Inborn errors of metabolism are a heterogeneous group of disorders that may be inherited or may occur as the result of spontaneous mutation. These diseases involve failure of the metabolic pathways involved in either the break-down or storage of carbohydrates, fatty acids, and proteins. Although any given inborn error of metabolism is very rare, taken as a group, inborn errors occur in 1 in 2500 births, making them quite common. They can present at any age, and therefore, a working knowledge of these diseases, their presentations, and their evaluation is critical for the emergency provider.
Inborn errors of metabolism are inherited disorders caused by mutations in genes coding for proteins that function in metabolism. Most are inherited as autosomal recessive. Rarely, they are autosomal dominant and X-linked. Environmental, epigenetic, and microbiome factors and additional genes are potential modifying etiologic factors in those with inborn errors of metabolism.
Inborn errors of metabolism occur in 1 out of 2500 births. Because of their heterogeneity, different disorders have different distinct epidemiologies, presentations, and heritabilities. For instance, mitochondrial disorders are inherited from mother to 100% of her offspring, while other disorders may have variable penetrance or be sex-linked. The disorder may cause complete dysfunction of the involved enzyme, or it may be partial or incomplete. Although neonatal birth screens seek to identify many inborn errors of metabolism early, different states and even different hospitals have differing panels through which they screen. Neonatal screens may identify 8 to 50 different diseases, but unfortunately, there are thousands of diseases. Furthermore, screens may be falsely negative in children tested too early after birth (before they have had the time to accumulate the measurable diagnostic metabolites) or in those who have received transfusions. Because of all these factors, although medical professionals often think about inborn errors of metabolism as diseases of the neonatal period, 50% of all inborn errors present outside of the neonatal period, and some are not diagnosed until adulthood.
Inborn errors disrupt carbohydrate metabolism, protein metabolism, fatty acid oxidation, or glycogen storage. In the body, dietary substances are broken into glucose (the primary energy source of the body) and other metabolic products that are eventually excreted. Glucose that is ingested but is more than what is needed is stored as glycogen in the liver and muscles for use in times of fasting. When the body needs glucose, it utilizes glycogen stores. When these stores are depleted, the body will make new glucose from amino acids (gluconeogenesis) and then, finally, will use fatty acid oxidation to create a substrate for the Kreb's cycle.
Although there are detailed entries in StatPearls for specific inborn errors of metabolism, it is helpful to understand these diseases as a whole. Diseases that result in errors of metabolizing and breaking down food will often cause hypoglycemia. Diseases that interfere with excretion of metabolites will cause intoxication (i.e., hyperammonemia). Diseases that interfere with fatty acid oxidation result in hypoglycemia and acidosis. Glycogen storage disorders do not generally present acutely, and will not be discussed here.
History and Physical
Patients with severe errors in carbohydrate metabolism present early (typically in the neonatal period) and catastrophically. Clinically, they can be indistinguishable from septic neonates, with hypoglycemia, brady/and tachydysrhythmias, hypothermia or hyperpyrexia, seizures, and poor tone. These children cannot metabolize food to fuel, and the prognosis with severe early involvement is poor. Patients with severe errors in excretion pathways will present typically with intoxication, with lethargy and altered mental status, seizures, vomiting, and vital sign abnormalities. They often have elevations in ammonia and other metabolites. Patients with errors in pathways involved in accessing stored energy may appear well for prolonged periods of time and can be asymptomatic as long as they have an ongoing intake of carbohydrates. However, should the child develop a gastrointestinal illness, have a change in diet, or begin to forgo night feeds, he or she will be unable to access stored energy adequately and will present with hypoglycemia or seizures. These children may present with an illness that seems minor and short-lived, but appear quite ill.
Although all these presentations exist on a spectrum depending upon degree and type of enzyme involvement, inborn errors of metabolism have some common features. The most common presentation of these diseases taken as a whole is neurologic abnormalities, which occurs in about 80% of individuals. These abnormalities include developmental delay, loss of milestones, poor tone, poor suck, and seizure. The second most common presentation is related to gastrointestinal symptoms, including vomiting, hepatomegaly, food intolerance, diarrhea, food aversion, exercise intolerance, and dehydration. More than half of children have both neurologic and gastrointestinal abnormalities. Therefore, inborn errors of metabolism should be considered in the differential of any child with neurologic and/or gastrointestinal findings. Inborn errors should also be considered in children with failure to thrive, recurrent feeding issues and formula changes, "reflux" or "gastroparesis," autonomic instability, or behavioral or learning issues.
Definitive diagnosis of inborn errors of metabolism is not a realistic goal in an emergency setting. However, because lab abnormalities in these patients may be transient, it is important to draw extra blood for future testing at the time of initial presentation. Although a definitive specific diagnosis is unlikely in an emergency department, some labs are helpful in screening for these diseases. Most children with inborn errors of metabolism will have an elevated lactate level, hypoglycemia, hyperammonemia, or acidosis on blood testing, or ketonuria/elevated urinary reducing substances on urine testing. These tests can, therefore, be used as a screen for possible inborn errors, with extra tubes saved for further serum amino-acid and organic-acid testing should these tests be positive. If the child is undergoing lumbar puncture for any reason, an extra tube of cerebrospinal fluid should also be saved.
Enhancing Healthcare Team Outcomes
The management of patients with inborn errors of metabolism is extremely complex and challenging. Because there is no cure, the disorders are best managed by an interprofessional team that includes pharmacists, nurses, therapists, dietitians, and social workers.
In many cases, there is no specific treatment and symptoms are managed as they arise. The overall outlook for most patients with inborn errors of metabolism is poor.