Skip to main content
SpringerLink
Log in

Recognition and management of fatty acid oxidation defects: A series of 107 patients

  • Published:
Journal of Inherited Metabolic Disease

Abstract

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bergman AJ, Donckerwolcke RA, Duran M, et al (1994) Rate-dependent distal renal tubular acidosis and carnitine palmitoyltransferase I deficiency. Pediatr Res 36: 582-588.

    PubMed  CAS  Google Scholar 

  • Bohm N, Uy J, Kiessling M, et al (1982) Multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II), congenital polycystic kidneys, and symmetric warty dysplasia of the cerebral cortex in two newborn brothers: II. Morphology and pathogenesis. Eur J Pediatr 139: 60-65.

    Article  PubMed  CAS  Google Scholar 

  • Boles RG, Buck EA, Blitzer MG, et al (1998) Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr 132: 924-933.

    Article  PubMed  CAS  Google Scholar 

  • Bonnefont JP, Specola NB, Vassault A, et al (1990) The fasting test in paediatrics: application to the diagnosis of pathological hypo-and hyperketotic states. Eur J Pediatr 150: 80-85.

    Article  PubMed  CAS  Google Scholar 

  • Bougnères PF, Saudubray JM, Marsac C, Bernard O, Odièvre M, Girard J (1981) Fasting hypoglycemia resulting from hepatic carnitine palmitoyl transferase deficiency. J Pediatr 98: 742-746.

    Article  PubMed  Google Scholar 

  • Brivet M, Slama A, Saudubray JM, Legrand A, Lemonnier A (1995) Rapid diagnosis of long chain and medium chain fatty acid oxidation disorders using lymphocytes. Ann Clin Biochem 32: 154-159.

    PubMed  Google Scholar 

  • Brivet M, Slama A, Millington DS, et al (1996) Retrospective diagnosis of carnitine-acylcarnitine translocase deficiency by acylcarnitine analysis in the proband Guthrie card and enzymatic studies in the parents. J Inher Metab Dis 19: 181-184.

    Article  PubMed  CAS  Google Scholar 

  • Brivet M, Boutron A, Slama A, et al (1999) Defects in activation and transport of fatty acids. J Inher Metab Dis 22: 428-441.

    Article  PubMed  CAS  Google Scholar 

  • Burlina AB, Dionisi-Vici C, Bennett MJ, et al (1994) A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. J Pediatr 124: 79-86.

    Article  PubMed  CAS  Google Scholar 

  • Carroll JE, Shumate JB, Brooke MH, Hagberg JM (1981) RiboÑavin-responsive lipid myopathy and carnitine deficiency. Neurology 31: 1557-1559.

    PubMed  CAS  Google Scholar 

  • Colevas AD, Edwards JL, Hruban RH, Mitchell GA, Valle D, Hutchins GM (1988) Glutaric acidemia Type II. Arch Pathol Lab Med 112: 1133-1139.

    PubMed  CAS  Google Scholar 

  • Corr PB, Creer MH, Yamada KA, Saffitz JE, Sobel BE (1989) Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 83: 927-936.

    PubMed  CAS  Google Scholar 

  • Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Saudubray JM (1991) Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death: physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest 87: 859-864.

    Article  PubMed  CAS  Google Scholar 

  • Dimauro S, Dimauro PMM (1973) Muscle carnitine palmitoyl transferase deficiency and myoglobinuria. Science 182: 929-931.

    PubMed  CAS  Google Scholar 

  • Dionisi-Vici C, Burlina AB, Bertini E, et al (1991) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical and therapeutic considerations. J Pediatr 118: 744-746.

    Article  Google Scholar 

  • Dionisi-Vici C, Garavaglia B, Burlina AB, et al (1996) Hypoparathyroidism in mitochondrial trifunctional protein deficiency. J Pediatr 129: 159-162.

