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Inborn error of metabolism

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases, and these terms are considered synonymous. more...

ICF syndrome
Ichthyosis vulgaris
Imperforate anus
Inborn error of metabolism
Incontinentia pigmenti
Infant respiratory...
Infantile spinal muscular...
Infective endocarditis
Inflammatory breast cancer
Inguinal hernia
Interstitial cystitis
Iodine deficiency
Irritable bowel syndrome

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century. He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.

Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.

  • Disorders of carbohydrate metabolism
    • E.g., glycogen storage disease (E74.0)
  • Disorders of amino acid metabolism
    • E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0)
  • Disorders of organic acid metabolism
    • E.g., alcaptonuria (E70.2)
  • Disorders of fatty acid oxidation and mitochondrial metabolism
    • E.g., medium chain acyl dehydrogenase deficiency
  • Disorders of porphyrin metabolism
    • E.g., acute intermittent porphyria (E80.2)
  • Disorders of purine or pyrimidine metabolism
    • E.g., Lesch-Nyhan syndrome (E79.1)
  • Disorders of steroid metabolism
    • E.g., congenital adrenal hyperplasia (E25.0)
  • Disorders of mitochondrial function
    • E.g., Kearns-Sayre syndrome (H49.8)
  • Disorders of peroxisomal function
    • E.g., Zellweger syndrome (Q87.8)
  • Lysosomal storage disorders
    • E.g., Gaucher's disease (E75.22)

Manifestations and presentations

Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems:

  • Growth failure, failure to thrive, weight loss
  • Ambiguous genitalia, delayed puberty, precocious puberty
  • Developmental delay, seizures, dementia, encephalopathy, stroke
  • Deafness, blindness, pain agnosia
  • Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
  • Dental abnormalities
  • Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
  • Many forms of cancer
  • Recurrent vomiting, diarrhea, abdominal pain
  • Excessive urination, renal failure, dehydration, edema
  • Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
  • Hepatomegaly, jaundice, liver failure
  • Unusual facial features, congenital malformations
  • Excessive breathing (hyperventilation), respiratory failure
  • Abnormal behavior, depression, psychosis
  • Joint pain, muscle weakness, cramps
  • Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus


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Folate and homocysteine levels in pregnancy
From British Journal of Biomedical Science, 1/1/04 by Megahed, Magda A


This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18-24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P

KEY WORDS: Folic acid. Homocysteine. Pregnancy.


Folate, a member of the B-vitamin family, is a polyglutamate compound. Folate plays an important role in two biochemical cycles: one involving DNA biosynthesis and the other involving one-carbon metabolism (DNA, lipid and protein methylation).1 In addition, folate is a substrate for the enzymatic conversion of many amino acids and in vitamin metabolism. Folate is needed for normal embryonic development and growth, and deficiency has been associated with the development of neural tube defects and low birthweight. Maternal folate deficiency remains a frequent and mostly unrecognised disorder, and is associated with recurrent miscarriage, placental abruption and intrauterine growth restriction.2

Recent reports indicate that concentrations of folate in maternal serum, plasma and red blood cells decrease from the fifth month of pregnancy onwards, and continue to decrease during the weeks after pregnancy such that by the second to third post-partum month a third of all mothers can have subnormal concentrations of folate in serum and red blood cells.3 By the sixth post-partum month, 20 % of mothers remain deficient of folate.4

Homocysteine is a sulphur-containing amino acid that is a demethylated derivative of methionine. Homocysteine is metabolised via two main pathways: remethylation to methionine or transulphuration to cystathionine and then to cysteine. A defect in either leads to an accumulation of circulating homocysteine.

The defect may be congenital, due to an inborn error of cystathionine-B- synthetase, or to homozygosity for a C[arrow right]T mutation of nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) gene.5 Other reasons for mild hyperhomocysteinaemia are nutrient-related: deficiencies of folate, vitamin B12 or vitamin B6 cause homocysteine to accumulate because remethylation to methionine requires folate and vitamin B12, and transulphuration to cystathionine requires vitamin B6.6

Plasma homocysteine is normally lower during pregnancy,7 and Vollset et al.8 reported that hyperhomocysteinemia may be an important marker for, and possibly a cause of or contributor to, complications and an adverse outcome of pregnancy. Thus, the purpose of this study is to determine serum folate and plasma homocysteine levels in normal pregnant women following short (six months or less) or long (18-24 months) interpregnancy intervals.

Materials and methods

Both verbal and written informed consents was received from all participants in the study.

