Clinical Phenotypes: Diagnosis/Algorithms

ABSTRACT

• Despite the abundance of new case reports, there is considerable evidence that many inherited metabolic disorders remain undiagnosed or misdiagnosed. There are a number of reasons, the most important of which is the fact that many physicians are not aware of most of the highly specific symptoms or syndromes that are excellent keys to the diagnosis and consequently do not perform comprehensive examinations.

• From a clinical point of view, all the inborn errors of metabolism can be divided into two large categories: Category 1. Diseases that involve only one functional system or affect only one organ or anatomic system. Presenting symptoms are uniform, and diagnosis is usually easy even when the basic biochemical lesion gives rise to systemic consequences. Category 2. Diseases in which the basic biochemical lesion either affects a metabolic pathway common to a large number of cells or organs or is restricted to one organ but gives rise to humoral and systemic consequences. Presenting symptoms are very diverse. The central nervous system is frequently involved in advanced disease, and diagnosis may be rendered difficult by the presence of secondary abnormalities. This category includes most inborn errors of intermediary metabolism, diseases of intracellular trafficking, and lysosomal disorders.

• The second category can be subdivided on the basis of pathophysiology into three groups that are useful for diagnosis. Group 1. Diseases that disturb the synthesis or catabolism of complex molecules (lysosomal and peroxisomal disorders; disturbances of intracellular trafficking and secretory protein processing). Clinical symptoms are permanent, progressive, independent of intercurrent events, and unrelated to food intake. Group 2. Inborn errors of intermediary metabolism that lead to acute or progressive intoxication caused by accumulation of toxic compounds proximal to the metabolic block. The group includes aminoacidopathies, most organic acidurias, congenital urea cycle defects, and sugar intolerances. In these conditions, a symptom-free interval is followed by clinical signs of acute or chronic intoxication and by recurrent metabolic disturbances. Clinical expression is often late in onset and intermittent. Diagnosis is easy, relying mainly on chromatography of plasma and urine amino acids or organic acids. Treatment involves removing the toxin. Group 3. “Energy deficiency” disorders, in which symptoms are caused at least partly by a deficiency in energy production or utilization resulting from an inborn error of intermediary metabolism in liver, myocardium, muscle, or brain. This group includes glycogenosis, gluconeogenesis defects, congenital lactic acidemias, fatty acid oxidation defects, and mitochondrial respiratory chain disorders. These diseases present an overlapping clinical spectrum, and manifestations sometimes result from accumulation of toxic compounds as well as from the deficiency in energy production. Common symptoms include hypoglycemia, hyperlactacidemia, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden infant death syndrome, and congenital malformations, the last suggesting that the abnormal process affected fetal energy pathways.

• The clinical diagnostic circumstances observed in inborn errors of metabolism are divided in this chapter into eight categories: presentation in the neonatal period, intermittent late-onset acute presentation, ...