Institute of Human Genetics

  Publications | Conferences | Careers | Contact Us
News & Updates
Biochemical Genetics

Inborn errors of metabolic Disorders (IEM)

IEM comprise of a large group of genetic disorders involving abnormal metabolism of carbohydrates, fat, protein, amino acid, organic acid, nucleic acid and various others. The majority are due to single gene defects that code for specific metabolites to facilitate conversion of various substances into other active products. In most of the IEM 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.

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in the early 20th century (1908). He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on 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
  • Disorders of amino acid metabolism
    • e.g., phenylketonuria, maple syrup urine disease, glutaric acidemia type 1
  • Urea Cycle Disorder or Urea Cycle Defects
    • e.g., Carbamoyl phosphate synthetase I deficiency
  • Disorders of organic acid metabolism (organic acidurias)
    • e.g., alcaptonuria
  • Disorders of fatty acid oxidation and mitochondrial metabolism
    • e.g., Medium-chain acyl-coenzyme A dehydrogenase deficiency (often shortened to MCADD.)
  • Disorders of porphyrin metabolism
    • e.g., acute intermittent porphyria
  • Disorders of purine or pyrimidine metabolism
    • e.g., Lesch-Nyhan syndrome
  • Disorders of purine or pyrimidine metabolism
    • e.g., Lesch-Nyhan syndrome
  • Disorders of steroid metabolism
    • o e.g., lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia
  • Disorders of mitochondrial function
    • e.g., Kearns-Sayre syndrome
  • Disorders of peroxisomal function
    • e.g., Zellweger syndrome
  • Lysosomal storage disorders : There are nearly 40 storage disorders with most common one of
    • Gaucher's disease, Niemann Pick disease, Tay Sachs and many different Mucopolysaccharide disorders


In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 1,400 births,[1] overall representing more than approximately 15% of single gene disorders in the population.[1]

Type of inborn error


Disease involving amino acids (e.g. PKU), organic acids,
primary lactic acidosis, galactosemia, or a urea cycle disease

24 per 100 000 births[1]

1 in 4,200[1]

Lysosomal storage disease

12 per 100 000 births [2]

1 in 7000 [2]

Peroxisomal disorder

~3 to 4 per 100 000 of births[1]

~1 in 30,000[1]

Respiratory chain-based mitochondrial disease

~3 per 100 000 births[1]

1 in 33,000[1]

Glycogen storage disease

2.3 per 100 000 births[1]

1 in 43,000[1]

Signs and symptoms

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: many manifestations may develop

  • Growth failure, failure to thrive, weight loss
  • Ambiguous genitalia, delayed puberty, precocious puberty
  • Developmental delay, seizures, dementia, encephalopathy, stroke
  • Deafness, blindness, pain amnesia
  • Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
  • Dental abnormalities
  • Immunodeficiency, thrombocytopenia, anemia, splenomegaly, 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


Many congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. There is a revolutionary GC/MS based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 genetic metabolic disorders.
Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

  • Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)
  • Ninhydrin paper chromatography (detected abnormal amino acid patterns)
  • Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, GC/MS or molecular analysis.
  • Quantitative measurement of amino acids in plasma and urine
  • Urine organic acid analysis by Gas chromatography-mass spectrometry
  • Plasma acylcarnitines analysis by mass spectrometry
  • Urine purines and pyrimidines analysis by Gas chromatography-mass spectrometry


  • Applegarth DA, Toone JR, Lowry RB (2000). Incidence of inborn errors of metabolism in British Columbia, 1969 – 1996". Pediatrics 105 (1):10. doi: 10.1542/peds.105.1.e10. PMID 10617747.
  • J Sheth, M Mistri, F Sheth, R Shah, A Bavdekar, K Godbole, N Nanavati, C Datar, M Kamate, N Oza, C Ankleshwaria, S Mehta, M Jackson (2014). Burden of Lysosomal Storage Disorders in India: Experience of 387 affected children from a single diagnostic facility. Journal of Inherited Metabolic Disease. JIMD Reports 12: 51–63.


Triple Marker Study:

Women Less Than 35 Years of Age

Until recently, no screening tests were available to identify fetuses with Down syndrome in women less than 35 years of age. However, with the introduction of maternal serum alpha-fetoprotein, followed by the addition of other blood markers, women less than 35 years of age can be screened for Down syndrome.

Maternal serum screening involves obtaining a small amount of blood from the pregnant woman's arm. Her blood is tested for the amount of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. These substances are made by the mother's placenta and the fetus. At each week of pregnancy there are different amounts of these substances in the mother's blood. Using isolated or combinations of these blood tests, between 20% and 60% of fetuses with Down syndrome can be identified.

