What Causes a False Positive MPS I Newborn Screening?

Getting a call that your baby’s newborn screening came back positive for Mucopolysaccharidosis type I (MPS I) is a terrifying experience. It is entirely normal to feel anxious, overwhelmed, and scared. However, a positive screen does not mean your baby has the disease.

In fact, the vast majority of initial positive screens for MPS I turn out to be a “false positive” or a “false alarm.” Furthermore, babies born with true MPS I typically look and act completely healthy at birth, so closely watching your baby for “symptoms” right now will only increase your anxiety without providing any answers. Understanding why false alarms happen and what the next steps are can help you navigate this difficult waiting period.

How the Newborn Screen Works

The newborn screening test uses a few drops of blood taken from your baby’s heel shortly after birth. For MPS I, the test measures the activity of an enzyme called alpha-L-iduronidase (IDUA).

Enzymes are specialized proteins that act like recycling centers in the body’s cells. In true cases of MPS I, the baby’s body does not produce enough working IDUA enzyme. This means complex sugars called glycosaminoglycans (GAGs) build up in the cells and cause damage.

The newborn screen is designed to be extremely sensitive to catch any baby who might have low enzyme levels. Because the test is designed to cast a wide net, it often flags babies whose enzyme levels are lower than normal for reasons completely unrelated to the actual disease ^[1][2].

Why False Positives Happen

False positive results in newborn screening for MPS I are very common. They are almost always caused by harmless genetic variations rather than true disease ^[3][4]. There are two main reasons why a healthy baby might have a false positive result:

Pseudodeficiency Alleles

The most common cause of a false positive MPS I screen is a genetic quirk known as a pseudodeficiency allele ^[5].

An “allele” is simply a version of a gene. We all have normal variations in our genes that make us unique, much like variations that dictate eye or hair color. A pseudodeficiency allele is a specific, harmless variation in the IDUA gene.

If your baby has a pseudodeficiency allele, the enzyme acts a bit “shy” in the laboratory test tube. The newborn screening equipment registers the enzyme’s activity as very low ^[5][6]. However, inside your baby’s body, the enzyme is working perfectly well—breaking down the complex sugars just like it is supposed to. Babies with a pseudodeficiency allele are completely healthy and will never develop MPS I ^[5][7].

Being a Carrier (Heterozygosity)

Every person has two copies of the IDUA gene—one inherited from each parent. A baby is a carrier if they have one normal gene and one gene that doesn’t work well. This is scientifically referred to as heterozygosity.

Carriers do not have MPS I. The single working gene produces more than enough enzyme to keep them healthy. However, because they only have one fully functioning gene copy instead of two, their overall enzyme levels in the blood spot might be slightly lower than average—sometimes just low enough to trip the sensitive alarm on the newborn screen ^[3][4]. If your baby turns out to be a carrier, you and your partner may want to speak with a genetic counselor to discuss your own carrier status and family planning.

Next Steps: Confirming or Ruling Out MPS I

Because the initial screen casts such a wide net, a positive result requires immediate follow-up testing (sometimes called second-tier testing) to confirm or definitively rule out the diagnosis ^[8][1]. While waiting for results is agonizing, doctors will typically run two types of tests to figure out if it was a false alarm:

1. Biomarker Testing (GAG Analysis)

The most critical follow-up test measures the actual buildup of the complex sugars (GAGs) in your baby’s blood or urine.

• If a baby truly has MPS I, the enzyme isn’t working, and GAG levels will be very high.
• If the baby has a pseudodeficiency or is a carrier (a false positive), the enzyme is working fine inside the body, and their GAG levels will be completely normal ^[3][8].

Measuring GAGs is incredibly accurate at distinguishing a false alarm from true MPS I ^[8]. In many modern newborn screening programs, state labs automatically test GAG levels on the original blood spot before ever calling the parents, though procedures vary by hospital ^[8][9]. If a new sample is needed, GAG results often come back faster than genetic testing.

2. DNA Sequencing (Genetic Testing)

The doctor will also order a genetic test to look at your baby’s exact IDUA genes. By reading the DNA code, doctors can look for known pseudodeficiency alleles or identify true disease-causing mutations.

While genetic testing is very helpful, interpreting the results can sometimes be complex if a baby has a rare or unique genetic variation ^[10][11]. In some instances, the genetic testing reveals a “grey area” (variants of uncertain significance), and doctors may recommend watchful waiting and regular monitoring rather than immediate treatment. This is why doctors rely heavily on the GAG analysis alongside the genetic test to make a final determination.

If the follow-up tests confirm that your baby truly has severe MPS I, your medical team will move quickly. Early identification through this screening process is critical because it allows for prompt, life-saving treatments like enzyme replacement therapy or a stem cell transplant before irreversible damage occurs ^[12][13]. But until those confirmatory results return, remember that the highest likelihood is that your baby is completely healthy.