Fifty healthy gravid multiparous women were included who were non-smokers, had no history of hypertension, no personal or family history of deep venous thrombosis, no prior significant illnesses, no vitamin deficiency, and were not receiving any medication. None of subjects studied had a history of liver disease, or signs and symptoms of nutritional deficiency. Women with a history of neural tube defects were excluded.

Twenty-five normal non-pregnant control female subjects of comparable age and socioeconomic state, and not receiving hormonal contraception, were included as a control group (group I). The pregnant women were divided according to the length of interpregnancy interval into group II (six months or less) and group III (18-24 months).

A detailed history was taken and thorough clinical examination and ultrasonography were performed. The women were asked not to take routine daily multivitamin supplementation two days before the date of sampling. Venous blood samples were taken only once, at 36 weeks' gestation in groups II and III, and from those in the control group.

Venous blood was drawn from the antecubital vein. Samples for red blood cell folate9 and homocysteine10 determination were collected in potassium EDTA and plasma was stored at -20°C until analysis. Blood samples for vitamin B12,9 serum folate9 and albumin11 were collected in plain tubes. After coagulation, samples were centrifuged for 10 min at 3000 xg to separate the serum, and this was stored at -20 °C until analysis.

Tests for haemoglobin12 and haematocrit13 were performed to exclude anaemia. Liver function tests included serum aminotransferases (ALT and AST).14

Student's t-test was used for comparisons between the groups. Correlations between homocysteine and both serum albumin and red cell folate were also examined.


Table 1 illustrates the haemoglobin concentration, haematocrit and ALT and AST activities. No significant change in these parameters was seen in groups II and III compared to the control group. Table 2 demonstrates that there was a significant decrease in red cell folate and serum folate in group II compared to the control group (P

There was a significant positive correlation between homocysteine and serum albumin in the three groups studied (r=0.42, P


It has been reported that a relative folate shortage may be equally as damaging as a deficiency.15 Such an observation could explain the presence of cases of intrauterine growth retardation in group II in the present study, as it is documented that folate deficiency results in impairment of cell proliferation and folate-dependent vitamin and amino acid metabolism.

The remethylation of homocysteine into the amino acid methionine is blocked by a lack of folate, which results in hyperhomocysteinaemia;16 however, increased homocysteine concentration can be corrected easily by low-dose folate supplementation. It is recognised that hyperhomocysteinaemia produces thrombogenesis, vasodilation and endothelial damage, and is associated with cardiovascular and cerebrovascular disease, as well as recurrent miscarriage, placenta! abruption, pre-eclampsia, intrauterine growth restriction and perinatal death.

Khong and Hague17 demonstrated deficient trophoblast-induced physiological vascular changes, acute atherosis, intrauterine endovascular trophoblasts in the third trimester, infarction, retroplacental haematoma formation, and accelerated villous maturity. Uteroplacental vascular thrombosis was also seen. They attributed these features to a combination of increased apoptosis, endothelial damage and thrombosis secondary to folate deficiency and hyperhomocysteinaemia.

Higgins et al.18 demonstrated that folate catabolism is increased significantly during normal pregnancy. The rate of folate catabolism peaks in the third trimester and falls sharply in the days following delivery. This corresponds with the period of maximal increase in fetal mass. This peak rate is more than twice the rate found in the non-pregnant group.

Alteration in methionine metabolism in humans due to folate or vitamin B12 shortage may play a role in the aetiology of neural tube defect, recurrent miscarriage, placental infarct and placental abruption.19 The causes of these complications of pregnancy may be traced to the first gestational weeks.20

Methionine is essential for cell proliferation and DNA and transfer RNA (tRNA) methylation. It is converted to S-adenosylmethionine and, following decarboxylation, this methyl donor is the source of the 3-carbon moieties of the polyamines spermidine and spermine. In addition, S-adenosylmethionine is involved in the methylation of DNA.21 The homocysteine derived from methionine is normally present in blood in low concentration, and elevated intracellular and extracellular levels may be cytotoxic; however, whether or not elevated circulating levels of homocysteine are embryotoxic remains unknown.22

The results obtained in the present study are consistent with previous reports.7 The decrease in homocysteine in the pregnant groups could be attributed to the significant decrease in albumin and the significant positive correlation between albumin and homocysteine (Table 2).