In 1994, the American College of Obstetricians and Gynecologists recommended that every pregnant woman less than 35 years of age be offered this test during the second trimester of pregnancy (Down Syndrome Screening. ACOG Committee Opinion. 141, August 1994). The Genetics Disease Branch of the state of California has implemented a statewide program in which Triple Marker Screening is offered to all pregnant women less than 35 years of age.

Women 35 Years of Age and Older

The current detection rate of 40% to 60% for Down syndrome is acceptable for women less than 35 years of age since the detection rate prior to maternal blood screening was close to 0%. However, a 60% detection rate is not acceptable for women at 35 years and greater when the alternative is diagnostic testing using amniocentesis, which has a detection rate of 99%. However, by adjusting the number of patients undergoing amniocentesis, the rate of detection of Down syndrome can be increased.

This concept was recently reported in a study published in The New England Journal of Medicine by researchers who suggested that the Triple Marker Screening blood test could be used to adjust the risk for trisomy 21 in patients of advanced maternal-age (35 years of age and older). They compared their findings with universal amniocentesis in which 100% of patients undergo genetic amniocentesis, which identifies 99% of Down syndrome fetuses. The study reported identifying 89% of fetuses with Down syndrome, which would only require 25% of the high-risk patients to undergo amniocentesis. However, unlike universal amniocentesis, which identifies 99% of all chromosomal abnormalities, Triple Marker Screening only identified 65% of all chromosomal abnormalities.

To counter this argument, however, the authors stated that the other chromosomal defects were either lethal (trisomy 13 and 18), or were so infrequent (unbalanced translocations) that the benefit of saving normal fetuses from loss far outweighed the identification of rare chromosomal abnormalities.

Following the above study, the state of California implemented the Expanded Alpha-Fetoprotein Screening Program. In this program women over the age of 35 are given a brochure to read entitled, Prenatal Testing Choices For Women at 35 Years and Older. In which the options of the Triple Marker Screening blood test, chorionic villus biopsy, and genetic amniocentesis are explained.

The most important concept to recognize, which is explained in the brochure, is that the detection rate for Down syndrome varies as a function of maternal age. In The New England Journal of Medicine article it was reported to be 89%. This, however, was the average for all women of 35 years of age and older. In reality, the detection rate of Down syndrome is less than 89% for women between the ages of 35 and 39. THIS IS AN IMPORTANT CONCEPT WHICH MAY NOT BE CLEARLY UNDERSTOOD BY MANY PATIENTS AND PHYSICIANS, even though the above brochure clearly explains this. The following graph illustrates this principle.

Thirteen percent (13%) of women 35 years of age will have an abnormal Triple Marker Blood test indicating an increased risk for trisomy 21, thus requiring an amniocentesis. However, only 71% of fetuses with trisomy 21will be identified. Thus, for every 10 fetuses with Down syndrome, only 7 will be detected. From this graph you can see that the detection rate of Down syndrome is lower than that reported in The New England Journal of Medicine (89%) for women between 35 and 39 years of age.

Advantages of Triple Marker Screening For Women at 35 Years of Age and Older

The advantage of the Triple Marker Screening Program for women 35 years of age and older is that it adjusts the risk for trisomy 21 for women who might not choose to undergo universal amniocentesis based only upon their age-related risk. For many of these women this is a better alternative than no test at all!

In addition, if the Triple Marker Screening Test is negative, the risk for having a fetus with Down syndrome is less than the risk of miscarriage if they were then to have an amniocentesis. For example, if a 35-year-old patient had a normal Triple Marker Screening test and then elected to have an amniocentesis, the risk of miscarriage would be 6 times greater than having a child with Down syndrome.

Limitations of Triple Marker Screening For Patients at 35 Years of Age and Older

Although the Triple Marker Screening test is useful for identifying Down syndrome, it has the following limitations:

  • Identifies between 71% and 87% of fetuses with Down syndrome in women between 35 and 39 years of age. These age groups contain the largest number of women seeking genetic amniocentesis because of advanced maternal age.
  • Identifies less than 50% of fetuses with trisomy 18 and rarely identifies a fetus with trisomy 13. Although the majority of fetuses with these chromosomal abnormalities will die within the first year of life, these conditions are still quite serious.
  • Identifies less than 65% of all chromosomal abnormalities.
  • If the test is negative, patients may not be offered an ultrasound examination, which is routinely performed prior to amniocentesis. The advantage of an ultrasound is that it may identify birth defects, which are not associated with abnormal chromosomes.
  • The blood test is not valid if performed before 15 weeks or after 20 weeks of pregnancy.