Hunter syndrome
Encyclopedia
Hunter syndrome, or mucopolysaccharidosis
Type II, is a lysosomal storage disease
caused by a deficient (or absent) enzyme
, iduronate-2-sulfatase
(I2S). The syndrome is named after physician Charles A. Hunter (1873–1955), who first described it in 1917. Born in Scotland, Hunter emigrated to Canada and had a medical practice in Winnipeg, Manitoba.
II (MPS II), is a serious genetic disorder
that primarily affects males (X-linked recessive
). It interferes with the body's ability to break down and recycle specific mucopolysaccharides, also known as glycosaminoglycans or GAG. Hunter syndrome is one of several related lysosomal storage diseases.
In Hunter syndrome, GAG builds up in cells throughout the body due to a deficiency
or absence of the enzyme
iduronate-2-sulfatase
(I2S). This buildup interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical manifestations for some people with Hunter syndrome include distinct facial features and large head. In some cases of Hunter syndrome, central nervous system
involvement leads to developmental delays and nervous system
problems. Not all people with Hunter syndrome are affected by the disease in exactly the same way, and the rate of symptom progression varies widely. However, Hunter syndrome is always severe, progressive
, and life-limiting.
. In general, the time of diagnosis usually occurs from about 2 to 4 years of age. Doctors may use laboratory
tests to provide additional evidence that an MPS disorder is present, before making a definitive diagnosis by measuring the iduronate-2-sulfatase (I2S) enzyme activity. The most commonly used laboratory screening test for an MPS disorder is a urine test for GAG. It is important to note that the urine test for GAG can occasionally be normal and yet the child still may have an MPS disorder. A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum
, white blood cell
s, or fibroblast
s from skin biopsy
. In some people with Hunter syndrome, analysis of the I2S gene
can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid
or in chorionic villus tissue.
) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell
in the human body
has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.
If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. Alternatively, during egg and sperm formation, a mutation
can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling
is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected.
depends on a vast array of biochemical reactions to support critical functions, including the production of energy
, growth and development
, communication within the body, and protection from infection
. Another critical function is the breakdown of large biomolecules, which is the underlying problem in Hunter syndrome (MPS II) and related storage disorders.
The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue of the body known as the extracellular matrix
. This matrix is made up of a variety of sugars and proteins and helps to form the architectural framework of the body. The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together. One of the parts of the extracellular matrix is a complex
molecule
called a proteoglycan
. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides, otherwise known as GAG. There are several types of GAG, each found in certain characteristic places in the body
In Hunter syndrome, the problem concerns the breakdown of two GAG: dermatan sulfate
and heparan sulfate
. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme
I2S. In people with Hunter syndrome, this enzyme is either partially or completely inactive. As a result, GAG build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this buildup continues, it interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. The rate of GAG buildup is not the same for all people with Hunter syndrome, resulting in a wide spectrum of medical problems.
. Since these symptoms are quite common among all infants, they are not likely to lead a doctor to make a diagnosis of Hunter syndrome right away. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical appearances of many children with Hunter syndrome include a distinctive coarseness in their facial features, including a prominent forehead
, a nose with a flattened bridge, and an enlarged tongue
. For this reason, unrelated children with Hunter syndrome often look alike. They may also have a large head as well as an enlarged abdomen. Many continue to have frequent infections of the ears
and respiratory tract
.
The continued storage of GAG in cells can lead to organs being affected in important ways. The thickening of the heart valves along with the walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened as well, leading to breathing problems while sleeping (obstructive airway disease). People with Hunter syndrome may also have limited lung capacity due to pulmonary involvement. As the liver
and spleen
grow larger with time, the belly may become distended, making hernias more noticeable. All major joints (including the wrists, elbows, shoulders
, hips
, and knees) may be affected by Hunter syndrome, leading to joint stiffness
and limited motion. Progressive involvement of the finger and thumb joints results in decreased ability to pick up small objects. The effects on other joints, such as hips and knees, can make it increasingly difficult to walk normally. If carpal tunnel syndrome
develops, a further decrease in hand function can occur. The bones themselves may be affected, resulting in short stature. In addition, pebbly, ivory-colored skin lesions may be found on the upper arms and legs and upper back of some people with Hunter syndrome. The presence or absence of the skin lesions is not helpful, however, in predicting clinical severity in Hunter syndrome. Finally, the storage of GAG in the brain
can lead to delayed development with subsequent mental retardation
. The rate and degree of progression may be different for each person with Hunter syndrome.