    Article  PubMed  CAS  Google Scholar 

  • Engel AG, Angelini C (1973) Carnitine deficiency of human skeletal muscle associated with lipid storage myopathy: a new syndrome. Science 179: 899-901.

    PubMed  CAS  Google Scholar 

  • Falik-Borenstein ZC, Jordan SC, Saudubray JM, et al (1992) Brief report: renal tubular acidosis in carnitine palmitoyltransferase type 1 deficiency. N Engl J Med 327: 24-27.

    Article  PubMed  CAS  Google Scholar 

  • Fernandes J, Saudubray JM (1995) Diagnostic procedures: function tests and postmortem protocol. In Fernandes J, Saudubray JM, Van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 2nd edn. Berlin: Springer-Verlag, 41-46.

    Google Scholar 

  • Freinkel N, Lewis NJ, Azakawa S, Roth SI, Gorman I (1984) The honeybee syndrome: implications of teratogenicity of mannose in rat-embryo culture. N Engl J Med 310: 223-230.

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Silva MT, Ribes A, Campos Y, Garavaglia B, Arenas J (1997) Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria. Pediatr Neurol 17: 165-170.

    Article  PubMed  CAS  Google Scholar 

  • Green A, Marshall TG, Bennett MJ, Gray RGF, Pollit RJ (1985) Riboflavin-responsive ethylmalonyladipic aciduria. J Inher Metab Dis 8: 67-70.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg CR, Wanders RJA, Roe CR, Grewar D, Seargeant LE (1997) Complete deficiency of CPT I in an infant born to a mother with acute fatty liver of pregnancy. Poster, 7th International Congress of Inborn Errors of Metabolism, Vienna, May 21-25, 1997. (Abstract).

  • Hale D, Bennett MJ (1992) Fatty acid oxidation disorders: a new class of metabolic diseases. J Pediatr 121: 1-11.

    Article  PubMed  CAS  Google Scholar 

  • Hale DE, Thorpe C, Braat K, et al (1990a) The L-3-hydroxyacyl-CoA dehydrogenase defi-ciency. In Tanaka K, Coates PM, eds. Fatty Acid Oxidation: Clinical, Biochemical and Molecular aspects. New-York: Alan R. Liss, 503-510.

    Google Scholar 

  • Hale DE, Thorpe C, Braat K, et al (1990b) The L-3-hydroxyacyl-CoA dehydrogenase deficiency. Prog Clin Biol 321: 503-510.

    CAS  Google Scholar 

  • Harding CO, Gillingham MB, Van Calcar SC, Wolff JA, Verhoeve JN, Mills MD (1998) Effects of docosahexaenoic acid (DHA) supplementation upon retinal function in children with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Inher Metab Dis 21 (supplement 2): O6 (abstract).

    Google Scholar 

  • Harpey JP, Charpentier C, Coude M, Divry P, Paturneau-Jouas M (1987) Sudden infant death syndrome and multiple acyl-coenzyme A dehydrogenase deficiency, ethylmalonicadipic acidemia, or systemic carnitine deficiency. J Pediatr 110: 881-884.

    Article  PubMed  CAS  Google Scholar 

  • Hug G, Bove KE, Soukup S (1991) Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med 325: 1862-1864.

    Article  PubMed  CAS  Google Scholar 

  • Innes AM, Seargeant LE, Balachandra K, et al (1997) An expanding spectrum of metabolic disorders can cause acute fatty liver of pregnancy (AFLP), hemolysis, elevated liver enzymes and low platelets syndrome (HELLP), and hyperemesis gravidarum. Am J Hum Genet A252 (abstract).

  • Millington DS, Kodo N, Norwood DL, Roe CR (1990) Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J Inher Metab Dis 13: 321-324.

    Article  PubMed  CAS  Google Scholar 

  • Millington DS, Terada N, Chace DH, et al (1992) The role of tandem mass spectrometry in the diagnosis of fatty acid oxidation disorders. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. Progress in Clinical and Biological Research. New York: Wiley-Liss, 339-354.

