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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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Dysfunction of iron utilization - Letter to the Editor
From Townsend Letter for Doctors and Patients, 11/1/03 by Judy Kitchen


Dysfunction of iron utilization, excess iron and iron deficiency are conditions that are sadly becoming more common. (1-3) The absorption of iron, which depends on sufficient gastric acidity, is often misunderstood. (3) A stomach pH of at least 4.0 is required to free iron from food and to convert the most common form of dietary iron, ferric iron, to the more absorbable, ferrous form. (2) Ninety percent of consumed iron remains unabsorbed, (4) (unless one has an inborn or acquired error of metabolism, an iron deficiency, or a malignancy, when more iron is absorbed). (1,2) Heme iron, found only in animal products, is more bioavailable (12-20%) when it hasn't been cooked. Prolonged cooking at high temperatures reduces its absorption by 40% (Bothwcll et al. 1989). (5)

To be useful, iron has to be joined to a protein. (3,6) Liquid crystalloid electrolytes of copper, manganese, molybdenum and also vitamin, A and the B complex are required to complete iron absorption. (4,6) Heme iron (the iron--porphyrin complex) is absorbed intact, but the iron in heme alone is not absorbed as efficiently as, for example, the iron in liver from range fed cattle. (5-7) Protein, amino acids and vitamin C bind onto the nonheme iron ion and carry it across the walls of the duodenum and jejunum. (2-5) Ascorbic acid (vitamin C) reduces ferric iron to ferrous iron, thereby increasing its absorption by as much as 30%. (4,6), (7) However, high doses of vitamin C deplete calcium and copper; both of these minerals must be present for iron to function properly. (4) All of the aforementioned minerals need a healthy level of stomach acid for their assimilation, unless they are unprocessed and unheated. (8,9)

The large majority (80%) of patients with iron-deficiency anemia have been found to have low stomach acidity. (8) When supplementary HCl is given to anemic people with hypochlorhydria, their anemia disappears. (8) A vegetarian diet can also cause anemia. (2) The most soluble supplemental iron for a vegetarian is a ferrous salt, respectively ferrous succinate, ferrous lactate, ferrous glycine sulfate or ferrous fumarate. (8,8b) However, even a ferrous supplement forms insoluble salts when taken with certain alkali or antacids. (4,8) For example, calcium carbonate (Tums) binds with the ferrous salt to form insoluble ferric carbonate, thus reducing iron absorption by at least 67%. (8) The higher the antacid or alkali dose, the greater the reduction in the absorption of iron. (8)

Once stored, iron may be used repeatedly. (4,10) But iron overload is toxic, induces oxidative damage, and also causes a mild to moderate anemia. (2,4,6) Iron supplements should only be taken when there is an iron deficiency. (6,10) Removal of excess iron is most difficult. (10) In severe cases a patient may need phlebotomy or chelation therapy. (2) Excesses of copper, zinc, manganese and some toxic metals can be excreted in bile, whereas iron cannot. (10) However, chronic physical and emotional stress have been shown to cause a greater loss of iron (44%) than any other trace mineral tested. (9,11) Average daily absorption of iron in developed countries is up to 2mg a day; healthy individuals need an average of 20 to 25mg of iron each day. (2) Therefore, about 95% of the iron required needs to be recycled iron. (11)

With low gastric activity, the iron is often stored, but is inaccessible because of infections, inflammation, toxicities and deficiencies. (6,9) For example, with an iron deficiency there are initially higher levels of transferrin, the transport protein that carries iron to the tissues and also to the membranes of developing blood cells. (2,9) Elevated transferrin levels cause cholesterol to crystallize rapidly and form gallstones. (9) Eventually, hypochlorhydria's deficiencies interfere with the liver's synthetic pathways resulting in a reduction in serum transferrin. (2,9) These deficiencies also cause transferrin to transport aluminum, as well as iron, to the brain's oligodendrocytes, thus increasing the brain's lipid peroxidative damage. (2,9) The greater the hepatic dysfunction, the more pronounced the deficiency of transferrin. (2) Significantly, transferrin is also required to release iron from the storage compound, ferritin. (2) Furthermore, a serious problem may develop in the bloodstream, with a progressive deficiency of the transport protein hemopexin, which normally binds iron that has been oxidized and transports it to the liver. (2,12) Consequently the oxidized iron accumulates in the bloodstream causing ongoing free radical damage to red blood cells and to the vasculature. (9,12) The production and proper function of all endogenous proteins depend on the minerals (such as iron), coenzymes and amino acids that sufficient stomach acid provides. (12-15)

