Inborn Errors of Metabolism

Abstract

Inborn errors of metabolism (IEMs) are a set of relatively uncommon complicated medical conditions involving abnormalities in the complex biochemical and metabolic pathways of the human body system. They involve great complexity of the underlying pathophysiology, biochemical workup, and analysis and have complicated therapeutic options for management. These children are often sick with significant complications and high rates of morbidity and mortality. The understanding of these complex disorders requires special in-depth training and experience. Most primary care physicians are less familiar with these disease conditions and therefore less willing to deal with them because of the complexity involved. There are metabolic specialists available, mostly in large medical centers, with expertise to deal with these intricate complicated issues. Primary care physicians and pediatricians usually are the first point of contact for most of these newborns, children, or adolescents, however. Therefore, it is important that primary care physicians become comfortable in being able to recognize early signs and symptoms, be able to initiate appropriate diagnostic and therapeutic interventions, and be able to make appropriate referrals. This chapter summarizes the key issues basic to understanding IEMs.

Introduction

Inborn errors of metabolism (IEMs) have been known for approximately the past 100 years, with the term being first used by Sir Archibald Garrod (1857–1936) in 1902 [1]. The initial disorders described were alkaptonuria, benign pentosuria, albinism, and cystinuria at that time, to be followed by description of one of the major IEMs, namely phenylketonuria (PKU), by Ivar Asbjørn Følling (1888–1973) in 1934. Since that time, advances in medicine have uncovered more than 500 IEMs [2].

Definition

The term metabolism encompasses the net result of a multitude of complex biochemical processes that occur in living organisms to maintain cellular activities. These processes are organized into specific metabolic pathways with the primary function to maintain daily life activities. Each pathway depends on certain substrates and specific enzymes to ensure smooth functioning. IEMs are a group of heritable genetic disorders interfering with these metabolic pathways in different ways, leading to inadequate functioning of a particular pathway. This interference in the normal enzymatic or metabolic pathway has varying consequences, including deficiency of a particular end product or excessive accumulation of a substrate that may be toxic. Either of these two scenarios leads to significant morbidity and mortality by hampering normal functioning of a particular metabolic pathway.

Epidemiology

The incidence of IEMs is highly variable among the many specific clinical entities, ranging from 1 in 400 US African Americans for hemoglobinopathies, 1 in 4,500 for congenital hypothyroidism, 1 in 15,000 for PKU, to 1 in 100,000 for most of the fatty acid disorders (except MCAD) and organic acidemias. Incidences of some common inborn errors are listed in Table 4.1 [3]. Some of the common metabolic disorders are listed in Table 4.2 [3, 4].

Table 4.1 Some common disorders of inborn errors of metabolism

Table 4.2 Incidence of some inborn errors of metabolism

Etiopathogenesis

Several patterns of inheritance are possible for the different IEMs. It is important to detail a three- to four-generation pedigree to evaluate the mode of inheritance accurately.

Autosomal recessive (AR) inheritance is the most common mode of inheritance for metabolic disorders. In this case, both the parents are heterozygous for the mutant gene; hence, they do not express the disorder, but the offspring are homozygous for that particular gene defect; hence, they express the defect and present clinically with the disorder. The family history is generally negative in the parents, but there may be a history of early neonatal deaths or a clinical disorder expressed as a concern. Consanguinity has an increased chance of expression of an AR disorder. Rarely, these mutations may occur de novo [5].

X-linked recessive inheritance may also be seen in some IEMs, in which one copy of the mutated gene on the X-chromosome is sufficient for causing the disorder. Therefore, in this mode of inheritance, the disorder is transmitted from a carrier mother to her male offspring. Also, de novo mutations are observed with a much higher incidence in this pattern of inheritance [5].

Autosomal dominant (AD) inheritance is a less common mode of inheritance for IEMs. The incidence of de novo mutations causing AD disorders is much higher than in other patterns of inheritance. AD transmission generally means that one of the parents has the disease; 50% of the progeny have the disorder, and there is an equal gender distribution [5].

A mitochondrial mode of inheritance is also seen in some IEMs. It is interesting to note that the mitochondrial DNA is always maternal in origin; therefore, a mutation in the mitochondrial DNA is inherited only from the mother. Mitochondrial DNA is prone to de novo mutations; hence, diseases transmitted in this manner may be found to be sporadic in occurrence [5].