There is a broad range of severity in the symptoms of Hunter syndrome. It is important to note that though the term "mild" is used by physicians in comparing people with Hunter syndrome, the effects of even mild disease are quite serious. Two of the most significant areas of variability concern the degree of mental retardation and expected lifespan. Some people who have Hunter syndrome are not mentally retarded and live into their 20s or 30s; there are occasional reports of people who have lived into their 50s or 60s. The quality of life remains high in a large number of people, and many adults are actively employed. In contrast, others with Hunter syndrome develop severe mental impairment and have life expectancies of 15 years or fewer.
. There are about 30 Hunter Syndrome patients in Canada
. There is 1 Hunter Syndrome patient in New Zealand. There are 6 Hunter Syndrome patients in Ireland, 1 case in Saudi Arabia and 1 case in Chile.
A study in the United Kingdom indicated an incidence among males of approximately 1 in 130.000 male live births.
, treatment
has been proven very difficult.
For information on clinical trials visit Clinicaltrials.gov
of many bodily functions. Surgery
and psychiatry
are often pivotal here.
graft
. It has the advantage of procuring a new source of the missing I2S. However, the results have been considered imperfect at best.
While the treatment is able to stop most of the symptoms, it is nearly totally inefficient against the brain symptoms of the Hunter syndrome patients. Mostly, this translates in much improved life expectancy
, much improved life conditions but it does not solve the mental
deficiencies of the patients.
However, bone marrow graft is a major surgical operation with several adverse effects of such surgery, including life threatening risks for the patient.
Because of these reasons, grafts have seen a decrease in their application as Hunter syndrome treatment.
as an enzyme replacement treatment for Hunter syndrome. Elaprase is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA
technology in a human cell line. Elaprase may be one of the most expensive drugs ever produced, with an estimated cost of USD300,000 per patient, per year.
From the beginning, Elaprase has been considered as an opportunity to find most or all of the advantages of bone marrow grafts without some of its drawbacks.
A 53-week, randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that Elaprase provides clinically important benefits to Hunter syndrome patients. The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a 6-minute walk test and percent predicted forced vital capacity. Shire
is pleased to report that this endpoint achieved statistical significance
compared to placebo
. After one year of treatment, patients receiving weekly infusion
s of Elaprase experienced a mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo.
Treatment with ELAPRASE was generally well-tolerated by patients in the Phase II/III trial. Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate. The Elaprase label includes a boxed warning with information on the potential for hypersensitivity
reactions. The boxed warning states that “Anaphylactoid reactions, which may be life threatening, have been observed in some patients during Elaprase infusions. Therefore, appropriate medical support should be readily available when Elaprase is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.”
In all phases of clinical study for Elaprase, eleven patients experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of a hypersensitivity reaction. The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache
and arthralgia
.
Fifty-one percent (32 of 63) of patients in the weekly Elaprase treatment arm in the pivotal clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies.
Parents of Hunter syndrome patients should be aware that the therapy implies a strict regimen of long duration IV transfusion
. For hyperactive boys like most young Hunter syndrome patient, this is still a considerable constraint. Similarly, the permanent nature and the heaviness of this treatment is to be kept in mind.
, West Sussex
, England
, suffocated his 10 year old son Jacob with a pillow, because of the boy's disabilities related to Hunter syndrome.
On December 13, 2005 Andrew Wragg walked out of Lewes Crown Court
a free man after a jury determined that he did not murder his 10-year-old son. A military security
specialist, Wragg also claimed that he was under stress after returning from the war in Iraq
. He denied murdering Jacob, but pleaded guilty to manslaughter
by reason of diminished capacity.
Mrs. Justice Anne Rafferty, calling the case "exceptional", gave Wragg a two-year prison sentence for manslaughter, then suspended his sentence for two years. Rafferty said there was "nothing to be gained" from sending Wragg to prison for the crime.
