inborn errors of metabolism

Inborn Errors of Metabolism (IEM) are genetic disorders that often occur as enzyme deficiencies which interfere with the normal biochemical processes of the human body. Very often these disorders are not apparent at birth because the mother’s biochemical processes work for the baby in the womb. Shortly after birth, the infant begins to get into significant trouble when his own enzymes are deficient or insufficient to carry the biochemical load. Many of these disorders are eminently treatable, allowing the treated individual to lead a normal life or a life whose quality is vastly improved over untreated individuals. Thus detecting IEM and treating them before the baby becomes ill is the primary purpose of newborn screening (NBS) programs worldwide. The seeds of newborn screening (NBS) in the US began back in the early 1960s when Dr. Robert Guthrie developed a bacterial inhibition assay for phenylalanine and demonstrated that it could be used to screen entire populations for the presence of a devastating yet treatable disease called phenylketonuria (PKU). In 1960 Maine became the first State to offer newborn screening for PKU to all infants born in Maine.

In the years that followed this advent, the prevalence of NBS grew slowly and sporadically. Along the way there was debate over which disorders to include; at one time a disorder had to meet a long list of criteria to be included. In addition, the NBS performed in any given state is dependent on that state’s ability and willingness to fund the program. Even today, NBS is not nationally mandated but is in the purview of the individual states. Each state decides which disorders to screen for.

As late as 1997, only 2 disorders (PKU and congenital hypothyroidism) were screened for by all 50 states. However in the mid- to late 1990’s a technological development revolutionized NBS. The ability to screen for up to 50 different IEM from a single dried blood spot punch using tandem mass spectrometry changed the face of NBS. The American College of Medical Genetics (ACMG) fielded a task force called the Newborn Screening Expert Group which published a recommendation in 2006 entitled “Newborn Screening: Toward a Uniform Screening Panel and System”(1). This Group recommended a set of 29 “core conditions” that every state should screen for, as well as a set of “secondary conditions” that will be picked up during the differential diagnosis of the core conditions. They also revised the inclusion criteria into a set of three basic criteria for disease inclusion in NBS programs: the disorder must be detectable within 24-48 hours of birth, before it’s clinically detectable, a screening test with appropriate sensitivity and specificity must be available, and the disorder must be treatable with benefits to treatment. Currently all 50 states screen their newborns for the 29 Core Conditions recommended by the ACMG and the US Department of Health and Human Services. Thanks to a laboratory technology, NBS is now much closer to being standardized than ever before and covers the majority of the most common IEM.

1) https://www.acmg.net/ACMG/Publications/Practice_Guidelines_docs/NBS_report.aspx

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

In general when people think of a genetic defect or an inborn error of metabolism (IEM), they think in terms of disorders that are diagnosed and treated in infancy or early childhood. Interestingly, the more we learn about IEM, the more we see that IEM can be diagnosed at nearly any age. Milder forms of the disorders may present in later years, anywhere from adolescence through adulthood.

Classical presentations of IEM are generally due to total or near total enzyme deficiencies that result in life-threatening medical crises, or major developmental delay and mental retardation. Adults or near adults who present with a range of milder symptoms may be misdiagnosed or nor diagnosed at all.

A few examples of IEM that may have later and milder presentations include:

1) Ornithine transcarbamylase (OTC ) deficiency, the most common urea cycle defect which is often fatal in newborn male infants, can and does present in the teenage years as altered mental status, when a protein load cannot be handled and ammonia levels rise and impact brain function.

2) Carnitine palmitoyltransferase 2 (CPT2) deficiency, a disorder of fatty acid metabolism, presents with cardiomyopathy and liver failure in the newborn period. It can also present with muscle weakness, myopathy and rhabdomyolysis in the teenage or young adult years when the teenager tries out for a sports team and the muscle cannot metabolize adequate fats.

3) 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency, a disorder of leucine metabolism, may present in infants or toddlers as feeding difficulties, neurological symptoms including seizures, and can cause death. 3MCC can also present in a completely asymptomatic mother whose infant is picked up on newborn screening because of the Mom’s abnormal metabolites in the infant’s blood.

In most of these cases the deficiency is mild enough that the individual is self-regulating, avoiding foods or activities that make them feel bad. In addition, the IEM may not manifest unless some other confounding factor precipitates it, such as stress, illness, or fasting. The important thing to remember though, is that altered mental status in a teenager does not always represent alcohol, drug or other mood altering substances. IEM can be diagnosed at any age and should always be considered as part of the differential diagnosis.