Recent research has revealed that an iron deficiency causes a heme deficiency, resulting in oxidative damage to mitochondria, with the consequent loss of mitochondrial function and the loss of mitochondrial DNA. (15) A heme deficiency also occurs when iron cannot be utilized for the aforementioned reasons. (2) The production of hydrochloric acid in the oversized mitochondria of the parietal cells in the stomach's lining would certainly be adversely affected by a deficiency of heme. (9,15) Both an increase in excess free radical activity and a decrease in the production of heme, cause or exacerbate low gastric activity in many ways, leading eventually to achlorhydria and a great deal of unnecessary suffering. (16)


1. Teitelbaum, Jacob, MD, Jump-Starting Your Body's Energy Furnaces, Part 3, The Importance of Nutrition in Fatigue and Pain, Townsend Letter for Doctors & Patients, May 2003 #238.

2. Harmening, Denise M., Clinical Hematology and Fundamentals of Hemostasis, Third Edition, F.A., Davis Company, Philadelphia 1997.

3. Redmon, George L., PhD, ND, Minerals: What Your Body Really Needs and Why, Avery, NY 1999.

4. Duane, Lavon, Nutrition Almanac 3rd Edition, McGraw-Hill, NY 1990.

5. FAO/WHO, Bioavailability of Heme iron, 1988.

6. Balch, James, MD, Balch, Phyllis, CNC, Prescription for Nutritional Health 3rd Edition, Avery Publishing, NY 2000.

7. Murray, Michael, ND, Pizzorno, Joseph, ND, Encyclopedia of Natural Medicine, Revised 2nd Edition, Prima Publishing 1998.

8. Wright, Jonathan V., MD, Lane, Lenard, PhD, Why Stomach Acid is Good For You. M. Evans and Company, Inc., New York 2001.

8b. Passwater, Richard A., PhD, Cranton, Elmer M., M.D., Trace Elements, Hair Analysis and Nutrition, Keats Publishing, Connecticut 1983.

9. Kitchen, Judy, Hypochlorhydria: A Review, Townsend Letter for Doctors & Patients, October, 2001.

10. Schroeder, Henry A., MD, The Trace Elements and Man, The Devin-Adair Company, Connecticut 1973.

11. Martlew, Gillian, ND, Electrolytes--The Spark of Life, Nature's Publishing, Ltd., Florida 1994.

12. Ullmann, Ronald, Biochemist, A Modern Scientific Perspective on Prof. Dr. Enderlein's Concept of Microbial Life Cycles, Townsend Letter for Doctors & Patients, May 2003 #238.

13. Naturopathic Research Laboratories, Informational Literature, Florida.

14. Cichoke, Anthony J., MA, DC, DACBN, The Complete Book of Enzyme Therapy, Avery Publishing, NY 1999.

15. Atamna, Hani, Liu, Jiankang, Ames, Bruce N., PhD, Heme Deficiency Selectively Interrupts Assembly of Mitochondrial Complex IV in Human Fibroblasts, The American Society for Biochemistry and Molecular Biology, 2001.

16. Kitchen, Judy, Niacin, Heme Synthesis and Porphyria, Townsend Letter for Doctors & Patients, June 2003, #239.

Judy Kitchen

3637 Serra Road

Malibu, California 90265 USA

310-456-6837 (phone/fax)

COPYRIGHT 2003 The Townsend Letter Group
COPYRIGHT 2004 Gale Group

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