Mucopolysaccharidosis
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and...
Type II, is a lysosomal storage disease
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
caused by a deficient (or absent) enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, iduronate-2-sulfatase
Iduronate-2-sulfatase
Iduronate-2-sulfatase is a sulfatase enzyme associated with Hunter syndrome.-External links:* -See also:* Idursulfase...
(I2S). The syndrome is named after physician Charles A. Hunter (1873–1955), who first described it in 1917. Born in Scotland, Hunter emigrated to Canada and had a medical practice in Winnipeg, Manitoba.
Overview
Hunter syndrome, or mucopolysaccharidosisMucopolysaccharidosis
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and...
II (MPS II), is a serious genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that primarily affects males (X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
). It interferes with the body's ability to break down and recycle specific mucopolysaccharides, also known as glycosaminoglycans or GAG. Hunter syndrome is one of several related lysosomal storage diseases.
In Hunter syndrome, GAG builds up in cells throughout the body due to a deficiency
Deficiency
A deficiency is generally a lack of something. It may also refer to:*A deficient number, in mathematics, a number n for which σ A deficiency is generally a lack of something. It may also refer to:...
or absence of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
iduronate-2-sulfatase
Iduronate-2-sulfatase
Iduronate-2-sulfatase is a sulfatase enzyme associated with Hunter syndrome.-External links:* -See also:* Idursulfase...
(I2S). This buildup interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical manifestations for some people with Hunter syndrome include distinct facial features and large head. In some cases of Hunter syndrome, central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
involvement leads to developmental delays and nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
problems. Not all people with Hunter syndrome are affected by the disease in exactly the same way, and the rate of symptom progression varies widely. However, Hunter syndrome is always severe, progressive
Progressive illness
The term progressive illness describes the course of an illness that gradually progresses and changes mode, generally to the worse. In contrast, non-progressive or chronic illnesses are relatively constant.-Examples:...
, and life-limiting.
Diagnosis
The visible signs and symptoms of Hunter syndrome (MPS II) in younger people are usually the first clues leading to a diagnosisDiagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
. In general, the time of diagnosis usually occurs from about 2 to 4 years of age. Doctors may use laboratory
Laboratory
A laboratory is a facility that provides controlled conditions in which scientific research, experiments, and measurement may be performed. The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories...
tests to provide additional evidence that an MPS disorder is present, before making a definitive diagnosis by measuring the iduronate-2-sulfatase (I2S) enzyme activity. The most commonly used laboratory screening test for an MPS disorder is a urine test for GAG. It is important to note that the urine test for GAG can occasionally be normal and yet the child still may have an MPS disorder. A definitive diagnosis of Hunter syndrome is made by measuring I2S activity in serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
, white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s, or fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s from skin biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
. In some people with Hunter syndrome, analysis of the I2S gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
can determine clinical severity. Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid
Amniotic fluid
Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of amniotic fluid :...
or in chorionic villus tissue.
Genetics
Since Hunter syndrome is an inherited disorder (X-linked recessiveX-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
) that primarily affects males, it is passed down from one generation to the next in a specific way. Nearly every cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
in the human body
Human body
The human body is the entire structure of a human organism, and consists of a head, neck, torso, two arms and two legs.By the time the human reaches adulthood, the body consists of close to 100 trillion cells, the basic unit of life...
has 46 chromosomes, with 23 derived from each parent. The I2S gene is located on the X chromosome. Females have two X chromosomes, one inherited from each parent, whereas males have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.
If a male has an abnormal copy of the I2S gene, he will develop Hunter syndrome. A male can obtain an abnormal copy of the I2S gene in one of two ways. His mother is often a carrier; i.e., she has one abnormal and one normal I2S gene, and she passes along the abnormal gene to him. Alternatively, during egg and sperm formation, a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
can develop in the I2S gene on his X chromosome. In this second case, the mother is not a carrier and the risk of a spontaneous mutation occurring again in a future sibling
Sibling
Siblings are people who share at least one parent. A male sibling is called a brother; and a female sibling is called a sister. In most societies throughout the world, siblings usually grow up together and spend a good deal of their childhood socializing with one another...
is low but not zero. Females can carry one abnormal copy of the I2S gene and are usually not affected.
