Inborn Errors of Metabolism: A New Purview of Internal Medicine

Historically, the diagnosis and care of patients with inborn errors of metabolism have been the realm of pediatricians. That most of these have been thought to present exclusively in infancy and childhood and that screening programs for several exist in 40 states have served to establish the boundaries. Early diagnosis, excellent dietary management, biochemical interventions, and good general medical care, however, have begun to erase the previous limits, with a steadily increasing number of patients with inherited biochemical defects surviving into adulthood. The article by Talente and colleagues [1] in this issue of Annals, detailing the medical complications found in adult patients with glycogen storage disease, emphasizes a disorder that was previously the purview of pediatricians but now deserves the attention of internists.

Indeed, this disease is only one example of the many childhood biochemical disorders that now extend into adulthood. Patients with cystic fibrosis now live into their 30s and require care by internal medicine subspecialists. Many patients with phenylketonuria now survive to adulthood, and pregnant women must be carefully monitored because the lack of proper dietary management has devastating consequences for the newborn. Older patients with galactosemia may develop neurologic syndromes, and most women with the disorder have ovarian failure that requires hormonal management and treatment of abnormally low bone density. These are merely a few illustrations from a group of more than 300 monogenic diseases in which the basic biochemical defects are known. The scope is constantly enlarging, with descriptions of new entities and variants of classic disorders appearing in nearly every issue of genetic and metabolic disease journals.

In addition to the increasing age of survival of persons with early-onset biochemical disorders, some variants are indolent throughout infancy and childhood and first present clinically as adult-onset disease. Adults with propionic acidemia and movement disorder [2], citrullinemia with hyperammonemic symptoms [3], hexosaminidase A deficiency (Tay-Sachs disease) with psychosis [4], and recurrent hypoglycemia with glutaric aciduria type II [5] are some examples. For the most part, the age of onset is determined by the presence of variable activities of the defective enzyme that results from different genetic mutations. The phenomenon is highlighted by adult female carriers of the X-linked ornithine transcarbamylase deficiency who express variable manifestations of hyperammonemia after protein ingestion—confusion, ataxia, migraine headache, or even frank coma [6]. The last has been the initial mode of presentation after the catabolic stress of parturition [7].

The problem confronting the internist is confounded by a whole new group of disorders caused by mutations in mitochondrial DNA that express themselves as disorders of cellular energy metabolism secondary to electron transport chain defects [8, 9]. When the composite deficit in energy metabolism is regional rather than global in nature, the disorder may mimic an idiopathic, organ-specific, degenerative disease [10]. Because mitochondria are derived from the ova, these disorders appear to be maternally transmitted. Affected persons present throughout a broad age span with numerous findings of myopathy, ophthalmoplegias, encephalopathy, and strokes, as well as cardiac lesions. The cardinal biochemical feature is lactic acidemia, but lactic acid elevation in the cerebrospinal fluid may be the sole abnormality. The variable expression results from the proportion of abnormal mitochondria in various tissues as well as the deterioration of mitochondrial function with age. The rate of spontaneous mutation in mitochondrial DNA far exceeds the rate in nuclear DNA, hinting at the likely incidence of these disorders in the adult population. The sequencing of the entire mitochondrial genome has fostered the laboratory diagnosis of these disorders by DNA analysis.

Rapid advances in molecular genetic mutational analysis have resulted from the sequencing of normal genes that code for many enzymes whose defective function is responsible for inherited biochemical disorders. In many, the associated phenotypes result from several different genetic mutations, and many afflicted persons are, therefore, compound heterozygotes. Gene mutation analysis has not only enabled the detection of the carrier state but also has begun to permit genotype-phenotype correlations. The careful evaluation of associated phenotypic expressions throughout life in relation to specific mutations presents a powerful prognosticating tool. The ability to predict different severities of a disorder would indicate which children would be expected to survive into adulthood. It is now possible to explain what was a long-standing enigma: why persons affected by the same autosomal recessive disease do not, unlike Mendel's peas, follow the rules.

New molecular diagnostic techniques for heterozygote detection present important issues for the internist. This is pertinent not only to patients with the hyperlipidemias and the hypercholesterolemic syndromes but also to carriers for homocystinuria due to cystathionine β-synthase deficiency who appear to have an increased incidence of myocardial infarctions and other macrovascular diseases. The internist can play an important role in delineating subtle disease in obligate carriers of inborn errors of metabolism.

The “leap” of inborn errors into the realm of internal medicine creates several concerns. Many older patients do not wish to continue to see the inborn-error specialists in pediatric centers, nor do adult patients with suspected inherited biochemical disorders wish to be seen in pediatric clinics for work-up for these entities. Conversely, pediatricians frequently feel uncomfortable caring for adults with their attendant medical problems. In addition, pediatric centers cannot provide facilities for adult patients, especially those requiring hospitalization. These patients need dietary monitoring, metabolite quantitation, and continuous follow-up care by physicians who can manage decompensated metabolic states.

Internists must not only assume responsibility for satisfying these needs but also should be competent to diagnose the adult-onset diseases. At present, few internists have the required expertise to assume this task. What is needed is the establishment of a cadre of internists expert in biochemical genetics and intermediary metabolism who are capable of diagnosing these disorders as well as providing short- and long-term care. In addition, sections devoted to these patients should be established within departments of medicine and inborn-error clinics in adult tertiary care medical centers. Cooperation must be achieved between pediatric subspecialists in biochemical disorders in pediatric centers and internists in large, adult medical facilities. However, the responsibility rests with departments of medicine to provide the physicians, nurse specialists, and metabolic dieticians that these adult patients need for optimal care. Collaborative study of this growing number of patients by pediatric and adult subspecialists, as exemplified by the study by Talente and colleagues [1], holds the promise of enormously fruitful clinical and biochemical investigation.

• Copyright ©2004 by the American College of Physicians