OVERVIEW: What every practitioner needs to know.

How can you be sure your patient has an inborn error of metabolism? What are the typical findings for this disease?

Background: Traditional newborn screening and expanded newborn screening for rare inborn errors of metabolism

Traditional newborn screening (before screening via tandem mass spectroscopy [MS/MS]) includes the following conditions:

Metabolic disorders (phenylketonuria [PKU], galactosemia, biotinidase deficiency)

Genetic disorders (cystic fibrosis, glucose-6-phosphate dehydrogenase deficiency)

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Endocrine disorders (congenital hypothyrodism, congenital adrenal hyperplasia)

Hemoglobinopathies (thalassemias, sickle cell disease)

Infectious disorders (toxoplasmosis, HIV)

Expanded newborn screening in the United States includes a recommended core panel of 29 disorders and an additional 25 conditional disorders that can be detected in the newborn (traditional methods and MS/MS):

Amino acid disorders (PKU, maple syrup urine disease, tyrosinemias, homocystinuria, citrullinemia [low citrullin may raise concern for urea cycle disorders])

Fatty acid oxidation disorders (medium-chain acyl CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA, very long-chain acyl-CoA dehydrogenase, carnitine-acylcarnitine translocase deficiency)

Organic acidurias (methylmalonic acidemia, proprionic acidemia, glutaric acidemias, 3-methylcrotonyl-CoA carboxylase deficiency)

How is newborn screening done? Why it is important to perform newborn screening at the recommended time?

Screening newborns for inherited and treatable disorders started in the 1960s (1962 screening for PKU was implemented). In the United States, newborn screening is controlled and funded by the states. State legislatures are responsible for appropriating funds or authorizing fees to make newborn screening possible. The extent of legislative involvement in newborn screening varies. In some cases, the panel of disorders screened for is set forth in state statutes, whereas in other instances the state health department or other entity has the authority to alter the panel.

Testing for newborn screening is commonly performed on whole blood samples (blood spot from heel stick) collected on specially designed filter paper. The filter paper is typically attached to a form containing required information about the infant and parents, including date and time of birth, sex, date and time of sample collection, and the infant’s weight and gestational age. The form also should have information about whether the baby has received a blood transfusion or any additional nutrition (total parenteral nutrition).

Most states require screening samples to be collected from all newborns, unless the parent or legal guardian opts out of the process in writing. Samples can be collected at the hospital, at the delivery clinic, or by midwives (home births). Ideally, newborn screening samples should be collected from the infant at 24-48 hours (first screen) and optionally again at 1-2 weeks after birth (this second screen is currently mandated in only 9 US states).

The timing of sample collection is extremely important for proper testing. Although enzyme defects in the newborn can be identified right after birth, detection of IEMs by abnormal metabolite levels, such as in PKU and maple syrup urine disease, requires that there be an accumulation of metabolites, which typically does not occur until after a period of protein intake or fasting. If collected too early, the IEM may be missed. However if collected and sent too late, the patient may already be symptomatic before results of newborn screening are available.

Why is expanded newborn screening so important for detecting inborn errors of metabolism? What causes many inborn errors of metabolism to develop in the newborn period?

The goal of newborn screening is to identify infants that appear healthy at birth but are afflicted with treatable conditions that can cause severe illness or death. With reliable early detection, these conditions can be managed before the newborn or infant experiences serious medical complications, some of which can be irreversible.

Without newborn screening or a known previously affected individual within a family (positive family history) triggering a genetic work-up, in most cases IEMs are identified only after a patient becomes symptomatic. Although many IEMs (milder forms) can present later in infancy, in childhood, or even in early adolesence, the acute onset in the newborn period or early infancy indicates more severe and often life-threatening forms.

Most IEMs are difficult to detect (by biochemical testing) in a healthy well-fed child. Onset of symptoms is most often associated with “metabolic stress,” i.e, prolonged fasting, increased protein intake, and illness with fever, vomiting/diarrhea, or decreased oral intake (“catabolic state”).

