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Ethylmalonic encephalopathy
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Since the initial report, only about 40 cases of ethylmalonic encephalopathy have been described worldwide, suggesting that this condition is an ultra-rare autosomal recessive disorder. Most patients with ethylmalonic encephalopathy have been, with a few exceptions, of Mediterranean [5, 6, 8, 14] or Arabic [7] descent. However, the actual incidence of this condition could have been significantly underestimated because the biochemical phenotype may be incorrectly attributed to other metabolic disorders, particularly defects of the mitochondrial electron-transfer pathway. Several patients of ethylmalonic encephalopathy were initially diagnosed as glutaric aciduria type II, but this diagnosis was not confirmed by in vitro enzyme assays or molecular studies. Some of these patients were proven and more could have been ethylmalonic encephalopathy.
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Abraham J. Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch
Organic acids consist of a group of small molecules that are products of intermediary metabolism. Using gas chromatography–mass spectrometry (GC–MS) methods, hundreds of metabolites can be detected in one run (Figure 3) and such methods are informative regarding amino acid catabolic pathways and mitochondrial energy metabolism, including free fatty acid oxidation and other metabolic pathways [13]. MDs may present with unpredictable organic acid patterns, from strictly normal organic acid profiles to accumulations of lactic acid, TCA cycle intermediates, and other specific molecules. In MDs, abnormalities in the organic acids contained in urine may be caused by disturbed intracellular oxidation–reduction potentials due to elevated NADH/NAD+ and FADH2/FAD ratios, which cause accumulations of lactic acid and Krebs cycle intermediates (mainly malate, fumarate, alpha-ketoglutarate, and succinate) (Figure 3). Accumulation of other intermediates such as dicarboxylic acids, alpha-hydroxybutyrate, or branched chain keto-acids can also be observed in MDs. Interestingly, accumulations of some organic acids are highly specific to the underlying diseases. A list of these specific biomarkers that are used in the diagnosis of some MDs and the diseases in which they accumulate are listed in Table 1. As mentioned previously, neither specificity nor sensitivity is expected for most of these biomarkers. However, some of them can facilitate differential diagnoses with respect to other genetic causes, such as ethylmalonic acid (ethylmalonic encephalopathy versus free fatty acid oxidation defects), 2-hydroxy-glutaric acid (l and d: metabolic repair defects associated with the TCA cycle), methylmalonic acid (commonly associated with nutritionally- and genetically-related cobalamin deficiencies but also with some mtDNA depletion syndromes), methylglutaconic acid (that can be elevated in different genetic conditions affecting mitochondrial metabolism, mainly the activity of ATP synthase of complex V of the OXPHOS system), or acylglycines profiles, which can easily identify some mitochondrial free fatty acid oxidation defects.