Biochemistry
The human bodyHuman body
The human body is the entire structure of a human organism, and consists of a head, neck, torso, two arms and two legs.By the time the human reaches adulthood, the body consists of close to 100 trillion cells, the basic unit of life...
depends on a vast array of biochemical reactions to support critical functions, including the production of energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
, growth and development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
, communication within the body, and protection from infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. Another critical function is the breakdown of large biomolecules, which is the underlying problem in Hunter syndrome (MPS II) and related storage disorders.
The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue of the body known as the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
. This matrix is made up of a variety of sugars and proteins and helps to form the architectural framework of the body. The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together. One of the parts of the extracellular matrix is a complex
Complexity
In general usage, complexity tends to be used to characterize something with many parts in intricate arrangement. The study of these complex linkages is the main goal of complex systems theory. In science there are at this time a number of approaches to characterizing complexity, many of which are...
molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
called a proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides, otherwise known as GAG. There are several types of GAG, each found in certain characteristic places in the body
In Hunter syndrome, the problem concerns the breakdown of two GAG: dermatan sulfate
Dermatan sulfate
Dermatan sulfate is a glycosaminoglycan found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs....
and heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
I2S. In people with Hunter syndrome, this enzyme is either partially or completely inactive. As a result, GAG build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. As this buildup continues, it interferes with the way certain cells and organs in the body function and leads to a number of serious symptoms. The rate of GAG buildup is not the same for all people with Hunter syndrome, resulting in a wide spectrum of medical problems.
Signs and Symptoms
The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth, but usually start to become noticeable after the first year of life. Often, the first symptoms of Hunter syndrome may include abdominal hernias, ear infections, runny noses, and coldsCommon cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
. Since these symptoms are quite common among all infants, they are not likely to lead a doctor to make a diagnosis of Hunter syndrome right away. As the buildup of GAG continues throughout the cells of the body, signs of Hunter syndrome become more visible. Physical appearances of many children with Hunter syndrome include a distinctive coarseness in their facial features, including a prominent forehead
Forehead
For the Arsenal striker see GervinhoIn human anatomy, the forehead is the fore part of the head. It is, formally, an area of the head bounded by three features, two of the skull and one of the scalp. The top of the forehead is marked by the hairline, the edge of the area where hair on the scalp...
, a nose with a flattened bridge, and an enlarged tongue
Tongue
The tongue is a muscular hydrostat on the floors of the mouths of most vertebrates which manipulates food for mastication. It is the primary organ of taste , as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly...
. For this reason, unrelated children with Hunter syndrome often look alike. They may also have a large head as well as an enlarged abdomen. Many continue to have frequent infections of the ears
EARS
EARS may refer to:* Electoral software* Electronic Arts, Redwood Shores campus.* Emirates Amateur Radio Society...
and respiratory tract
Respiratory tract
In humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
.
The continued storage of GAG in cells can lead to organs being affected in important ways. The thickening of the heart valves along with the walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened as well, leading to breathing problems while sleeping (obstructive airway disease). People with Hunter syndrome may also have limited lung capacity due to pulmonary involvement. As the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
grow larger with time, the belly may become distended, making hernias more noticeable. All major joints (including the wrists, elbows, shoulders
Shoulders
Shoulders is drinking game that involves players competing in a fast paced game attempting to "count" to 21.-Game play:*The game begins with a player slapping his left/right shoulder, this starts the count at 1....
, hips
HIPS
HIPS may refer to:* High impact polystyrene* Home Information Pack* Host-based intrusion-prevention system, a computer security system oriented towards workstations...
, and knees) may be affected by Hunter syndrome, leading to joint stiffness
Joint stiffness
Joint stiffness may be either the symptom of pain on moving a joint, the symptom of loss of range of motion or the physical sign of reduced range of motion. Doctors prefer the latter two uses but patients often use the first meaning....
and limited motion. Progressive involvement of the finger and thumb joints results in decreased ability to pick up small objects. The effects on other joints, such as hips and knees, can make it increasingly difficult to walk normally. If carpal tunnel syndrome
Carpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
develops, a further decrease in hand function can occur. The bones themselves may be affected, resulting in short stature. In addition, pebbly, ivory-colored skin lesions may be found on the upper arms and legs and upper back of some people with Hunter syndrome. The presence or absence of the skin lesions is not helpful, however, in predicting clinical severity in Hunter syndrome. Finally, the storage of GAG in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
can lead to delayed development with subsequent mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
. The rate and degree of progression may be different for each person with Hunter syndrome.
