Abstract
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is an autosomal recessive disorder of mitochondrial fatty acid oxidation. Apart from life-threatening metabolic derangement with hypoketotic hypoglycemia, patients often show liver disease, cardiomyopathy, and neuropathy. A common mutation (1528G>C) in the gene coding for the α-subunit of the mitochondrial trifunctional protein harboring LCHAD activity is found in 87% of the alleles of patients. LCHAD is considered a rare disorder with only 63 patients reported in the literature. Whether this is due to a truly low prevalence of the disorder or because many patients remain unrecognized as a result of aspecific symptomatology is not clear. A remarkable association between LCHAD deficiency and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, which is a severe complication of pregnancy, has been reported. Because of this, we studied the frequency of the common LCHAD mutation in the Dutch population by analyzing 2047 Guthrie cards and 113 women who had suffered from HELLP syndrome. To be able to perform this large-scale study in dried bloodspots, we developed a new sensitive PCR-restriction fragment length polymorphism method. The carrier frequency for the common LCHAD mutation in the Dutch population was found to be low (1:680), consistent with the observed low incidence of the disorder. In the group of women with a history of HELLP syndrome, the prevalence of the common LCHAD mutation was also low (1:113). We conclude that LCHAD deficiency is, indeed, a rare disorder and that heterozygosity for the common mutation is not a major cause of the HELLP syndrome.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- AFLP:
-
acute fatty liver of pregnancy
- HELLP:
-
hemolysis elevated liver enzymes and low platelets
- LCHAD:
-
long-chain 3-hydroxyacyl-CoA dehydrogenase
- MCAD:
-
medium-chain acyl-CoA dehydrogenase
- PCR-RFLP:
-
PCR-restriction fragment length polymorphism
References
Roe CR, Coates PM 1995 Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 7th Ed. McGraw-Hill, New York, 1510–1515.
Tynii T, Palotie A, Viinikka L, Valanne L, Salos MK, von Dobeln U, Jackson S, Wanders RJA, Venizelos N, Pihko H 1997 Long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of 13 patients. J Pediatr 130: 67–76.
Pons R, Roig M, Riudor E, Ribes A, Briones P, Ortigosa L, Baldellou A, Gil-Gibernau J, Olesti M, Navarro C, Wanders RJA 1996 The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Neurol 14: 236–243.
Bertini E, Dionici-Vici C, Garavaglia B, Burlina AB, Sabatelli M, Rimoldi M, Bartuli A, Sabetta G, DiDonato S 1992 Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxyacyl CoA dehydrogenase deficiency. Eur J Pediatr 151: 121–126.
Dionisi Vici C, Burlina AB, Bertini E, Backmann C, Mazziotta MRM, Sabatelli G, Hale DE 1991 Progressive neuropathy and recurrent myoglobinuria in a child with long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. J Pediatr 118: 744–746.
Duran M, Wanders RJA, de Jager JP, Dorland L, Bruinvis L, Ketting D, IJlst L, van Sprang FJ 1990 3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment. Eur J Pediatr 150: 190–195.
Millington DS, Terada N, Chace DH, Chen YT, Ding JH, Kodo N, Roe CR 1992 The role of tandem mass spectrometry in the diagnosis of fatty acid oxidation disorders. Prog Clin Biol Res 375: 339–354.
IJlst L, Mandel H, Oostheim W, Ruiter JP, Gutman A, Wanders RJA 1998 Molecular basis of hepatic carnitine palmitoyltransferase I deficiency. J Clin Invest 102: 527–531.
Wanders RJA, IJlst L, Poggi I, Bonnefont JP, Munnich A, Brivet M, Rabier M, Saudubray JM 1992 Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid β-oxidation. Biochem Biophys Res Commun 188: 1139–1145.
Wanders RJA, IJlst L, van Gennip AH, Jakobs C, de Jager JP, Dorland L, van Sprang FJ, Duran M 1990 Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 13: 311–314.