Birth in general (loss of maternal/placental resource of nutrition and clearance), birth complications (respiratory distress, feeding problems, infection), lack of maternal breast milk supply and increase in protein intake, can be considered metabolic stress; it typically results in a newborn at risk (affected by a severe IEM) displaying early, often nonspecific symptoms (reduced alertness/activity, decreased appetite/intake, emesis, lethargy, and unresponsiveness). When parents or providers miss these signs, the process is aggravated and can progress very quickly to coma, organ failure, and death.

How are positive/abnormal results of newborn screening comunicated to the provider or the parents? What is the impact on families in cases of false-positive newborn screening results?

The goal of newborn screening is to report abnormal results within a short time. If newborn screening normal, a paper report is sent to the submitting hospital or physician’s office. If an abnormality is found, employees of the responsible state agency begin to try to contact the physician, hospital, and/or nursery listed on the newborn screening card by telephone. In many states in the United States the appropriate specialist physician is notified simultaneously so that an evaluation by the primary care provider or by the specialist physician can be arranged and preventive treatment as well as confirmatory testing can be initiated.

Because of the likely distress caused to the parents of a newborn by receiving a call about an abnormal newborn screening result, it is often advisable to let the primary care provider (who typically has an established physician patient relationship) relay the information and suggest follow-up with the specialist for any questions. One of the responsibilities of the metabolic specialist is to identify false-positive results by repeating the tests or by using a different method or laboratory (confirmatory testing).

Which laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A very important aspect of newborn screening for IEMs by MS/MS is the arbitrary determination of positive reporting thresholds. In many recessive metabolic disorders there is significant overlap of biochemical marker levels between heterozygote carriers and homozygous affected individuals. The problem lies in allowing for maximum sensitivity for detection of true-positive results (affected individuals at risk) versus limiting the number of false-positive results (unaffected individuals who flag positive on screening). Many states in the United States have varying reporting thresholds below 100% sensitivity, which means that true-positive results will be missed, and some unaffected carriers will be reported as abnormal.

Communicating the limitations of newborn screening to the parents of a newborn with an abnormal result is paramount, as many families equate a positive screening result with a definite diagnosis. In most cases, confirmatory testing for a positive newborn screening result reveals a false-positive result. To reduce the emotional stress on the parents, but also to optimize the treatment for infants with true-positive results, confirmatory testing should be initiated without delay.

With few exceptions (glutaric acidemia type I, nonketotic hyperglycinemia, confirmation or exclusion of suspected IEMs can be achieved by obtaining quantitative serum amino acid levels, urine organic acid levels, a plasma acylcarnitine profile,or by quantative determination of disease-specific metabolites (PKU, galactosemia). In some instances, enzymatic studies or molecular testing (DNA analysis) is needed to conclusively rule out a disorder or confirm a specific subtype.

Would imaging studies be helpful? If so which ones?

Although imaging studies typically are not helpful in the confirmation of a specific IEM, certain studies (brain magnetic resonance imaging/magnetic resonance spectroscopy, ultrasonography of the liver) can raise general suspicion for a metabolic disorder, indicate ongoing central nervous system injury and allow for correlation, depending on severity of the IEM.

Imaging studies do play an important role in establishing a patient’s baseline status, in monitoring for complications of an identified/suspected IEM, or in assessing response to treatment.

Confirming the diagnosis

Clinical decision algorithms for expanded newborn screening were developed by the American College of Medical Genetics (ACMG), which recommend appropriate follow-up/confirmatory testing and treatment for markers (analytes) used in screening. For each marker, there is (1) an action sheet that describes the short-term actions a health professional should follow in communicating with the family and determining the appropriate steps in the follow-up of the infant that has had positive results on screening and (2) an algorithm that presents an overview of the basic steps involved in determining the final diagnosis in the infant.

If you are able to confirm that the patient has an inborn error of metabolism, what treatment should be initiated?

For chronic long-term treatment/management of confirmed IEMs, please refer to the chapter describing the specific disorder. Acute treatment of a suspected or confirmed IEM, with few exceptions (see below), is based on two principles:

Avoid a catabolic state (i.e., fasting) in the patient by providing sufficient calories. If the patient has feeding problems or decreased oral intake, this can be achieved preferably through administration of intravenous glucose (glucose infusion rate [GIR] of 10-12 mg/kg/min for a newborn and 8-10 mg/kg/min for infants). A high GIR must be maintained, and resulting increased blood glucose levels may need to be titrated with insulin,

Reduce the nutritional component affected by the metabolic deficiency (enzymatic blockage). This most often requires a reduction of dietary protein or a switch to a source of protein other than breast milk (at least in the acute phase). It may be appropriate to suspend protein intake for 24 hours until a diagnosis is confirmed, especially if the patient presents symptomatically before newborn screening results become available. In addition, initiation of nutrional supplements and vitamins (i.e., carnitine, arginine, folate, vitamin B12, or tetrahydrobiopterin) or specific drugs may be needed.

