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The disease course is often complicated by acute life\u2010threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia\/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long\u2010term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so\u2010called \u2018toxic metabolite\u2019 hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl\u2010CoA, 2\u2010methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites (\u2018trapping\u2019 hypothesis\u2019) is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.<\/jats:p>","DOI":"10.1007\/s10545-007-0571-5","type":"journal-article","created":{"date-parts":[[2007,9,10]],"date-time":"2007-09-10T22:57:13Z","timestamp":1189465033000},"page":"35-43","source":"Crossref","is-referenced-by-count":119,"title":["Neurodegeneration and chronic renal failure in methylmalonic aciduria\u2014A pathophysiological approach"],"prefix":"10.1002","volume":"31","author":[{"given":"M. A.","family":"Morath","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Division of Inherited Metabolic Diseases University Children's Hospital Heidelberg Im Neuenheimer Feld 150 Heidelberg 69120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. G.","family":"Okun","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Division of Inherited Metabolic Diseases University Children's Hospital Heidelberg Im Neuenheimer Feld 150 Heidelberg 69120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I. B.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Division of Inherited Metabolic Diseases University Children's Hospital Heidelberg Im Neuenheimer Feld 150 Heidelberg 69120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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