Zhang QX, Baldwin GS 1994 Structures of the human cDNA and gene encoding the 78 kD gastrin-binding protein and of a related pseudogene. Biochim Biophys Acta 1291: 567–575.
IJlst L, Ruiter JPN, Hoovers JMN, Jakobs ME, Wanders RJA 1996 Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Clin Invest 98: 1028–1033.
IJlst L, Wanders RJA, Ushikubo S, Kamijo T, Hashimoto T 1994 Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the α-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta 1215: 347–350.
Sims HF, Brackett JC, Powell CK, Treem WR, Hale DE, Bennett MJ, Gibson B, Shapiro S, Strauss AW 1995 The molecular basis of pediatric long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci USA 92: 841–845.
Treem WR, Shoup ME, Hale DE, Bennett MJ, Rinaldo P, Millington DS, Stanley CA, Riely CA, Hyams JS 1996 Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Gastroenterol 91: 2293–2300.
Wilcken B, Leung K, Hammond J, Kamath R, Leonard JV 1993 Pregnancy and fetal long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Lancet 341: 407–408.
Geary M 1997 The HELLP syndrome. Br J Obstet Gynaecol 104: 887–891.
Rolfes DB, Ishak KG 1985 Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. Hepatology 5: 1149–1158.
Treem WR, Rinaldo P, Hale DE, Stanley CA, Millington DS, Hyams JS, Jackson S, Turnbull DM 1994 Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Hepatology 19: 339–345.
Schoeman MN, Batey RG, Wilcken B 1991 Recurrent acute fatty liver of pregnancy associated with fatty-acid oxidation defect in the offspring. Gastroenterology 100: 544–548.
Walsh PS, Metzger DA, Higuchi R 1991 Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 10: 506–513.
Parker RA, Philips JA III 1994 Population screening for carrier status: effects of test limitations on precision of carrier prevalence rates. Am J Med Genet 49: 317–322.
Sibai BM 1990 The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?. Am J Obstet Gynecol 162: 311–316.
Iafolla AK, Thompson RJ, Roe CR 1994 Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children. J Pediatr 124: 409–415.
Gregersen N, Winter V, Curtis D, Deufel T, Mack M, Hendrickx J, Willems PJ, Ponzone A, Parella T, Ponzone R, Ding JH, Zhang W, Chen YT, Kahler S, Kolvraa S, Schneidermann AK, Andresen BS, Bross P, Bolund L 1993 Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Hum Hered 43: 342–350.
de Vries HG, Niezen-Koning K, Kliphuis JW, Smit GPA, Schepper H, ten Kate LP 1996 Prevalence of carriers of the most common medium-chain acyl-CoA dehydrogenase (MCAD) deficiency mutation (G985A) in The Netherlands. Hum Genet 98: 1–2.
Ding J, Yang B, Nada MA, Roe CR 1996 Improved detection of the G1528C mutation in LCHAD deficiency. Biochem Mol Med 58: 46–51.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Den Boer, M., Ijlst, L., Wijburg, F. et al. Heterozygosity for the Common LCHAD Mutation (1528G>C) Is Not a Major Cause of HELLP Syndrome and the Prevalence of the Mutation in the Dutch Population Is Low. Pediatr Res 48, 151–154 (2000). https://doi.org/10.1203/00006450-200008000-00006
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-200008000-00006
This article is cited by
-
Genetic diversity in Kashubs: the regional increase in the frequency of several disease-causing variants
Journal of Applied Genetics (2022)
-
Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Orphanet Journal of Rare Diseases (2018)
-
Acute Fatty Liver Disease of Pregnancy: Updates in Pathogenesis, Diagnosis, and Management
American Journal of Gastroenterology (2017)
-
Urgent metabolic service improves survival in long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening
Journal of Inherited Metabolic Disease (2011)
-
A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency in Poland
Journal of Inherited Metabolic Disease (2010)