There is a broad range of severity in the symptoms of Hunter syndrome. It is important to note that though the term "mild" is used by physicians in comparing people with Hunter syndrome, the effects of even mild disease are quite serious. Two of the most significant areas of variability concern the degree of mental retardation and expected lifespan. Some people who have Hunter syndrome are not mentally retarded and live into their 20s or 30s; there are occasional reports of people who have lived into their 50s or 60s. The quality of life remains high in a large number of people, and many adults are actively employed. In contrast, others with Hunter syndrome develop severe mental impairment and have life expectancies of 15 years or fewer.
Prevalence and incidence
There are estimated to be approximately 2,000 people afflicted with Hunter Syndrome worldwide, 500 of whom live in the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. There are about 30 Hunter Syndrome patients in Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
. There is 1 Hunter Syndrome patient in New Zealand. There are 6 Hunter Syndrome patients in Ireland, 1 case in Saudi Arabia and 1 case in Chile.
A study in the United Kingdom indicated an incidence among males of approximately 1 in 130.000 male live births.
Treatment
Because of the very specific nature of the illnessIllness
Illness is a state of poor health. Illness is sometimes considered another word for disease. Others maintain that fine distinctions exist...
, treatment
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
has been proven very difficult.
For information on clinical trials visit Clinicaltrials.gov
Palliative treatment
Because of the nature of the illness, and in front of the lack of really efficient treatment, it is important to emphasize the need for extensive palliative treatment against the diverse symptoms. Their objective is to reduce the effects of the deteriorationDeterioration
Deterioration is a term now commonly used in health care, to describe worsening of a patient's condition. It is often used as a shortened form of 'deterioration not recognised or not acted upon'. Much work to reduce harm from deterioration has been undertaken by the National Patient Safety Agency...
of many bodily functions. Surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
and psychiatry
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
are often pivotal here.
Bone marrow graft
For a long time, the most efficient approach has been to use bone marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
graft
Bone grafting
Bone grafting is a surgical procedure that replaces missing bone in order to repair bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly....
. It has the advantage of procuring a new source of the missing I2S. However, the results have been considered imperfect at best.
While the treatment is able to stop most of the symptoms, it is nearly totally inefficient against the brain symptoms of the Hunter syndrome patients. Mostly, this translates in much improved life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
, much improved life conditions but it does not solve the mental
Mind
The concept of mind is understood in many different ways by many different traditions, ranging from panpsychism and animism to traditional and organized religious views, as well as secular and materialist philosophies. Most agree that minds are constituted by conscious experience and intelligent...
deficiencies of the patients.
However, bone marrow graft is a major surgical operation with several adverse effects of such surgery, including life threatening risks for the patient.
Because of these reasons, grafts have seen a decrease in their application as Hunter syndrome treatment.
Elaprase
Originally developed and introduced by 'Shire Human Genetic Therapies Ltd' (previously named 'Transkaryotic Therapies, Inc.'), on July 24, 2006, a synthetic version of I2S, called Elaprase (Idursulfase), was approved by the United States Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
as an enzyme replacement treatment for Hunter syndrome. Elaprase is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
technology in a human cell line. Elaprase may be one of the most expensive drugs ever produced, with an estimated cost of USD300,000 per patient, per year.
From the beginning, Elaprase has been considered as an opportunity to find most or all of the advantages of bone marrow grafts without some of its drawbacks.
A 53-week, randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that Elaprase provides clinically important benefits to Hunter syndrome patients. The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a 6-minute walk test and percent predicted forced vital capacity. Shire
Shire
A shire is a traditional term for a division of land, found in the United Kingdom and in Australia. In parts of Australia, a shire is an administrative unit, but it is not synonymous with "county" there, which is a land registration unit. Individually, or as a suffix in Scotland and in the far...
is pleased to report that this endpoint achieved statistical significance
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
compared to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. After one year of treatment, patients receiving weekly infusion
Infusion
An infusion is the outcome of steeping plants with desired chemical compounds or flavors in water or oil.-History:The first recorded use of essential oils was in the 10th or 11th century by the Persian polymath Avicenna, possibly in The Canon of Medicine.-Preparation techniques:An infusion is very...
s of Elaprase experienced a mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo.
