Introduction to Inborn Errors of Metabolism

Rebecca S. Wappner

Bryan E. Hainline

The concept of inherited biochemical genetic disorders was described first by Garrod in his 1908 published lecture, “Inborn Errors of Metabolism.” His original description of four disorders has been expanded greatly since then. This expansion has occurred mainly since the late 1970s, through the development of improved diagnostic testing and advances in the molecular understanding of the bases for the disorders.

Inborn errors of metabolism are genetically determined abnormalities in the biochemical processes of the body. Most often, a single defective protein disrupts a metabolic pathway at a specific step, leading to an excessive accumulation of
immediate or precursor substrates and a deficiency of immediate and subsequent products of the reaction. The clinical manifestations of the disorders are related to the abnormal metabolism that occurs.

Individual disorders result from point mutations, deletions, or other alterations of DNA or RNA processing. Defects may occur in nuclear-encoded genes located on the autosomes or X chromosome or in genes located in mitochondrial DNA. Most disorders produce abnormalities in a single enzyme protein, but a regulatory, protective, or activator protein for the enzyme can be involved. Other inborn errors may be due to the faulty transport of molecules. Occasionally, several enzymes may be affected, giving a composite clinical picture incorporating features of several enzyme deficiencies. Multiple sulfatase deficiency and combined methylmalonic acidemia and homocystinuria are typical examples. Conversely, identical clinical phenotypes may be seen with mutations in different proteins. An example of the latter is Sanfilippo syndrome, which may be caused by the deficient activity of any one of four different enzymes.

Most of the disorders are inherited as autosomal recessive traits. Some are inherited as X-linked conditions, whereas others show maternal, or mitochondrial, inheritance. An accurate diagnosis should be established so that appropriate information and genetic counseling can be given to family members and affected individuals concerning prognosis, treatment options, recurrence risks, carrier detection, and prenatal diagnosis.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

The inborn errors of metabolism vary widely in clinical presentation and age of onset. Those that affect essential pathways in the body are more severe and present at early ages with acute metabolic disease (i.e., urea cycle defects or organic acidemias). Others are indolent and associated with the gradual onset of organomegaly (i.e., Gaucher disease) or neurologic impairment (i.e., phenylketonuria). Still others are benign and result in no significant clinical problems (i.e., iminoglycinuria or pentosuria). Although inborn errors of metabolism classically have been considered disorders of childhood, they may present at any age. Mild variants of all types have been reported with increasing frequency in adolescents and adults.

TABLE 383.1. CLINICAL MANIFESTATIONS OF INBORN ERRORS OF METABOLISM

Clinical Manifestation	General Type of Disorder
Clinical Manifestation	AA	OA	UREA	FAO	MIT	CARB	PER	MPS	SL
Episodic nature	++	++	++	++	+	+	–	–	–
Poor feeding	+	+	++	+	+	+	+	–	–
Abnormal odor	+	+	–	+	–	–	–	–	–
Lethargy, coma	+	++	++	++	+	+	–	–	–
ALTE	+	+	+	+	+	+	–	–	–
Seizures	+	+	+	–	+	+	+	+	+
Developmental regression	+	+	+	–	+	–	+	++	+
Hepatomegaly	+	+	+	+	+	+	+	+	+
Hepatosplenomegaly	–	–	–	–	–	–	–	+	+
Splenomergaly	–	–	–	–	–	–	–	–	+
Hypotonia	+	+	+	+	+	+	+	+	+
Cardiomyopathy	–	+	–	+	+	+	+	+	+
Coarse facies	–	–	–	–	–	–	–	++	+
Birth defects	–	+	–	+	+	–	+	–	–
Hypoglycemia	+	+	–	+	+	+	–	–	–
Acidosis	+	++	–	+	+	+	–	–	–
Hyperammonemia	+	+	++	+	+	–	–	–	–
Ketosis	+	+	–	+	–	+	–	–	–
Hypoketosis	–	–	–	+	–	–	–	–	–
++, usually present; +, may be present; -, usually not present; AA, amino acidopatheis; ALTE, acute life-threatening event; CARB, disorders of carbohydrate; FAO, mitochondrial fatty acid oxidation defects; MIT, mito-chondrial disordes of oxidative phosphorylation; MPS, mucopolysaccharidoses; OA, organic acidopathies PER, peroxisomal disorders; SL, sphingolipidoses; UREA, disorders of the urea cycle. Adapted from Wappner RS. Biochemical diagnosis of genetic diseases. Pediatr Ann 1993;22;283.

Often, the pattern of clinical findings points to a specific inborn error and usually is related directly to the pathway affected. Those involving amino acid or organic acid metabolism may have an acute metabolic presentation with decreased intake and lethargy, followed by encephalopathy, coma, or death if not recognized and treated. Laboratory testing will reveal profound acidosis (often with hyperammonemia) that is refractory to standard therapy. Unusual odors may be noted. Frequently, patients with urea cycle disorders develop acute neurologic deterioration in the neonatal period. Often, disorders of fatty acid oxidation and carbohydrate metabolism present with lethargy, encephalopathy, and hypoglycemia at times of decreased carbohydrate intake or fasting. Hepatomegaly and hypotonia frequently are noted. Lactic acidosis, cardiomyopathies, myopathies, and other neurologic symptoms commonly are seen with mitochondrial disorders. Lysosomal storage disorders are characterized by progressive hepatomegaly, splenomegaly, neurologic regression, short stature, and coarse facies. Frequently, patients with peroxisomal disorders have dysmorphic features and neurologic problems. Other inborn errors present with only psychomotor handicaps. Rarely, inborn errors result in urinary tract stones, immunodeficiencies, and self-mutilation.

A history of cyclic vomiting and lethargy, especially if related to the intake of protein or specific carbohydrates, should arouse suspicions, as should repeated episodes of acute, life-threatening events. A family history possibly may reveal similarly affected individuals or unexplained early infant deaths.

Table 383.1 lists the patterns of clinical findings associated with certain groups of the disorders. Table 383.2 lists the findings in specific inborn errors. Table 383.3 lists the abnormal
common laboratory testing results that may suggest an inborn error of metabolism. Table 383.4 lists specific specialty testing for inborn errors of metabolism. These tables and lists may aid physicians in determining which disorder to consider and which tests to perform. Although clinical features of disorders of mitochondrial oxidative phosphorylation, disorders of copper metabolism, and the porphyrias are listed in the tables for comprehensive coverage, these disorders are discussed in Chapters 386 and 412.

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