufgrund der Heterogenität ist die Diagnostik schwierig und bedarf des sinnvollen Einsatzes unterschiedlicher klinischer, biochemischer und molekulargenetischer Methoden. Letztere haben sich durch die Einführung des Next Generation Sequencing enorm entwickelt. Die Therapie ist im Wesentlichen noch symptomatisch, jedoch zeichnen sich dank des zunehmenden Verständnis von Pathomechanismen neue kausale Therapieansätze ab. Die Betreuung der Patienten ist komplex, weswegen die frühzeitige Einbindung eines Spezialisten sinnvoll ist.

• Literatur

• 1 Schaefer AM, Taylor RW, Turnbull DM et al. The epidemiology of mitochondrial disorders – past, present and future. Biochim Biophys Acta 2004; 1659: 115-120
• 2 Skladal D, Halliday J, Thorburn DR. Birth prevalence of mitochondrial respiratory chain deficiencies in children. Brain 2003; 196: 1905-1912
• 3 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: 391-403
• 4 Mayr JA, Freisinger P, Schlachter K et al. Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet 2011; 89: 806-812
• 5 Mayr JA, Haack TB, Freisinger P et al. Spectrum of combined respiratory chain defects. J Inherit Metab Dis 2015; 38: 629-640
• 6 Lee IC, El-Hattab AW, Wang J et al. SURF1-associated Leigh syndrome: a case series and novel mutations. Hum Mutat 2012; 33: 1192-200
• 7 Jonckheere AI, Smeitink JA, Rodenburg RJ. Mitochondrial ATP synthase: architecture, function and pathology. J Inherit Metab Dis 2012; 35: 211-225
• 8 Ahting U, Mayr JA, Vanlander AV et al. Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency. Front Genet 2015; 13: 123
• 9 Emmanuele V, López LC, Berardo A et al. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 2012; 69: 978-983
• 10 Stehling O, Wilbrecht C, Lill R. Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 2014; 100: 61-77
• 11 Mayr JA, Feichtinger RG, Tort F et al. Lipoic acid biosynthesis defects. J Inherit Metab Dis 2014; 37: 553-563
• 12 Haack TB, Makowski C, Yao Y et al. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis 2012; 35: 943-948
• 13 Area-Gomez E, Schon EA. Mitochondrial genetics and disease. J Child Neurol 2014; 29: 1208-1215
• 14 Koopman WJH, Willems PHGM, Smeitink JAM. Monogenic Mitochondrial Disorders. N Engl J Med 2012; 366: 1132-1141
• 15 Powell CA, Nicholls TJ, Minczuk M. Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Front Genet 2015; 6: 79
• 16 Mayr JA. Lipid metabolism in mitochondrial membranes. J Inherit Metab Dis 2015; 38: 137-144
• 17 DiMauro S, Schon EA, Carelli V et al. The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013; 9: 429-444
• 18 Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiat 1951; 14: 216-221
• 19 Baertling F, Rodenburg RJ, Schaper J et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry 2014; 85: 257-265
• 20 Copeland WC, Longley MJ. Mitochondrial genome maintenance in health and disease. DNA Repair (Amst) 2014; 19: 190-198
• 21 Uusimaa J, Moilanen JS, Vainionpää L et al. Prevalence, segregation, and phenotype of the mitochondrial DNA 3243 A > G mutation in children. Ann Neurol 2007; 62: 278-287
• 22 Parikh S, Goldstein A, Koenig MK et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial MedicineSociety. Genet Med 2014; 11. Epub ahead of print
• 23 Diagnostik und Therapieansätze bei Mitochondriopathien im Kindes- und Jugendalter, Leitlinien Kinderheilkunde und Jugendmedizin. AWMF-Leitlinien-Register Nr. 027/016 http://www.awmf.org/leitlinien/detail/ll/027-016.html
• 24 Wortmann SB, Duran M, Anikster Y et al. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis 2013; 36: 923-928
• 25 Scaglia F, Towbin JA, Craigen WJ et al. Clinical spectrum,morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004; 114: 925-931
• 26 Stickler DE, Valenstein E, Neiberger RE et al. Peripheral neuropathy in genetic mitochondrial diseases. Pediatr Neurol 2006; 34: 127-131
• 27 Carroll CJ, Brilhante V, Suomalainen A. Next-generation sequencing for mitochondrial disorders. Br J Pharmacol 2014; 171: 1837-1853
• 28 Haack TB, Haberberger B, Frisch EM et al. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet 2012; 49: 277-283
• 29 Klopstock T, Yu-Wai-Man P, Dimitriadis K et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 2011; 134: 2677-2686
• 30 Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). J Inherit Metab Dis 2012; 35: 679-687
• 31 Brown G. Defects of thiamine transport and metabolism. J Inherit Metab Dis 2014; 37: 577-585
• 32 El-Hattab AW, Adesina AM, Jones J et al. MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 2015; Jun Epub ahead of print
• 33 Scholl-Bürgi S, Höller A, Pichler K et al. Ketogenic diets in patients with inherited metabolic disorders. J Inherit Metab Dis 2015; 38: 765-773
• 34 Taivassalo T, Gardner JL, Taylor RW et al. Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Brain 2006; 129: 3391-3401
• 35 Tarnopolsky MA. Exercise as a therapeutic strategy for primary mitochondrialcytopathies. J Child Neurol 2014; 29: 1225-1534
• 36 Martinelli D, Catteruccia M, Piemonte F et al. EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome. Mol Genet Metab 2012; 107: 383-388
• 37 Tischner C, Wenz T. Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders. Mitochondrion 2015; 24: 32-49
• 38 Viscomi C, Bottani E, Zeviani M. Emerging concepts in the therapy of mitochondrial disease. Biochim Biophys Acta 2015; 1847: 544-557
• 39 Burgstaller JP, Johnston IG, Poulton J. Mitochondrial DNA disease and developmental implications for reproductive strategies. Mol Hum Reprod 2015; 21: 11-22