Hunter syndrome (MPS II)

Mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, is a lysosomal storage disease. Lysosomes are the parts of a cell that break down and recycle materials. In MPS II, they cannot break down long sugar chains called glycosaminoglycans, or GAGs. The GAGs build up and slowly damage many organs.

MPS II ranges from severe to milder forms. In the severe, or neuropathic, form, the brain is affected and children lose skills over time. This form makes up about two-thirds of cases. In the milder, or non-neuropathic, form, thinking is not affected. Experts now see the two forms as ends of a range rather than two separate types.

MPS II is caused by changes in the IDS gene. This gene carries the instructions for an enzyme called iduronate-2-sulfatase (I2S). With little or no working enzyme, GAGs pile up inside cells throughout the body.

The IDS gene is on the X chromosome, and MPS II is inherited in an X-linked recessive way. A boy needs only one changed copy to be affected, so the condition occurs almost only in boys, though a few girls have been reported. In each pregnancy, a mother who carries the change has a 1 in 2 chance of passing it on: a son who inherits it will be affected, and a daughter who inherits it will be a carrier. A father cannot pass it to his sons.

Babies with MPS II look healthy at birth. Signs usually appear between 18 months and 4 years of age. They can include hernias near the belly button or groin, frequent ear infections, a runny nose and snoring, a large liver and spleen, and full lips and rounded cheeks.

Over time the disease can narrow the airway and cause pauses in breathing during sleep (sleep apnea). Many people develop heart valve problems. Most people develop hearing loss. Joints become stiff, and growth slows after about age 5. Many children also get carpal tunnel syndrome, which causes numbness and weakness in the hands.

In the severe form, children gain skills at first and then lose them, usually starting between ages 6 and 8. Behavior changes such as hyperactivity and trouble paying attention are common. Heart disease and a blocked airway are major causes of death in both forms.

In the United States, MPS II was added to the recommended newborn screening panel in 2022, and many states now screen for it. The screen measures the I2S enzyme in the newborn blood spot. If it is low, a second test on the same spot measures GAGs, which cuts down on false alarms. A positive screen is not a diagnosis. Families are usually connected with a doctor who knows MPS II to guide the follow-up tests.

Confirming MPS II takes low I2S activity in the blood (plasma or white blood cells) and raised GAGs in the urine. A test for another enzyme, arylsulfatase A, helps rule out a related condition called multiple sulfatase deficiency. A genetic test of the IDS gene can add detail. About 15% of cases come from larger changes to the chromosome, some of which need special tests to find. The gene result does not always predict how severe the disease will be.

Children who were not screened are usually diagnosed after signs appear, often between 18 months and 4 years of age. Once a boy is diagnosed, his mother, sisters and other relatives can be offered testing, because women can carry the gene change without symptoms.

Idursulfase (Elaprase) is an enzyme replacement given by vein once a week. Each infusion takes about 3 hours at first and can be shortened to 1 hour if there are no reactions. It was approved in the United States in 2006 and in the European Union in 2007. It has been shown to improve walking ability in people 5 years and older. It does not cross into the brain in useful amounts, so it does not treat the loss of thinking skills.

The idursulfase label carries a boxed warning for life-threatening allergic reactions (anaphylaxis). These can happen during an infusion or up to 24 hours after, so patients are watched closely where emergency care is ready.

On March 25, 2026, the U.S. Food and Drug Administration (FDA) gave accelerated approval to tividenofusp alfa (Avlayah). It is an enzyme medicine built to cross the blood-brain barrier, the lining that keeps most medicines out of the brain. It is approved for the brain-related effects of Hunter syndrome in children who weigh at least 5 kg (about 11 pounds), when started before advanced brain damage. It is given by vein once a week over about 4 hours and is not recommended together with other enzyme medicines. The approval was based on a large drop in a spinal-fluid marker called heparan sulfate. A randomized trial is under way to confirm whether children actually do better.

Other brain-directed enzyme treatments are approved elsewhere: pabinafusp alfa in Japan, idursulfase beta given into the brain’s fluid spaces in Japan, and verenafusp alfa in Russia. No gene therapy for MPS II is approved in the United States. Gene therapies are being tested in clinical trials, including one that uses a boy’s own corrected stem cells.

A donor stem cell transplant is another option for some boys. Cells that grow from the donor’s stem cells make the missing enzyme, and some of them settle in the brain. A nationwide Japanese study found the most benefit when the transplant came before brain shrinkage or heart-valve leakage appeared. Its use is limited by the need for a specialist center and a donor, and experts disagree about when it should be offered.

Without newborn screening, MPS II is usually found only after signs appear. Newborn screening is starting to change this in parts of the United States. Once MPS II is found, many boys start weekly infusions, which can be a heavy load for families over the long term.

Care usually involves a team of specialists, because the disease affects many parts of the body. As the airway narrows, some people need medical help to keep it open. Surgery may be needed for pressure on the spinal cord or for fluid on the brain (hydrocephalus). Braces or surgery can help with bone and joint problems.

For boys with the severe form, families also face changes in behavior, sleep and learning, and over time the loss of skills. If a transplant is chosen, it starts with strong chemotherapy (conditioning). Its risks include the graft not taking, graft-versus-host disease and death.

A transplant for MPS II uses blood-forming stem cells from another person. European guidance for storage diseases prefers a well-matched unrelated donor who does not carry the gene change over a family donor who is a carrier, because a carrier makes less enzyme. In MPS II, a boy’s mother and sisters may be carriers. A brother who does not have MPS II does not carry the change, because boys have only one X chromosome.

Donated umbilical cord blood is often preferred to bone marrow for these diseases. Children who receive it tend to end up with a higher share of donor cells, and it can usually be ready sooner, though it may be rejected a little more often. In Japan, cord blood transplants have been used for boys with the severe form who were found through newborn screening or family testing.

A transplant works best before brain changes begin, so time matters. For families who choose this path and have no suitable brother, unrelated volunteers and public cord blood units can make an early transplant possible.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

Outlook depends mostly on the form. MedlinePlus Genetics describes a life expectancy of 10 to 20 years for the severe form. People with the milder form also have a shorter lifespan but usually live into adulthood, and their thinking is not affected. Heart disease and a blocked airway are major causes of death in both forms.

Enzyme replacement with idursulfase eases many body-wide problems, but it does not stop the brain disease. Whether the newer brain-directed medicines and early transplant change the long-term course is still being studied.

In a nationwide Japanese study, 21 patients who had a transplant were followed for about 10 years on average. Their daily living skills stayed near where they started, and brain scans stabilized or improved in many. The researchers saw the most benefit when the transplant came before brain shrinkage or heart-valve leakage.