In vitro studies in the rat suggest that the embryotoxic effect of L-homocysteine is due to inhibition of methyl donation by S-adenosylmethionine.23 Also, the effect of homocysteine toxicity on vascular endothelium of the spiral or yolk sac arteries cannot be excluded. The development of neural tube defect might be explained partly by the decreased availability of methionine, folate and cobalamin, and the subsequent derangement of methionine metabolism during early human pregnancy, resulting in decreased DNA synthesis and distorted cell proliferation. The prevention of neural tube defect by periconceptional folate supplementation might be explained, in part, by the correction of disturbed methionine metabolism.24

A further possible mechanism for the reduction in homocysteine level during pregnancy is utilisation by the fetus. A decreasing plasma homocysteine concentration gradient exists from the maternal vein to the umbilical artery, suggesting incorporation of homocysteine into the fetal metabolic cycle.25

Hyperhomocysteinaemia is associated with obstetric complications such as placental abruption, pre-eclampsia, neural tube defect, stillbirth and recurrent miscarriage.26 The mechanisms involved remain unknown but there is experimental evidence to indicate that hyperhomocysteinaemia causes endothelial dysfunction.27

In vitro studies suggest that this dysfunction is mediated through the generation of potent reactive oxygen species, in particular hydrogen peroxide.28 In vivo, homocysteinaemia alters the effect of many clotting proteins on the endothelial cell surface, leading to a prothrombotic environment.29 Thus, it is conceivable that hyperhomocysteinaemia could affect placental function or maternal uteroplacental perfusion via any of these mechanisms.30

Studies of athersclerosis have shown that a graded risk of vascular disease is associated with increasing homocysteine level;31 thus, reduction of high-normal levels of homocysteine may provide benefit. Potentially, folic acid supplementation in pregnancy could reduce the risk of obstetric complications related to high levels of homocysteine.(30)

Folate deficiency can be explained by the hypothesis proposed by Smits and Essed.32 They suggest that maternal folate concentration decreases from the fifth month of pregnancy, and continues to do so during the first post-partum months, irrespective of lactation. If a subsequent pregnancy commences after a sufficiently long restorative period, the probability of maternal folate deficiency is equivalent to that of a first pregnancy. However, they concluded that commencement of a further pregnancy before complete folate restoration has taken place will result in a higher risk of maternal folate deficiency.

Concentrations of other micronutrients such as zinc and vitamins A, B6 and B12 also fall during pregnancy but they return to normal within a few weeks following delivery and/or do not affect the outcome of pregnancy.3,4,33,34 Thus, folate deficiency appears to be the most important nutritional factor associated with the higher risk of poor pregnancy outcome after a short interpregnancy interval.32

Furthermore, a two-fold increase in the risk of neural tube defect was observed for pregnancies conceived within six months of a previous live birth.35 Also, the effect of short interpregnancy interval on the risk of smallness for gestational age also has been documented.36

In conclusion, pregnancy following a short interpregnancy interval is more likely to involve folate deficiency, and thus supplementation is highly recommended. Also, the value of health education about the prevention of folate deficiency, which is associated with the occurrence of neural tube defect, should be stressed.

Clearly, educational strategies are required to increase folate awareness among women and to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods needs to be defined and monitored.


1 Hague WM. Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol 2003 ; 17(3): 459-69.

2 Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000; 71 (5 Suppl): 1295S-303S.

3 Ackurt F, Wetherilt H, Loker M, Hacibektro M. Biochemical assessment of nutritional status in pre- and post-natal Turkish women and outcome of pregnancy. Eur J Clin Nutr 1995; 49: 613-22.

4 Bruinse HW, Van den Berg H. Changes of some vitamin levels during and after normal pregnancy. Eur J Obstet Gynecol Reprod Biol 1995; 61: 31-7.

5 Mudd SH, Levy HL, Skovby F. Disorders in transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of molecular disease. New York: McGraw-Hill, 1995: 1279-327.

6 Picciano MF. Is homocysteine a biomarker for identifying women at risk of complications and adverse pregnancy outcomes? Am J Clin Nutr 2000; 71: 857-8.

7 Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 1999; 180: 660-4.

8 Vollset SE, Refsum H, Irgens LM et al. Plasma total homocysteine, pregnancy complications and adverse pregnancy outcomes: The Hordaland Study. Am J Clin Nutr 2000; 71: 962-8.

9 Dawson DW, Delamore IW, Fish DI et al. An evaluation of commercial radioisotope methods for the determination of folate and vitamin B12. J Clin Pathol 1980; 33: 234-42.

10 Frantzen F, Faaren AL, Alfheim I, Nordhei AK. An enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem 1998; 44: 311-6.

11 Peters T Jr, Biamonte GT, Doumas BT. Protein (total protein) in serum, urine and cerebrospinal fluid, albumin in serum. In: Faulkner WR, Meites S, eds. Selected methods of clinical chemistry (Vol. 9). Washington DC: American Association for Clinical Chemistry, 1982.

