Branched-chain organic acidurias

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Branched chain organic acidurias are a group of disorders that result from an abnormality of specific enzymes involving the catabolism of branched chain amino acids (leucine, isoleucine, valine). Maple syrup urine disease (MSUD), isovaleric acidaemia (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) represent the most commonly encountered abnormal organic acidurias. All these four disorders present in neonates as a neurologic distress of the intoxication type with either ketosis or ketoacidosis and hyperammonaemia. There is a free interval between birth and clinical symptoms. MMA, PA and IVA present with a severe dehydration, leuconeutropenia and thrombopenia which can mimic sepsis. All these disorders can be diagnosed by identifying acylcarnitine and other organic acid compounds in plasma and urine by gas chromatography mass spectrometry or tandem MS-MS. These disorders are amenable to treatment by removing toxic compounds and by using special diets and carnitine.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Seminars in Fetal and Neonatal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Orban T
        • Mpofu C
        • Blackensee D
        Severe CNS bleeding followed by a good clinical outcome in the acute neonatal form of isovaleric acidaemia.
        J Inherit Metab Dis. 1994; 17: 755-756
        • Wendel U
        • Eibler A
        • Perl W
        • Schaedewaldt P
        On the differences between urinary metabolite excretion and odd-numbered fatty acid production in propionic and methylmalonic acidaemias.
        J Inherit Metab Dis. 1995; 18: 584-591
        • Leonard JV
        Stable isotope studies in propionic and methylmalonic acidaemia.
        Eur J Pediatr. 1996; 156: S67-S69
        • Burns SP
        • Iles RA
        • Saudubray JM
        • Chalmers RA
        Propionylcarnitine excretion is not affected by metronidazole administration to patients with disorders of propionate metabolism.
        Eur J Pediatr. 1996; 155: 31-35
        • Holmes E
        • Foxall PJ
        • Spraul M
        750Mhz 1H NMR spectroscopy characterisation of the complex metabolic pattern of urine from patients with inborn errors of metabolism: 2-hydroxyglutaric aciduria and maple syrup urine disease.
        J Pharm Biom Anal. 1997; 15: 1647-1659
        • Johnson AW
        • Mills K
        • Clayton PT
        The use of automated electrospray ionization tandem MS for the diagnosis of inborn errors of metabolism from dried blood spots.
        Bioch Soc Trans. 1996; 24: 932-938
        • Bonafe L
        • Troxler H
        • Kuster T
        Evaluation of urinary acylglycines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias.
        Mol Gen Metab. 2000; 69: 302-311
        • Jakobs C
        • Ten Brink HG
        • Stellaard F
        Prenatal diagnosis of inherited metabolic disorders by quantification of characteristic metabolites in amniotic fluid: Facts and future.
        Prenat Diagn. 1991; 10: 265-271
        • Shigematsu Y
        • Hata I
        • Nakai A
        Prenatal diagnosis of organic acidemias based on amniotic fluid levels of acylcarnitines.
        Pediatr Res. 1996; 39: 680-684
        • Berry GT
        • Heindenreich R
        • Kaplan P
        Branched chain amino acid-free parenteral nutrition in the treatment of acute metabolic decompensation in patients with maple syrup urine disease.
        N Engl J Med. 1991; 324: 175-179
        • Parini R
        • Sereni LP
        • Bagozzi DC
        Nasogastric drip feeding as the only treatment of neonatal maple syrup urine disease.
        Pediatrics. 1993; 92: 280-283
        • Jouvet P
        • Poggi F
        • Rabier D
        Continuous venovenous haemofiltration in the acute phase of neonatal maple syrup urine disease.
        J Inherit Metab Dis. 1997; 20: 463-472
        • Elsas LJ
        • Ellerine NP
        • Klein PD
        Practical methods to estimate whole body leucine oxidation in maple syrup urine disease.
        Pediatr Res. 1993; 33: 445-451
        • Hilliges C
        • Awiszus D
        • Wendel U
        Intellectual performance of children with maple urine disease.
        Eur J Pediatr. 1993; 152: 144-147
        • Riviello JJ
        • Rezvani I
        • DiGeorge AM
        • Foley CM
        Cerebral edema causing death in children with maple syrup urine disease.
        J Pediatr. 1991; 119: 42-45
        • Levin ML
        • Scheimann A
        • Lewis RA
        • Beaudet AL
        Cerebral edema in maple syrup urine disease.
        J Pediatr. 1993; 122: 167-168
        • Taccone A
        • Schiaffino MC
        • Cerone R
        Computed tomography in maple syrup urine disease.
        Eur J Radiol. 1992; 14: 207-212
        • Danias J
        • Raab EL
        • Friedman AH
        Retinopathy associated with pancreatitis in a child with maple syrup urine disease.
        Br J Ophthalmol. 1998; 82: 841
        • Giacoia GP
        • Berry GT
        Acrodermatitis enteropathica-like syndrome secondary to isoleucine deficiency during treatment of maple syrup urine disease.
        Am J Dis Child. 1993; 147: 954-956
        • Fries MH
        • Rinaldo P
        • Schmidt-Sommerfeld E
        Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy.
        J Pediatr. 1996; 129: 449-452
        • Leonard JV
        The management and outcome of propionic and methylmalonic acidaemia.
