ABSTRACT
Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class. In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS. PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3-methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype. Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias.
Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , DNA, Mitochondrial/genetics , Kearns-Sayre Syndrome/urine , Lipid Metabolism, Inborn Errors/urine , Mitochondrial Diseases/urine , Muscular Diseases/urine , 3-Hydroxybutyric Acid/urine , Acyl-CoA Dehydrogenase, Long-Chain/genetics , Acyl-CoA Dehydrogenase, Long-Chain/urine , Adolescent , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , Fumarates/urine , Glutarates/urine , Humans , Hydroxybutyrates/urine , Infant , Kearns-Sayre Syndrome/diagnosis , Kearns-Sayre Syndrome/genetics , Lactic Acid/urine , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Pyruvic Acid/urine , Retrospective Studies , Valerates/urineABSTRACT
A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.
Subject(s)
Adipates/urine , Kearns-Sayre Syndrome/urine , 2-Aminoadipic Acid/blood , 2-Aminoadipic Acid/urine , Adipates/blood , Adult , Black People/genetics , Child , Child, Preschool , Coma/blood , Coma/genetics , Coma/urine , DNA, Mitochondrial/blood , DNA, Mitochondrial/genetics , Female , Humans , Hydrogen-Ion Concentration , Kearns-Sayre Syndrome/blood , Kearns-Sayre Syndrome/genetics , Ketosis/blood , Ketosis/genetics , Ketosis/urine , Macular Degeneration/blood , Macular Degeneration/genetics , Macular Degeneration/urine , Male , Sequence Deletion/geneticsABSTRACT
We found that patients with mitochondrial encephalomyopathies excreted urinary phosphatidylethanolamine, cardiolipin, and phosphatidylserine most likely derived from mitochondria and sulfatide which is specific to myelin or the kidney. It is of interest that four patients with myoclonus epilepsy with ragged-red fibers and one patient with chronic progressive external ophthalmoplegia all showed qualitatively similar abnormal excretion of such urinary lipids. It is conceivable that the urinary acidic phospholipids reflect abnormalities in the mitochondrial phospholipids, which are very important for mitochondrial enzymatic activities.
