Inherited Metabolic Disorders: A Generic View


What is Metabolism?

Metabolism refers to all the chemical reactions taking place in the body to convert or use energy. A few major examples of metabolism include:

  • Breaking down the carbohydrates, proteins, and fats in food to release energy.
  • Transforming excess nitrogen into waste products excreted in urine.
  • Breaking down or converting chemicals into other substances and transporting them inside cells.
  • Metabolism is an organized but chaotic chemical assembly line. Raw materials, half-finished products, and waste materials are constantly being used, produced, transported, and excreted. The “workers” on the assembly line are enzymes and other proteins that make chemical reactions happen.


What are the Inherited Metabolic Disorders?

Inherited metabolic disorders are genetic conditions that result in metabolism problems. Most people with inherited metabolic disorders have a defective gene that results in an enzyme deficiency. There are hundreds of different genetic metabolic disorders, and their symptoms, treatments, and prognoses vary widely.



In most inherited metabolic disorders, a single enzyme is either not produced by the body at all or is produced in a form that doesn’t work. The missing enzyme is like an absentee worker on the assembly line. Depending on that enzyme’s job, its absence means toxic chemicals may build up, or an essential product may not be produced.

The code or blueprint to produce an enzyme is usually contained on a pair of genes. Most people with inherited metabolic disorders inherit two defective copies of the gene — one from each parent. Both parents are “carriers” of the bad gene, meaning they carry one defective copy and one normal copy.

In the parents, the normal gene copy compensates for the bad copy. Their enzyme levels are usually adequate, so they may have no symptoms of a genetic metabolic disorder. However, the child who inherits two defective gene copies cannot produce enough effective enzymes and develops the genetic metabolic disorder. This form of genetic transmission is called autosomal recessive inheritance.



Each inherited metabolic disorder is quite rare in the general population. Considered all together, inherited metabolic disorders may affect about 1 in 1,000 to 2,500 newborns. In certain ethnic populations, such as Ashkenazi Jews (Jews of central and eastern European ancestry), the rate of inherited metabolic disorders is higher (WebMD).

A large majority of studies have indicated that early mortality is increased in the progeny of consanguineous unions when compared with children born to unrelated parents (Bittles, A. H. 2003). From the results of a 5-year prospective study, it was calculated that there would be approximately 7 out of 1,000 increase in rare inherited disorders per 0.01 increase in cousin marriages. Thus, countries like Pakistan where approximately 50% of marriages are between first cousins, some 22 out of 1,000 rare inherited disorders would be expected (Hussain R, Bittles AH 1998; Christianson A et al, 2006).

With the high prevalence of metabolic risk factors, the prevalence of metabolic syndrome in Pakistan – considering different definitions – is reported to be from 18% to 46%, comparable to the data from other South Asian countries (Basit, A., & Shera, A. S. 2008).



The symptoms of genetic metabolic disorders vary widely depending on the metabolism problem present. Some symptoms of inherited metabolic disorders include:

  • Lethargy
  • Poor appetite
  • Abdominal pain
  • Vomiting
  • Weight loss
  • Jaundice
  • Failure to gain weight or grow
  • Developmental delay
  • Seizures
  • Coma
  • Abnormal odor of urine, breath, sweat, or saliva

The symptoms may come on suddenly or progress slowly. Symptoms may be brought on by foods, medications, dehydration, minor illnesses, or other factors. Symptoms appear within a few weeks after birth in many conditions. Other inherited metabolic disorders may take years for symptoms to develop.


Diagnosis of Inherited Metabolic Disorders:

Inherited metabolic disorders are present at birth, and some are detected by routine screening. All 50 states of USA screen newborns for phenylketonuria (PKU). Most states of USA also test newborns for galactosemia.

If an inherited metabolic disorder is not detected at birth, it is often not diagnosed until symptoms appear. Once symptoms develop, specific blood or DNA tests are available to diagnose most genetic metabolic disorders. Referral to a specialized center (human genetics labs) increases the chances of a correct diagnosis.


Treatment of Inherited Metabolic Disorders:

Limited treatments are available for inherited metabolic disorders. The essential genetic defect causing the condition can’t be corrected with current technology. Instead, treatments try to work around the problem with metabolism.


Treatments for genetic metabolic disorders follow a few general principles:

  • Reduce or eliminate intake of any food or drug that can’t be metabolized properly.
  • Replace the enzyme or other chemical that is missing or inactive, to restore metabolism to as close to normal as possible.
  • Remove toxic products of metabolism that accumulate due to the metabolic disorder.


Treatment may include such measures as:

  • Special diets that eliminate certain nutrients
  • Taking enzyme replacements, or other supplements that support metabolism
  • Treating the blood with chemicals to detoxify dangerous metabolic by-products




  • Basit, A., & Shera, A. S. (2008). Prevalence of metabolic syndrome in Pakistan. Metabolic Syndrome and Related Disorders6(3), 171-175.
  • Bittles, A. H. (2003). Consanguineous marriage and childhood health. Developmental Medicine and child neurology45(8), 571-576.
  • Boelens, J. J., & Wynn, R. F. (2017). Inherited metabolic disorders. Clinical Manual of Blood and Bone Marrow Transplantation, 272-280.
  • Millington, D. S., Kodo, N., Norwood, D. L., & Roe, C. R. (1990). Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. Journal of inherited metabolic disease13(3), 321-324.
  • Modell, B., & Darr, A. (2002). Genetic counselling and customary consanguineous marriage. Nature Reviews. Genetics3(3), 225.
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