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Over 800 human diseases that are due to inborn errors of metabolism (IEM) are now recognized, and this number is constantly increasing. However, the incidence of inborn errors may well be underestimated because diagnostic errors are frequent. Despite the relative abundance of new case reports, there is considerable evidence, including that based on the recent introduction of next-generation sequencing, that many of these disorders remain undetected or misdiagnosed. More than 300 “new” disorders have been described in the past 5 years, 85% of which present with predominantly neurologic manifestations. Several factors conspire to make the clinical diagnosis of IEM difficult.

IEM are individually rare but collectively numerous. The application of tandem mass spectrometry (tandem MS) to newborn screening and prenatal diagnostic testing has enabled presymptomatic diagnosis for some IEMs. However, for many IEM disorders, neonatal screening tests are either too slow, too expensive, or too unreliable; consequently, a simple method of clinical screening is mandatory before initiating sophisticated biochemical investigations. The clinical diagnosis of IEM relies upon a limited number of principles:

  • Consider IEM in parallel with other more common conditions; for example, sepsis or anoxic-ischemic encephalopathy in neonates, and intoxication, encephalitis, and brain tumors in older patients.

  • Be aware of symptoms that persist and remain unexplained after the initial treatment and the usual investigations have been performed.

  • Collect blood and urine samples at the right time in relation to an acute illness.

  • Suspect that any neonatal death may be due to an IEM, particularly deaths that are attributed to sepsis.

  • Carefully review all autopsy findings.

  • Do not confuse a symptom (eg, peripheral neuropathy, retinitis pigmentosa, cardiomyopathy) or a syndrome (eg, Reye syndrome, Leigh syndrome, sudden infant death) with etiology.

  • Remember that an IEM can present at any age, from fetal life to old age.

  • Know that although most genetic metabolic errors are hereditary and transmitted as recessive disorders, the majority of individual cases appear sporadically.

  • Initially consider inborn errors that are amenable to treatment (mainly those that cause intoxication). Do not miss a treatable disorder.

  • In acute emergency situations, undertake first those few investigations that are able to diagnose treatable IEM: First take care of the patient (emergency treatment) and then the family (genetic counseling).

In this section, inborn errors amenable to treatment are printed in bold. Additional information and diagnostic checklists are available online.


The vast majority of IEMs involve abnormalities in enzymes and transport proteins. However, all the metabolic disorders can be divided into the following 2 large clinical categories.

Category 1

This category includes disorders that either involve only 1 functional system (eg, the endocrine system, immune system, coagulation factors, or lipoproteins) or affect only 1 organ or anatomic system (eg, the intestine, renal tubules, erythrocytes, or connective tissue). Presenting symptoms are uniform (eg, a bleeding tendency in coagulation ...

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