    Google Scholar 

  • Miyajima H, Orii KE, Shindo Y, et al (1997) Mitochondrial trifunctional protein deficiency associated with recurrent myoglobinuria in adolescence. Neurology 49: 833-837.

    PubMed  CAS  Google Scholar 

  • Nada M, Rhead W, Sprecher H, et al (1995) Evidence for intermediate channeling of mitochondrial β-oxidation. J Biol Chem 270: 530-535.

    Article  PubMed  CAS  Google Scholar 

  • Parini R, Garavaglia B, Saudubray JM, et al (1991) Clinical diagnosis of long-chain acylcoenzyme A-dehydrogenase deficiency: use of stress and fat-loading tests. J Pediatr 119: 77-80.

    Article  PubMed  CAS  Google Scholar 

  • Pollitt RJ (1989) Disorders of mitochondrial beta-oxidation; prenatal and early post-natal diagnosis and their relevance to Reye's syndrome and sudden infant death. J Inher Metab Dis 12 (supplement 1): 215-230.

    Article  PubMed  Google Scholar 

  • Poll-The BT, Bonnefont JP, Ogier H, et al (1988) Familial hypoketotic hypoglycaemia associated with peripheral neuropathy, pigmentary retinopathy and hydroxydicarboxylic C6-C14 aciduria. A new defect in fatty acid oxidation? J Inher Metab Dis 11(supplement 2): 183-185.

    Article  PubMed  Google Scholar 

  • Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P (1995) Diagnosis of inborn errors of metabolism in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 41: 1109-1114.

    PubMed  CAS  Google Scholar 

  • Rhead WJ (1990) Screening for inborn errors of fatty acid oxidation in cultured fibroblasts: an overview. In Tanaka K, Coates PM, eds. Fatty Acid Oxidation: Clinical, Biochemical and Molecular aspects. New York: Alan R. Liss, 365-382.

    Google Scholar 

  • Riudor E, Ribes A, Boronat M, Sabado C, Dominguez C, Balla Briga A (1986) A new case of C6-C14 dicarboxylic aciduria with favourable evolution. J Inher Metab Dis 9(supplement 2): 297-299.

    Article  Google Scholar 

  • Roettger V, Marshall T, Amendt B, Rhead WJ (1992) Multiple acyl-coenzyme A dehydrogenation disorders (MAD) responsive to riboflavin: biochemical studies in fibroblasts. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. Progress in Clinical and Biological Research. New York: Wiley-Liss, 317-326.

    Google Scholar 

  • Rocchiccioli P, Wanders RJA, Aubourg P, et al (1990) Deficiency of long-chain 3-hydroxyacylCoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. Pediatr Res 28: 657-662.

    PubMed  CAS  Google Scholar 

  • Rumsby G, Seakins JWT, Leonard JV (1986) A simple screening test for medium chain acylCoA dehydrogenase deficiency. Lancet 2: 467.

    Article  PubMed  CAS  Google Scholar 

  • Saudubray JM, Charpentier C (1995) Clinical phenotypes: diagnosis/algorithms. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th edn, New York: McGraw-Hill, 327-400.

    Google Scholar 

  • Saudubray JM, Coudé FX, Demaugre F, Johnson C, Gibson KM, Nyhan WC (1982) Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation. Pediatr Res 16: 877-881.

    PubMed  CAS  Google Scholar 

  • Saudubray JM, Ogier H, Bonnefont JP, et al (1989) Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey. J Inher Metab Dis 12(supplement 1): 25-41.

    Article  PubMed  Google Scholar 

  • Schmidt-Sommerfeld E, Penn D, Duran M, et al (1992) Detection and quantitation of acylcarnitines in plasma and blood spots from patients with inborn errors of fatty acid oxidation. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. Progress in Clinical and Biological Research. New York: Wiley-Liss, 355-362.

    Google Scholar 

  • Smelt AHM, Poorthuis JHM, Onkenhout W, et al (1998) Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset. Ann Neurol 43: 540-544.

