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Over 400 human diseases that are due to inborn errors of metabolism
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 that many of these disorders
remain undetected or misdiagnosed. Several factors conspire to make the
clinical diagnosis of inborn errors of metabolism (IEM) difficult.
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IEM are individually rare but collectively numerous. The recent
application of tandem mass spectrometry (tandem MS) to newborn screening
and prenatal diagnosis has enabled presymptomatic diagnosis for
some IEM. However, for most IEM, 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:
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- 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 (such as peripheral neuropathy, retinitis
pigmentosa, cardiomyopathy, etc) or a syndrome (such as Reye syndrome,
Leigh syndrome, sudden infant death, etc) 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).
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In this section, inborn errors amenable to treatment are printed
in bold. Additional information and diagnostic checklists are available online.
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The vast majority of IEM involve abnormalities in enzymes and
transport proteins. However, all the metabolic disorders can be divided
into the following two large clinical categories.
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Includes disorders that either involve only one functional system
(such as the endocrine system, immune system, coagulation factors,
or lipoproteins) or affect only one organ or anatomic system (such
as the intestine, renal tubules, erythrocytes, or connective tissue).
Presenting symptoms are uniform (e.g., a bleeding tendency in coagulation
factor defects or hemolytic anemia in defects of glycolysis), and
the correct diagnosis is usually easy to guess even when the basic
biochemical lesion gives rise to systemic consequences.
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