        J Inherit Metab Dis. 1995; 18: 430-434
        • Van der Meer SB
        • Poggi F
        • Spada M
        Clinical outcome of long-term management of patients with vitamin-B12unresponsive methylmalonic acidemia.
        J Pediatr. 1994; 125: 903-908
        • Van der Meer SB
        • Poggi F
        • Spada M
        Clinical outcome and long term management of 17 patients with propionic acidaemia.
        Eur J Pediatr. 1996; 155: 205-210
        • Nicolaides P
        • Leonard J
        • Surtees R
        Neurological outcome of methylmalonic acidaemia.
        Arch Dis Child. 1998; 78: 508-512
        • Pérez-Cerda C
        • Merinero B
        • Marti M
        An unusual late onset case of propionic acidaemia: biochemical investigations, neuroradiological findings and mutation analysis.
        Eur J Pediatr. 1998; 157: 50-52
        • Brismar J
        • Ozand PT
        CT and MR of the brain in disorders of the propionate and methylmalonate metabolism.
        Am J Neuroradiol. 1994; 15: 1459-1473
        • Hamilton RL
        • Haas RH
        • Nyhan WL
        Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions.
        J Child Neurol. 1995; 10: 25-30
        • Baumgartner ER
        • Viardot
        Long-term follow-up of 77 patients with isolated methylmalonic acidaemia.
        J Inherit Metab Dis. 1995; 18: 138-142
        • Rutledge SL
        • Geraghty M
        • Mroczek E
        Tubulointersticial nephritis in methylmalonic acidemia.
        Pediatr Nephrol. 1993; 7: 81-82
        • Van't Hoff WG
        • Dixon M
        Combined liver-kidney transplantation in methylmalonic acidemia.
        J Pediatr. 1998; 132: 1043-1044
        • Massoud AF
        • Leonard JV
        Cardiomyopathy in propionic acidaemia.
        Eur J Pediatr. 1993; 152: 441-445
        • Kahker SG
        • Sherwood WG
        • Woolf D
        Pancreatitis in patients with organic acidemias.
        J Pediatr. 1994; 124: 239-243
        • Bodemer C
        • De Prost Y
        • Bachollet B
        Cutaneous manifestations of methylmalonic and propionic acidaemia: a description based on 38 cases.
        Br J Dermatol. 1994; 131: 93-98
        • De Raeve L
        • De Meirleir L
        • Ramet J
        Acrodematitis enteropathica-like cutaneous lesions in organic aciduria.
        J Pediatr. 1994; 124: 416-420
        • Schlenzig JS
        • Poggi-Travert F
        • Laurent J
        Liver transplantation in two cases of propionic acidaemia.
        J Inherit Metab Dis. 1995; 18: 448-461
        • Wendel U
        • Saudubray JM
        • Bodner A
        • Schadewaldt P
        Liver transplantation in maple syrup urine disease.
        Eur J Pediatr. 1999; 158: S60-S64
        • Nellis MM
        • Danner DJ
        Gene preference in maple syrup urine disease.
        Am J Hum Genet. 2001; 68: 232-237
        • Moshen AA
        • Anderson BD
        • Volchenboum SL
        Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia.
        Biochemistry. 1998; 37: 10325-10335
        • Ugarte M
        • Perez-Cerda C
        • Rodriguez-Pombo P
        Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.
        Human Mutations. 1999; 14: 275-282
        • Fuchshuber A
        • Mucha B
        • Baumgartner ER
        Mut0 methylmalonic acidemia: eleven novel mutations of the methylmalonyl CoA mutase including a deletion-insertion mutation.
        Human Mutations. 2000; 16: 179
        • Wiesmann UN
        • Suormala T
        • Pfenninger J
        • Baumgartner ER
        Partial 3-methylcrotonyl-CoA carboxylase deficiency in an infant with fatal outcome due to progressive respiratory failure.
        Eur J Pediatr. 1998; 157: 225-229
        • Van Hove JLK
        • Rutledge SL
        • Nada MA
        3-hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency.
        J Inherit Metab Dis. 1995; 18: 592-601
        • Gallardo ME
        • Desviat LR
        • Rodriguez JM
        The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism.
        Am J Hum Genet. 2001; 68: 334-346
        • Baumgartner MR
        • Almashanu S
        • Suormala T
        The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.
        J Clin Invest. 2001; 107: 495-504
        • Krawinkel MB
        • Oldigs HD
        • Santer R
        Association of malonyl-CoA decarboxylase deficiency and heterozygote state for haemoglobin C disease.
        J Inherit Metab Dis. 1994; 17: 636-637
        • Buyukgebiz B
        • Jakobs C
        • Scholte HR
        Fatal neonatal malonic aciduria.
        J Inherit Metab Dis. 1998; 21: 76-77
        • Gregg AR
        • Warman AW
        • Thoburn DR
        • O'Brien WE
        Combined malonic and methylmalonic aciduria with normal malonyl-coenzyme A decarboxylase activity: A case supporting multiple aetiologies.
        J Inherit Metab Dis. 1998; 21: 382-390
        • Matalon R
        • Michaels K
        • Kaul R
        Malonic aciduria and cardiomyopathy.
        J Inherit Metab Dis. 1993; 16: 571-573
        • Gao J
        • Waber L
        • Bennett MJ
        Cloning and mutational analysis of human malonyl-coenzyme A decarboxylase.
        J Lipid Res. 1999; 40: 178-182