Some organic acidurias and urea cycle defects typically present with high ammonia levels, which may require ammonia scavengers, and dialysis should possibly be considered to prevent central nervous system injury.

►Important: If the patient responds adversely to a high GIR by experiencing seizures or severe lactic acidosis, defects in the mitochondrial respiratory chain enzymes, pyruvate dehydrogenase deficiency, or citrin deficiency must be considered. Of note, these are metabolic disorders typically not identified on expanded newborn screening and often require reduction of carbohydrate/glucose intake.

Specific interventions for selected metabolic disorders:

PKU: phenylalanine-restricted diet (metabolic formula + breast milk)

Galactosemia: immediate switch to a lactose-free infant formula

Tyrosinemia type I: nitisinone (also called NTBC) and a phenylalanine- + tyrosine-restricted diet

Methylmalonic acidemia and cobalamin disorders: vitamin B12 and protein restriction

Glutaric aciduria: high arginine/low lysine formula, carnitine

Urea cycle disorders: arginine or citrulline, protein restriction

Biotinidase deficiency/holocarboxylase deficiency: biotin

Nonketotic hyperglycinemia: sodium benzoate (optional: dextromethorphan)

What is the evidence that early detection and treatment has a positive impact on outcome of inborn errors of metabolism?

In 2006 the Maternal and Child Health Bureau commissioned the ACMG to assemble an expert panel to outline a process for the standardization of outcomes and guidelines for state newborn screening programs and to define responsibilities for collecting and evaluating outcome data, including a recommended uniform panel of conditions to include in state newborn screening programs. The results were published in Genetics in Medicine, the official journal of the ACMG.

The panel (representatives from various areas of subspecialty medicine and primary care, health policy, law, public health, and consumers) identified 29 conditions for which screening should be mandated, based on gathering expert opinion and review of the available scientific literature on the effectiveness of newborn screening. An additional 25 conditions were identified because they are part of the differential diagnosis of a condition in the core panel, they are clinically significant and revealed with screening technology but lack an efficacious treatment, or they represent incidental findings for which there is potential clinical significance.

What is the evidence?

Helpful online links


Sahai, I, Marsden, D. “Newborn screening”. Crit Rev Lab Med. vol. 46. 2009. pp. 55-82.

Abhyankar, S, Lloyd-Puryear, MA, Goodwin, RM. “Standardizing newborn screening results for health information exchange”. AMIA Annu Symp Proc. 2010. pp. 1-5.

Watson, MS, Mann, MY, Lloyd-Puryear. “Current status of newborn screening: decision-making about the conditions to include in screening programs”. Ment Retard Dev Disabil Res Rev. vol. 12. 2006. pp. 230-5.

Wilson, N. “Newborn DNA samples to be destroyed”. 2009.

ACMG ACT sheets and confirmatory algorithms. 2001.

Ongoing controversies regarding etiology, diagnosis, treatment

Newborn screening tests have become a subject of political controversy in the past decade. Instituting MS/MS screening often requires a sizable upfront expenditure. When states choose to run their own programs, the initial costs for equipment, training, and new staff can be significant. Money spent for these programs may reduce resources available for other potentially lifesaving programs.

Expanded newborn screening is also opposed among some health care providers, who are concerned that effective follow-up and treatment may not be available for some of the rare IEMs detected and that false-positive results on screening tests may cause significant harm to families.

The collection and storage of blood or DNA samples by government agencies during the routine newborn blood screen has raised concerns about the protection of this private health information. It was revealed that in Texas the state had collected and stored blood and DNA samples from millions of newborns without the parents’ knowledge or consent. These samples were then used by the state for genetic experiments and to set up a database to catalog all the samples from newborns.