Common Characteristics of Genetic Disorders of Metabolism

Although the manifestations of genetic metabolic disorders are quite variable, the following features are shared among most of these conditions:

Mass Screening of Newborn Infants

Common characteristics of genetic metabolic conditions make a strong argument for screening all newborn infants for the presence of these conditions. During the past half-century, methods have been developed to screen all infants inexpensively with accurate and fast-yielding results. Tandem mass spectrometry (MS/MS) is the latest technical advance in the field. This method requires a few drops of blood to be placed on a filter paper and mailed to a central laboratory for assay. A large number of genetic conditions can be identified by this method when complemented by a few equally efficient assays for other specific disorders (Tables 78-1 and 78-2). Severe forms of some of these diseases may cause clinical manifestations before the results of the newborn screening become available. It should also be noted that these methods may identify mild forms of inherited metabolic conditions, some of which may never cause clinical disease in the lifetime of the individual. Potential psychosocial implications of such findings can be devastating and deserves serious considerations. An example of this is 3-methylcrotonyl CoA carboxylase deficiency, which has been identified in an unexpectedly high frequency in screening programs using tandem mass spectrometry. The majority of these children have remained asymptomatic (Chapter 79.6).

Clinical Manifestations of Genetic Metabolic Diseases

Physicians and other health care providers who care for children should familiarize themselves with early manifestations of genetic metabolic disorders, because (1) severe forms of some of these conditions may cause symptoms before the results of screening studies become available, and (2) the current screening methods, although quite extensive, identify a small number of all inherited metabolic conditions. In the newborn period, the clinical findings are usually nonspecific and similar to those seen in infants with sepsis. A genetic disorder of metabolism should be considered in the differential diagnosis of a severely ill newborn infant, and special studies should be undertaken if the index of suspicion is high (Fig. 78-1).

Figure 78-1 Clinical approach to a newborn infant with a suspected genetic metabolic disorder. This schema is a guide to the elucidation of some of the metabolic disorders in newborn infants. Although some exceptions to this schema exist, it is appropriate for most cases.

Signs and symptoms such as lethargy, poor feeding, convulsions, and vomiting may develop as early as a few hours after birth. Occasionally, vomiting may be severe enough to suggest the diagnosis of pyloric stenosis, which is usually not present, although it may occur simultaneously in such infants. Lethargy, poor feeding, convulsions, and coma may also be seen in infants with hypoglycemia (Chapters 86 and 101) or hypocalcemia (Chapters 48 and 565). Measurements of blood concentrations of glucose and calcium and response to intravenous injection of glucose or calcium usually establish these diagnoses. Some of these disorders have a high incidence in specific population groups. Tyrosinemia type 1 is more common among French-Canadians of Quebec than in the general population. Therefore, knowledge of the ethnic background of the patient may be helpful in diagnosis. Physical examination usually reveals nonspecific findings; most signs are related to the central nervous system. Hepatomegaly is a common finding in a variety of inborn errors of metabolism. Occasionally, a peculiar odor may offer an invaluable aid to the diagnosis (Table 78-3). A physician caring for a sick infant should smell the patient and his or her excretions; for example, patients with maple syrup urine disease have the unmistakable odor of maple syrup in their urine and on their bodies.

Table 78-3 INBORN ERRORS OF AMINO ACID METABOLISM ASSOCIATED WITH PECULIAR ODOR

Occasionally, the onset of a genetic metabolic condition may occur months or even years after birth. These children usually have mutations that render the gene partially nonfunctional. Clinical manifestations such as mental retardation, motor deficits, developmental regression, convulsions, myopathy, recurrent emesis, and cardiomyopathy in a child beyond the neonatal period should raise the possibility of an inherited metabolic disease. There may be an episodic or intermittent pattern, with episodes of acute clinical manifestations separated by periods of seemingly disease-free states. The episodes are usually triggered by stress or a nonspecific catabolic insult such as an infection. The child may die during one of these acute attacks. A genetic disorder of metabolism should be considered in any child with one or more of the following manifestations: unexplained mental retardation, developmental delay or regression, motor deficit, or convulsions; unusual odor, particularly during an acute illness; intermittent episodes of unexplained vomiting, acidosis, mental deterioration, or coma; hepatomegaly; renal stones; muscle weakness or cardiomyopathy.

Diagnosis usually requires a variety of specific laboratory studies. Measurements of serum concentrations of ammonia, bicarbonate, and pH are often very helpful initially in differentiating major causes of genetic metabolic disorders (see Fig. 78-1). Elevation of blood ammonia is usually caused by defects of urea cycle enzymes. Infants with elevated blood ammonia levels from urea cycle defects commonly have normal serum pH and bicarbonate values; without measurement of blood ammonia, they may remain undiagnosed and succumb to their disease. Elevation of serum ammonia is also observed in some infants with certain organic acidemias. These infants are severely acidotic because of accumulation of organic acids in body fluids.

When blood ammonia, pH, and bicarbonate values are normal, other aminoacidopathies (such as hyperglycinemia) or galactosemia should be considered; galactosemic infants may also manifest cataracts, hepatomegaly, ascites, and jaundice.

Treatment

The majority of patients with genetic disorders of metabolism respond to one or all of the following treatments:

The last two modalities have the potential to cure the metabolic abnormalities. Replacement of the mutant gene with a normal one (gene therapy) is still in the experimental phase.

Treatment of genetic disorders of metabolism is complex and requires medical and technical expertise. The therapeutic regimen often needs to be tailored to the individual patient because of large phenotypic variations in the severity of the disease, even within a single family. Providing education and support for the family is the key to successful long range therapy. Effective treatment is best achieved by a team of specialists (physician specialist, nutritionist, geneticist, neurologist, and psychologist) in a major medical center.