    Article  PubMed  CAS  Google Scholar 

  • Sperl W, Geiger R, Lehnert W, Rhead W (1997) Stridor as the major presenting symptom in riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Eur J Pediatr 156: 800-802.

    Article  PubMed  CAS  Google Scholar 

  • Stanley CA, DeLeeuw S, Coates PM, et al (1991) Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 30: 709-716.

    Article  PubMed  CAS  Google Scholar 

  • Stanley CA, Sunaryo F, Hale DE, Bonnefont JP, Demaugre F, Saudubray JM (1992) Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase-1 deficiency. J Inher Metab Dis 15: 785-789.

    Article  PubMed  CAS  Google Scholar 

  • Tein I, Demaugre F, Bonnefont JP, Saudubray JM (1989) Normal muscle CPT I and CPT II activities in hepatic-presentation patients with CPT I deficiency in fibroblasts. Tissue specific isoforms of CPT I? J Neurol Sci 92: 229-245.

    Article  PubMed  CAS  Google Scholar 

  • Tein I, DeVivo DC, Hale DE, et al (1991) Short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency in muscle: a new cause for recurrent myoglobinuria and encephalopathy. Ann Neurol 30: 415-419.

    Article  PubMed  CAS  Google Scholar 

  • Tyni T, Rapola J, Palotie A, Pihko H (1997) Hypoparathyroidism in a patient with longchain-3-hydroxyacyl-coenzyme A dehydrogenase deficiency caused by the G1528C mutation. J Pediatr 131: 766-768.

    Article  PubMed  CAS  Google Scholar 

  • Van Hove JLK, Zhang W, Kahler SG, et al (1993) Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: diagnosis by acylcarnitine analysis in blood. Am J Hum Genet 52: 958-966.

    PubMed  CAS  Google Scholar 

  • Vianey-Saban C, Divry P, Gregersen N, Mathieu M (1987) The inborn errors of mitochondrial fatty acid oxidation. J Inher Metab Dis 10(supplement 1): 159-198.

    Article  Google Scholar 

  • Vianey-Saban C, Divry P, Brivet M, et al (1998) Mitochondrial very-long-chain acylcoenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta 269: 43-62.

    Article  PubMed  CAS  Google Scholar 

  • Wilson GN, De Chadarévian JP, Kaplan P, Loehr JP, Frerman FE, Goodman SI (1989) Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am J Med Genet 32: 395-401.

    Article  PubMed  CAS  Google Scholar 

  • Witt DR, Theobald M, Santa-maria M, et al (1991) Carnitine palmitoyl transferase-type 2 deficiency: two new cases and successful prenatal diagnosis. Am J Hum Genet 49 (supplement 4): 535 (abstract).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Hôpital Necker Enfants-Malades, Paris, France

    J. M. Saudubray, D. Martin, P. De Lonlay, G. Touati, F. Poggi-Travert, D. Bonnet & P. Jouvet

  2. Department of Biochemistry, Hôpital Bicêtre, Le Kremlin Bicêtre, France

    M. Boutron, A. Slama & M. Brivet

  3. Department of Biochemistry, Hôpital Debrousse, Lyon, France

    C. Vianey-Saban

  4. Department of Biochemistry, Hôpital Necker Enfants-Malades, Paris, France

    J. P. Bonnefont, D. Rabier & P. Kamoun

Authors
  1. J. M. Saudubray
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. De Lonlay
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Touati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Poggi-Travert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Bonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P. Jouvet
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Boutron
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Slama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Vianey-Saban
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J. P. Bonnefont
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D. Rabier
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P. Kamoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M. Brivet
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saudubray, J.M., Martin, D., De Lonlay, P. et al. Recognition and management of fatty acid oxidation defects: A series of 107 patients. J Inherit Metab Dis 22, 487–502 (1999). https://doi.org/10.1023/A:1005556207210

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005556207210

Keywords

Search

Navigation