Clinical Approach to Inherited Metabolic Disorders

Summary

Inborn errors of metabolism are individually rare, but collectively numerous. However, their incidence may well be underestimated as diagnostic errors are frequent. As a whole, they can not be recognized through systematic neonatal screening tests, which are too slow, too expensive, or unreliable. This makes it an absolute necessity to teach primary care physicians a simple method of clinical screening before deciding to initiate sophisticated biochemical investigations. Clinical diagnosis of inborn errors of metabolism may at times be diffi­cult. A number of generally accepted ideas contribute to this difficulty: (1) Many physicians think that because individual inborn errors are rare, they should be considered only after more common conditions (like sepsis) have been excluded. (2) In view of the large number of inborn errors, it might appear that their diagnosis requires precise knowledge of a large number of biochemical pathways and their interrelationships. As a matter of fact, adequate diagnostic approach can be based on the proper use of only a few screening tests. (3) The neonate has an apparently limited repertoire of responses to severe overwhelming illness and the predominant clinical signs and symptoms are nonspecific: poor feeding, lethargy, failure to thrive, etc. It is certain that many patients with such defects succumb in the newborn period without having received a specific diagnosis, death often having been attributed to sepsis or other common causes. (4) Classical autopsy findings in such cases are often unspecific and unrevealing. Infection is often suspected as the cause of the death, whereas sepsis is the common accompaniment of metabolic disorders. (5) Many general practitioners and pediatricians only think of inborn errors of metabolism in inadequate and very unspecific clinical circumstances like psychomotor retardation or seizures. Conversely, they ignore most of the highly specific symptoms which are excellent keys to the diagnosis. Another common mistake is to confuse “syndrome” (such as Leigh syndrome or Reye syndrome), which is a set of symptoms possibly due to different causes, with the etiology itself. (6) Although most genetic metabolic errors are hereditary and transmitted as recessive disorders, the majority of cases appear sporadic, because of the small size of sibships in developed countries. Finally, “hereditary” does not mean “congenital”, and many patients can present a late onset form in childhood, adolescence, or even in adulthood.

Within the last two decades, a total of more than 500 patients with inborn errors of metabolism have been clinically evaluated by the metabolic and genetics services at Hôpital des Enfants-Malades in Paris. Based mostly upon personal experience over 20 years, this chapter gives an overview of clinical keys to the diagnosis of inborn errors of metabolism.

As far as physiopathology is concerned, most inborn errors of intermediary metabolism affecting the synthesis or the catabolism of protein, carbohydrate, and fatty acids fall schematically into two categories.