Long-Chain Acyl CoA Dehydrogenase Deficiency Clinical Presentation
- Author: Fernando Scaglia, MD, FACMG; Chief Editor: Luis O Rohena, MD more...
See the list below:
- Acute metabolic crises precipitated by intercurrent infections usually present with hypoketotic hypoglycemia that may be accompanied by cardiomyopathy, hypotonia, and hepatomegaly. These metabolic crises occur more frequently in infancy and early childhood.
- Careful analysis of patients who presented with hypoglycemia revealed that most of them had a constellation of easily missed, nonspecific symptoms before the hypoglycemic episode.
- Many patients may present with myopathy characterized by profound weakness, which may also be accompanied by cardiomyopathy. According to a more recent retrospective study, three fourths of patients studied with trifunctional protein deficiency, including long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity (LCHAD) deficiency had long term myopathic symptoms.
- Some patients may present in infancy or childhood with myoglobinuria or as adults with exercise-induced muscle pains and rhabdomyolysis.
- Some patients present with peripheral sensorimotor polyneuropathy.
- Progressive visual loss has been documented in over 70% of cases with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
- Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy.
See the list below:
- Neurological examination
- The acute episode of hypoketotic hypoglycemic encephalopathy may begin with a seizure.
- Most patients are hypotonic, at least in infancy.
- Examination may reveal profound weakness, decreased movements, and a frog-leg position.
- Deep tendon reflexes may be absent in infancy.
- The patient may toe-walk and display an equinus deformity.
- Extensor plantar responses have been reported.
- Cardiac: Examination of the heart may reveal cardiomegaly, poor heart sounds, and gallop rhythm.
- Most patients have hepatomegaly.
- Jaundice may develop in infancy along with elevation of the transaminases.
- Ophthalmological examination
- In the youngest patients, the fundus may be pale. Thereafter, aggregation of pigment has been detected in the posterior pole and macular region.
- Progressive atrophy of the retinal pigment epithelium, choroid, neural retina, and retinal vessels follow initial pigment abnormalities. This may lead to a completely bare sclera in the central fundus.
- Posterior staphylomas and delicate lens opacities also may be observed. Cataracts have also been reported.
See the list below:
- A molecular defect that affects the mitochondrial trifunctional protein (MTP) causes long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
- Molecular defects are responsible for the 2 types of defect of MTP (ie, long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiencies, MTP deficiencies).
- The molecular defect affects the function of the MTP, which contains the activity of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.
- In most patients, the deficiency is isolated to long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity; yet, in some patients, defective activity of all 3 enzymes of the protein is observed.
- In isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency, most of the patients are homozygous for a guanine-to-cytosine transversion at position 1528, involving the alpha subunit of the MTP in the active site domain of the long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity encoding region. The nicotinamide adenine dinucleotide (NAD) cofactor-binding sequence resides in this region.
- Other mutations have been described, usually in compound with G1528C.
- MTP deficiency is caused by several mutations in either alpha or beta subunit DNA encoding regions with resulting decreased functioning of all 3 enzyme activities of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity.
Schiff M, Mohsen AW, Karunanidhi A, McCracken E, Yeasted R, Vockley J. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May. 109(1):21-7. [Medline]. [Full Text].
Scalais E, Bottu J, Wanders RJ, Ferdinandusse S, Waterham HR, De Meirleir L. Familial very long chain acyl-CoA dehydrogenase deficiency as a cause of neonatal sudden infant death: Improved survival by prompt diagnosis. Am J Med Genet A. 2014 Oct 22. [Medline].
Spiekerkoetter U, Lindner M, Santer R, et al. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis. 2009 Apr 29. [Medline].
[Guideline] Cunniff C. Prenatal screening and diagnosis for pediatricians. Pediatrics. 2004 Sep. 114(3):889-94. [Medline].
Stopek D, Gitteau Lala E, Labarthe F, et al. [Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency and choroidal neovascularization]. J Fr Ophtalmol. 2008 Dec. 31(10):993-8. [Medline].
