Hunter syndrome

February 7, 2017

Hunter Syndrome (or Mucopolysaccharidosis/MPS II) is a rare condition affecting between 1 in 100,000 to 1 in 150,000 male births, although it is estimated that the grouping of MPS conditions collectively affect 1 in 25,000 births in the United States (MPS conditions include MPS I, II, III, IV, VI, VII and ML II and III).

Hunter’s Syndrome is one of a family of disorders called enzyme deficiencies. Enzymes are special types of proteins required to break down food molecules into fuel during metabolism, the process by which the body gets energy for normal growth and development. Enzyme deficiencies, or the absence of these enzymes, are inherited defects that result in a number of life-changing or life-threatening conditions.

Hunter syndrome is often severe and always progressive. It affects the brain and spinal cord, resulting in debilitating signs and symptoms that include developmental delay, and progressive mental decline. It also affects the body resulting in loss of physical function, impaired language development (due to hearing loss and an enlarged tongue), corneal and retinal damage, carpal tunnel syndrome and restricted joint movement.

Unrelated children with Hunter Syndrome often look alike and have a distinctive coarseness in their facial features, including a prominent forehead, a nose with a flattened bridge, and enlarged lips and tongue. They may also have a large head, short neck, broad chest, thick hands, and an enlarged abdomen.

There is no cure for MPS diseases, but there are ways of managing and treating the problems they cause, including enzyme replacement therapies.

Causes

The cause of Hunter syndrome is a mutation in a gene which controls the production of (codes for) the enzyme iduronate sulfatase. This gene, known as IDS, is located on the long arm of the X chromosome (Xq27-28).

The enzyme iduronate sulfatase contributes to breaking down mucopolysaccharides (also known as glycosaminoglycans). These saccharides, with their long chains of carbohydrate units, are components of various tissues. Breakdown of the mucopolysaccharides normally takes place in the cell lysosomes, small units found in all cells except red blood cells. Lysosomes contain enzymes, proteins that contribute to chemical reactions without themselves undergoing any permanent change, and their function is to digest and break down various substances.

Mucopolysaccharides are long chains of sugar molecule used in the building of connective tissues in the body.

“saccharide” is a general term for a sugar molecule (think of saccharin)
“poly” means many
“muco” refers to the thick jelly-like consistency of the molecules

Hunter syndrome is characterized by iduronate sulfatase deficiency, which results in the build-up of undigested mucopolysaccharides in the cells. These aggregations damage various tissues and organs in the body.

Heridity – The inheritance pattern of Hunter syndrome is X-linked recessive. An X-linked recessive inheritance pattern is caused by a mutated gene located on the X chromosome, which is one of the chromosomes determining sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50% risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene.

Risk Factors

There are two major risk factors for developing Hunter syndrome:

Family history – Hunter syndrome is caused by a defective chromosome, and a child must inherit the defective chromosome to develop the disease. Hunter syndrome is what’s known as an X-linked recessive disease. This means that women carry the defective disease-causing X chromosome and can pass it on, but women aren’t affected by the disease themselves.
Sex – Hunter syndrome nearly always occurs in males. Girls are far less at risk of developing this disease because they inherit two X chromosomes. If one of the X chromosomes is defective, their normal X chromosome can provide a functioning gene. If the X chromosome of a male is defective, however, there isn’t another normal X chromosome to compensate for the problem.

Symptoms

Hunter syndrome is one type of a group of inherited metabolic disorders called mucopolysaccharidoses (MPSs), and Hunter syndrome is referred to as MPS II.

Hunter syndrome symptoms vary and range from mild to severe. Symptoms aren’t present at birth, but often begin around ages 2 to 4.

Common childhood occurrences but early symptoms of Hunter syndrome –

Inguinal hernia
Ear infections
Runny nose
Difficulty breathing
Heart murmur

Signs and symptoms may include –

An enlarged head (macrocephaly)
Thickening of the lips
A broad nose and flared nostrils
A protruding tongue
A deep, hoarse voice
Abnormal bone size or shape and other skeletal irregularities
A distended abdomen, as a result of enlarged internal organs
Diarrhea
White skin growths that resemble pebbles
Joint stiffness
Aggressive behavior
Stunted growth
Delayed development, such as late walking or talking

It is difficult to be precise about life expectancy because of variation in severity and age of onset. Some individuals whose brain is affected have lived into adulthood but this is usually accompanied by a decline in their quality of life as brain function deteriorates.

If the brain is not affected, a more normal life span can be expected, but significant physical problems can develop that, without treatment, may reduce life expectancy.

Complications

Airway obstruction
Carpal tunnel syndrome
Hearing loss that gets worse over time
Loss of ability to complete daily living activities
Joint stiffness that leads to contractures
Mental function that gets worse over time

Treatment

The U.S. Food and Drug Administration has approved the first treatment for Hunter syndrome. The medicine, called idursulfase (Elaprase), is given through a vein (intravenously).

Treatment focuses on managing signs, symptoms and complications to provide some relief for the child as the disease progresses –

Enzyme replacement therapy (ERT) can help slow the disease for boys with milder Hunter syndrome. It replaces the protein their body doesn’t make. ERT can help improve –

Walking, climbing stairs, and the ability to keep up in general
Movement and stiff joints
Breathing
Growth
Hair and facial features

ERT is the first treatment for kids whose brains aren’t affected. It doesn’t slow the disease in the brain.

Bone marrow and umbilical cord blood transplants – These transplants bring cells into your child’s body that can hopefully make the protein he’s missing. The new cells come from either a bone marrow donor whose cells match your child’s or the stem cells of umbilical cord blood from newborn babies.

Relief for respiratory complications – Removal of tonsils and adenoids can open up your child’s airway and help relieve sleep apnea. But as the disease progresses, tissues continue to thicken and these problems can come back.

Addressing heart complications – The child’s doctor will want to watch closely for cardiovascular complications, such as high blood pressure, heart murmur and leaky heart valves. If the child has severe cardiovascular problems, the doctor may recommend surgery to replace heart valves.

Treatment for skeletal and connective tissue problems – Because most children with Hunter syndrome don’t heal well and often have complications after surgery, options are limited for addressing skeletal and connective tissue complications. For example, surgery to stabilize the spine using internal hardware is difficult when bones are fragile.

Managing neurological complications – Problems associated with the buildup of fluid and tissue around the brain and spinal cord are difficult to address because of the inherent risks in treating these parts of the body.

Managing behavioral problems – If the child develops abnormal behavior as a result of Hunter syndrome, providing a safe home environment is one of the most important ways of managing this challenge.

Addressing sleep issues – The sleep patterns of a child with Hunter syndrome become more and more disorganized. Medications including sedatives and especially melatonin can improve sleep.

Reference –

http://www.aapd.org/assets/1/25/Downs-17-02.pdf

http://www.reactome.org/content/detail/2206296

https://umm.edu/health/medical/ency/articles/hunter-syndrome

http://www.news-medical.net/health/Hunter-Syndrome-Treatments.aspx

http://www.webmd.com/children/hunter-syndrome-mps-ii?page=3

http://armagen.com/our-focus/hunter-syndrome/

http://www.mpssociety.org.au/hunter-syndrome2

http://www.shirecanada.com/en/shire-canada/hunter-syndrome.aspx

http://www.chp.edu/our-services/rare-disease-therapy/conditions-we-treat/hunter-syndrome

http://www.nytimes.com/health/guides/disease/hunter-syndrome/overview.html

http://www.sciencedaily.com/releases/2006/08/060819115541.htm