Treatment with ELAPRASE was generally well-tolerated by patients in the Phase II/III trial. Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate. The Elaprase label includes a boxed warning with information on the potential for hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
reactions. The boxed warning states that “Anaphylactoid reactions, which may be life threatening, have been observed in some patients during Elaprase infusions. Therefore, appropriate medical support should be readily available when Elaprase is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.”
In all phases of clinical study for Elaprase, eleven patients experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of a hypersensitivity reaction. The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
and arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
.
Fifty-one percent (32 of 63) of patients in the weekly Elaprase treatment arm in the pivotal clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies.
Parents of Hunter syndrome patients should be aware that the therapy implies a strict regimen of long duration IV transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
. For hyperactive boys like most young Hunter syndrome patient, this is still a considerable constraint. Similarly, the permanent nature and the heaviness of this treatment is to be kept in mind.
Notable Cases
On July 24, 2004, Andrew Wragg, 38, of WorthingWorthing
Worthing is a large seaside town with borough status in West Sussex, within the historic County of Sussex, forming part of the Brighton/Worthing/Littlehampton conurbation. It is situated at the foot of the South Downs, west of Brighton, and east of the county town of Chichester...
, West Sussex
West Sussex
West Sussex is a county in the south of England, bordering onto East Sussex , Hampshire and Surrey. The county of Sussex has been divided into East and West since the 12th century, and obtained separate county councils in 1888, but it remained a single ceremonial county until 1974 and the coming...
, England
England
England is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
, suffocated his 10 year old son Jacob with a pillow, because of the boy's disabilities related to Hunter syndrome.
On December 13, 2005 Andrew Wragg walked out of Lewes Crown Court
Lewes Crown Court
Lewes Crown Court is a Crown Court in Lewes, East Sussex, England. It is housed in the Lewes Combined Court Centre which it shares with Lewes County Court in the Lewes High Street...
a free man after a jury determined that he did not murder his 10-year-old son. A military security
Security
Security is the degree of protection against danger, damage, loss, and crime. Security as a form of protection are structures and processes that provide or improve security as a condition. The Institute for Security and Open Methodologies in the OSSTMM 3 defines security as "a form of protection...
specialist, Wragg also claimed that he was under stress after returning from the war in Iraq
Iraq
Iraq ; officially the Republic of Iraq is a country in Western Asia spanning most of the northwestern end of the Zagros mountain range, the eastern part of the Syrian Desert and the northern part of the Arabian Desert....
. He denied murdering Jacob, but pleaded guilty to manslaughter
Manslaughter
Manslaughter is a legal term for the killing of a human being, in a manner considered by law as less culpable than murder. The distinction between murder and manslaughter is said to have first been made by the Ancient Athenian lawmaker Dracon in the 7th century BC.The law generally differentiates...
by reason of diminished capacity.
Mrs. Justice Anne Rafferty, calling the case "exceptional", gave Wragg a two-year prison sentence for manslaughter, then suspended his sentence for two years. Rafferty said there was "nothing to be gained" from sending Wragg to prison for the crime.
External links
- MPSsociety.org, National MPS Society
- About.com, "Hunter Syndrome", About.comAbout.comAbout.com is an online source for original information and advice. It is written in English, and is aimed primarily at North Americans. It is owned by The New York Times Company....
- CCHS-DL.SLIS.ua.edu, Hunter Syndrome Patient/Family Resources CCHS Resources.
- Hunterpatients.com
- NLM.NIH.gov, GeneReview/NIH/UW entry on Mucopolysaccharidosis Type II
- HideandSeek.org, Foundation For Lysosomal Disease Research
- Elaprase.com, (idursulfase) website.
- ClinicalTrials.gov
- LysosomalStorageResearch.ca, The Hunter Disease eClinic and eBook - virtual education ,