Amirkhan RH, Timmons CF, Brown KO, Weinberger MJ, Bennett MJ. Clinical, biochemical, and morphologic investigations of a case of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Arch Pathol Lab Med. 1997 Jul. 121(7):730-4. [Medline].
Bertini E, Dionisi-Vici C, Garavaglia B, et al. Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency. Eur J Pediatr. 1992 Feb. 151(2):121-6. [Medline].
den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002 Jan. 109(1):99-104. [Medline]. [Full Text].
Dyke PC 2nd, Konczal L, Bartholomew D, McBride KL, Hoffman TM. Acute dilated cardiomyopathy in a patient with deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. Pediatr Cardiol. 2009 May. 30(4):523-6. [Medline].
Gillingham MB, Connor WE, Matern D, et al. Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2003 Jun. 79(2):114-23. [Medline].
Gillingham MB, Purnell JQ, Jordan J, Stadler D, Haqq AM, Harding CO. Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. 2007 Jan. 90(1):64-9. [Medline].
Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. 2006 Sep-Oct. 89(1-2):58-63. [Medline].
IJlst L, Wanders RJ, Ushikubo S, Kamijo T, Hashimoto T. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta. 1994 Dec 8. 1215(3):347-50. [Medline].
Jackson S, Bartlett K, Land J, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res. 1991 Apr. 29(4 Pt 1):406-11. [Medline].
Lawlor DP, Kalina RE. Pigmentary retinopathy in long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Ophthalmol. 1997 Jun. 123(6):846-8. [Medline].
Merritt JL 2nd, Vedal S, Abdenur JE, Au SM, Barshop BA, Feuchtbaum L, et al. Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening. Mol Genet Metab. 2014 Apr. 111(4):484-92. [Medline].
Olpin SE, Clark S, Andresen BS, et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005. 28(4):533-44. [Medline].
Pervaiz MA, Kendal F, Hegde M, Singh RH. MCT oil-based diet reverses hypertrophic cardiomyopathy in a patient with very long chain acyl-coA dehydrogenase deficiency. Indian J Hum Genet. 2011 Jan. 17(1):29-32. [Medline]. [Full Text].
Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. 1995 Nov. 10 Suppl 2:S8-24. [Medline].
Pons R, Roig M, Riudor E, et al. The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Neurol. 1996 Apr. 14(3):236-43. [Medline].
Rocchiccioli F, Wanders RJ, Aubourg P, et al. Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. Pediatr Res. 1990 Dec. 28(6):657-62. [Medline].
Roe CR, Roe DS, Wallace M, Garritson B. Choice of oils for essential fat supplements can enhance production of abnormal metabolites in fat oxidation disorders. Mol Genet Metab. 2007 Dec. 92(4):346-50. [Medline].
Sewell AC, Bender SW, Wirth S, Munterfering H, Ijlist L, Wanders RJ. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a severe fatty acid oxidation disorder. Eur J Pediatr. 1994 Oct. 153(10):745-50. [Medline].
Spiekerkoetter U, Sun B, Zytkovicz T, Wanders R, Strauss AW, Wendel U. MS/MS-based newborn and family screening detects asymptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2003 Sep. 143(3):335-42. [Medline].
Takahashi Y, Sano R, Nakajima T, Kominato Y, Kubo R, Takahashi K, et al. Combination of postmortem mass spectrometry imaging and genetic analysis reveals very long-chain acyl-CoA dehydrogenase deficiency in a case of infant death with liver steatosis. Forensic Sci Int. 2014 Sep 6. [Medline].
Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology. 1994 Feb. 19(2):339-45. [Medline].
Tyni T, Majander A, Kalimo H, Rapola J, Pihko H. Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation. Neuromuscul Disord. 1996 Oct. 6(5):327-37. [Medline].
Tyni T, Pihko H. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr. 1999 Mar. 88(3):237-45. [Medline].
Wanders RJ, IJlst L, van Gennip AH, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 1990. 13(3):311-4. [Medline].
Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet. 1993 Feb 13. 341(8842):407-8. [Medline].