Table 4.3 lists the modes of inheritance of some common IEMs [5].

Table 4.3 Modes of inheritance in some common inborn errors of metabolism

Clinical Features

IEMs may present early in the newborn period, later on in early or late childhood, or much later in adulthood. A high index of suspicion needs to be maintained for IEMs, because the symptomatology of these disorders is often nonspecific and hence may lead to a workup for other medical conditions. The clinical presentation attributable to IEMs may be subclassified into a few broad categories.

Early-Onset Disorders

Silent Disorders

IEMs in this category do not cause life-threatening signs and symptoms in infancy but present later on in the early childhood period with mental retardation and developmental delay. This group includes PKU and congenital hypothyroidism [6].

Disorders Presenting with Acute Metabolic Encephalopathy

This group includes urea cycle disorders, organic acidemias, and aminoacidurias. These conditions may present with metabolic disturbances caused by accumulations of precursors or metabolites, which are reflected early in the newborn period with poor feeding, lethargy, persistent vomiting, seizures, hypotonia, apnea, respiratory distress, tachypnea, and tachycardia. These newborns usually end up getting a workup for sepsis with this type of presentation [6]. These features are attributed to the toxic effect of metabolites on the central nervous system, causing a picture of a metabolic encephalopathy. The biochemical features are significant for metabolic acidosis, hyperammonemia, or other metabolic abnormalities.

Disorders Presenting with Metabolic Acidosis

This group generally includes organic acidemias. These neonates exhibit severe metabolic acidosis with an increased anion gap along with elevated organic acid intermediates specific for the defect or lactate. Lactic acidosis is present in disorders of pyruvate metabolism including pyruvate dehydrogenase deficiency, defects in gluconeogenesis, pyruvate carboxylase deficiency, and mitochondrial disorders [7].

Disorders Presenting with Hyperammonemia

Many newborns with defects in the urea cycle, organic acidemias, and transient hyperammonemia of the newborn (THAN) present with metabolic encephalopathy and hyperammonemia.

Disorders Presenting Later on in Childhood

This group of IEMs includes lysosomal storage disorders, Tay–Sachs disease, Gaucher’s disease, and metachromatic leukodystrophy. These disorders generally present with progressive neurologic deterioration [8].

Other clinical signs and symptoms, including generalized nonspecific manifestations; neurologic signs and symptoms; developmental disorders; dysmorphic phenotypes; and disorders in the gastrointestinal, hematologic, and dermatologic systems, are summarized in Table 4.4 [6, 7, 9]. One of the most unique and intriguing features of IEMs is the presence of specific odors in some of these metabolic disorders. Some of these are listed in Table 4.5 [7, 9–11].

Table 4.4 Important clinical signs and symptoms of inborn errors of metabolism

Table 4.5 Odors characteristic of some inborn errors of metabolism

Table 4.6 Initial laboratory investigations for inborn errors of metabolism

Diagnosis

Clinical presentation should raise suspicion of an IEM. Details of history, including a family history of consanguinity, similar disorders in close and extended family, and any neonatal deaths, should be sought. Details of relation of symptoms to eating in terms of timing and in relation to specific type of food consumption, cyclic pattern of vomiting, lethargy, and behavioral changes should be inquired about. Signs manifested on clinical examination, including hepatosplenomegaly, skin lesions, and neurologic deficits, should guide one toward an initial laboratory workup. In children who may be critically ill, it is important to consider and then rule out options in the differential diagnosis of the specific clinical scenario. General laboratory investigations indicated are listed in Table 4.6 [6, 12]. Additional specific biochemical workup should be decided based on details of the history, clinical presentation, results of preliminary laboratory investigations, and suspicion of a specific IEM. It is preferred that extra blood and urine samples be drawn and saved for later investigations. A second tier of laboratory workup that may be indicated is listed in Table 4.7. Special precautions may be needed in the drawing and processing of some of these samples. The samples for plasma ammonia, lactate, and pyruvate should be obtained without the use of a tourniquet and need to be transported on ice for immediate analysis in the laboratory; pyruvate samples should be collected in perchlorate to prevent degradation [12]. Table 4.8 lists correlations with some alterations in laboratory evaluations with possible IEMs [12].