12 International Committee for Standardization in Haematology. Recommendation for haemoglobinometry in human blood (ICSH standard EP 6/2: 1977) and specifications for international haemoglobincyanide preparation (ICSH standard EP 6/3: 1977). J Clin Palhol 1978; 31: 139-43.

13 Williams WJ. Examination of the blood. In: Williams WJ, Buetler E, Erslev AJ, Lichtman MA, eds. Hematology (3rd edn). New York: McGraw-Hill, London, 1983: 9-24.

14 Wilkinson JH, Baron DN, Moss DW, Walker PG. Standardization of clinical enzyme assays. A reference method for aspartate and alanine transaminases. J Clin Pathol 1972; 25: 940.

15 Pietrzik KF, Thorand B. Folate economy in pregnancy. Nutrition 1997; 13: 975-7.

16 Steegers-Theunissen RPM, Smith SC, Steegers EAP, Guilbert LJ, Baker PN. Folate affects apoptosis in human trophoblastic cells. Br J Obstet Cynaecol 2000; 107: 1513-5.

17 Khong TY, Hague WM. The placenta in maternal hyperhomocysteinemia. Br J Obstet Gynaecol 1999; 106: 273-8.

18 Higgins JR, Quinlan EP, McPartlin J, Scott JM, Weir DG, Darling MRN. The relationship between increased folate catabolism and the increased requirement for folate in pregnancy. Br J Obstet Gynaecol 2000; 107: 1149-54.

19 Steegers-Theunissen RPM, Boers GHJ, Blom HJ et al. Neural tube defects and elevated homocysteine levels in amniotic fluid. Am J Obstet Gynecol 1995; 172: 1436-41.

20 Steegers-Theunissen RPM, Wathen NC, Eskes TKAB, Raaij-Selten BV, Chard T. Maternal and fetal levels of methionine and homocysteine in early human pregnancy. Br J Obstet Gynaecol 1997; 104: 20-4.

21 Seyoum G, Persaud TV In vitro effects of S-adenosyl methionine on ethanol embryopathy in the rat. Exp Toxicol Pathol 1994; 46: 177-81.

22 Starkebaum G, Harlan JM. Endothelial cell injury due to coppercatalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370-6.

23 Acrtsvan LAGJM, Blom HJ, Abreu de RA et al. Prevention of neural tube defects by and toxicity of L-homocysteine in cultured post-implantation rat embryos. Teratology 1994; 50: 348-60.

24 Mills JL, McPartlin JM, Kirke PN et al. Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 1995; i: 149-51.

25 Malinow MR, Rajkovic A, Duell PB, Hess DL, Upson BM. The relationship between maternal and neonatal umbilical cord plasma homocysteine suggests a potential role for maternal homocysteine in fetal metabolism. Obstet Gynecol 1998; 178: 228-33.

26 Den Heijer M, Koster T, Blom HJ et al. Hyperhomocysteinemia as a risk factor for deep vein thrombosis. N Engl J Med 1996; 334: 759-62.

27 Chambers JC, McCregor A, Jean-Marie J. Kooner JS. Acute hyperhomocysteinemia and endothelial dysfunction [Letter]. Lancet 1997; 351: 36-7.

28 Welch GN, Upchurch G Jr, Loscalzo J. Hyperhomocysteinemia and atherothrombosis. Ann N Y Acad Sci 1997; 811: 48-58.

29 Rodgers CM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990; 75: 895-901.

30 Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 1999; 180: 660-4.

31 Selhub J, Jacques PF, Bostom AG. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332: 286-91.

32 Smits LJM, Essed GGM. Short interpregnancy intervals and unfavourable pregnancy outcome: role of folate depletion. Lancet 2001; 358(9298): 2074.

33 Tamura T, Goldenberg RL, Johnston KE, Dubard M. Maternal plasma zinc concentrations and pregnancy outcome. Am I Clin Nutr 2000; 71:109-13.

34 Bendich A. Micronutrients in women's health and immune function. Nutrition 2001; 17(10): 858-67.

35 Todoroff K, Shaw GM. Prior spontaneous abortion, prior elective termination, interpregnancy interval and risk of neural tube defects. Am J Epidemiol 2000; 151: 505-11.

36 Zhu BPl, Rolfs RT, Nangle BE, Horan JM. Effect of the interval between pregnancies on perinatal outcomes. N Engl J Med 1999; 340: 589-94.


Department of Biochemistry, Medical Research Institute; and * Department of Obstetrics and Gynaecology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Accepted: 20 January 2004

Correspondence to: Dr Magda A. Megahed

Department of Biochemistry, Medical Research Institute, 165 El-Horreya Avenue, Alexandria 21561, Egypt.


Copyright Step Publishing Ltd. 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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