Table 4.7 Additional laboratory investigations for inborn errors of metabolism

Table 4.8 Laboratory findings in inborn errors of metabolism

Newborn Screening

Newborn screening (NS) for genetic disorders in all newborns endeavors to make early and timely diagnosis of otherwise potentially life-threatening or debilitating inherited disorders. For a genetic disorder to be considered for NS, several criteria should be justified. These include the following: the particular genetic disorder should result in significant morbidity or mortality; should have a known mechanism of pathogenesis; should offer the potential of prevention or adequate treatment; should have an easy, inexpensive, and rapid test available for screening; should have reliable follow-up confirmatory testing available; and the cost-to-benefit ratio of incorporating the testing in the NS should be less than the cost of diagnosing, testing, and managing the condition otherwise [3, 13].

NS was initially stated for PKU in 1959 by Robert Guthrie (1916–1995); since then, it has expanded to include an extended list of predominantly IEMs and some hematologic and endocrine disorders [8]. Advances in biochemical testing with tandem mass spectrometry have facilitated the incorporation of many genetic disorders in the NS. Common disorders screened for are listed in Table 4.9 [3, 14, 15]. Most NS programs in the United States are state controlled and state specific, and different states include different disorders in their specific NS programs. Many other countries worldwide offer variable genetic NS programs as well. It is therefore important to remember to look into the specific screening program that a particular newborn underwent. Moreover, it is imperative to realize that a normal newborn screen does not rule out all inborn or inherited disorders. The aim of the NS is to make an early diagnosis for the conditions being screened for. There may be false-positive and false-negative results. Once positive NS is obtained for an IEM, the primary care physician or pediatrician should perform a clinical examination and make an assessment and then seek consultation with the metabolic or genetic specialist who has expertise in the field for initiating further diagnostic testing and implementing the required therapeutic measures. These patients should be closely followed, preferably by the metabolic specialists. Early therapeutic intervention can lower morbidity and mortality significantly.

Table 4.9 Genetic disorders available for screening on the newborn screening programs

The aim of the NS is to make an early diagnosis for the previously mentioned conditions. There may be false-positive and false-negative results. Once positive NS is obtained for an IEM, the primary care physician or pediatrician should initiate dialog with the metabolic or genetic specialist who has expertise in the field for initiating further clinical examination and assessment, diagnostic testing, and implementation of the required therapeutic measures. These patients should preferably be followed closely by the metabolic specialist. With this early intervention, morbidity and mortality can be significantly lowered.

Principles of Management

General Principles of Treatment

The general measures of treatment are put into place before a definitive diagnosis of a specific IEM is made. Some of these interventions include withholding of all dietary oral intake until some specific investigations and guidelines can be established, preferably after consultation with metabolic specialists. In most cases, intravenous dextrose fluid with saline may be initiated after adequate hydration with normal saline. Acidosis may also need correction by replacement with bicarbonate [16].

Specific Therapeutic Measures

The specific therapeutic options are disease specific and are instituted once a particular IEM is diagnosed. These measures are geared toward addressing the specific concerns of the particular underlying defect. Figure 4.1 represents the underlying approaches to treatment strategies for various IEMs [8]. Table 4.10 outlines some of the specific therapeutic options available for various metabolic disorders [8].

Fig. 4.1

Approaches to treatment of IEMs. Treatment can be directed at (1) limiting the intake of a potentially toxic compound, (2) supplementing the deficient product, (3) stimulating an alternate metabolic pathway, (4) providing a vitamin cofactor to activate residual enzyme activity, (5) supplying the enzyme itself, (6) transplanting a body organ containing the deficient enzyme, and (7) [7] gene therapy (with permission from Batshaw and Tuchman [8], p. 339)

Table 4.10 Examples of treatment approaches for inborn errors of metabolism

Conclusions

The clinical outcome of children depends on multiple factors. These include severity of the underlying metabolic defect, ability to make the diagnosis early, availability of specific adequate treatment options, and appropriate institution of the therapeutic measures. Depending on all these variables, some IEMs have a relatively better prognosis than others. Many of these children are living longer, but many may be at high risk for developing progressive neurologic deficits, learning disabilities, and mental retardation. A study done to evaluate response to treatment in IEMs revealed improvement in clinical parameters in approximately half of the patients who have metabolic disorders [17].