Hurler syndrome
Encyclopedia
Hurler syndrome, also known as mucopolysaccharidosis
type I (MPS I), Hurler's disease, also gargoylism
, is a genetic disorder
that results in the buildup of glycosaminoglycans (formerly known as mucopolysaccharides) due to a deficiency of alpha-L iduronidase, an enzyme
responsible for the degradation of mucopolysaccharides in lysosome
s. Without this enzyme, a buildup of heparan sulfate
and dermatan sulfate
occurs in the body. Symptom
s appear during childhood and early death can occur due to organ
damage.
MPS I is divided into three subtypes based on severity of symptoms. All three types result from an absence of, or insufficient levels of, the enzyme α-L-iduronidase. MPS I H or Hurler syndrome is the most severe of the MPS I subtypes. The other two types are MPS I S or Scheie syndrome
and MPS I H-S or Hurler-Scheie syndrome.
Hurler syndrome is often classified as a lysosomal storage disease
, and is clinically related to Hunter Syndrome
. Hunter is X-linked while Hurler is autosomal recessive.
It is named for Gertrud Hurler.
Children born to an MPS I parent carry a defective IDUA gene, which has been mapped to the 4p16.3 site on chromosome 4. The gene is named IDUA because of its iduronidase
enzyme
protein product. , 52 different mutations in the IDUA gene have been shown to cause Hurler syndrome.
Because Hurler syndrome is an autosomal recessive
disorder, affected persons have two non-working copies of the IDUA gene. If someone is born with one normal and one defective copy of the gene (s)he is called a carrier and will produce less α-L-iduronidase than an individual with two normal copies of the gene. The slightly reduced production of the enzyme in carriers, however, remains sufficient for normal function and the person should not show any symptoms of the disease.
, dwarfism
and unique facial features. There is a progressive mental retardation
, with death frequently occurring by the age of 10 years.
Developmental delay is evident by the end of the first year, and patients usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Language
may be limited due to hearing loss and an enlarged tongue
. In time, the clear layers of the cornea
become clouded and retina
s may begin to degenerate. Carpal tunnel syndrome
(or similar compression of nerve
s elsewhere in the body) and restricted joint
movement are common.
Affected children may be large at birth
and appear normal but may have inguinal (in the groin) or umbilical (where the umbilical cord
passes through the abdomen
) hernias. Growth in height may be initially faster than normal, then begins to slow before the end of the first year and often ends around age 3. Many children develop a short body trunk and a maximum stature of less than 4 feet. Distinct facial features (including flat face, depressed nasal bridge, and bulging forehead) become more evident in the second year. By age 2, the ribs have widened and are oar-shaped. The liver
, spleen
and heart
are often enlarged. Children may experience noisy breathing and recurring upper respiratory tract and ear
infection
s. Feeding may be difficult for some children, and many experience periodic bowel problems. Children with Hurler syndrome often die before age 10 from obstructive airway disease, respiratory infections, or cardiac complications.
). Enzyme assay
s (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis
using amniocentesis
and chorionic villus sampling
can verify if a fetus
either carries a copy of the defective gene
or is affected with the disorder. Genetic counseling
can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.
provides therapeutics for mucopolysaccaradosis type I (MPS I), by manufacturing laronidase (Aldurazyme), commercialized by Genzyme
. Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain.
Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can be used as treatments for MPS. Abnormal physical characteristics, except for those affecting the skeleton and eyes, can be improved, and neurologic degeneration can often be halted. BMT and UCBT are high-risk procedures with high rates of morbidity and mortality. There is no cure for MPS I.
. This approach has been taken with retroviral, lentiviral, AAV
, and even nonviral vectors to deliver the iduronidase
gene. Successful treatment of the mouse, dog, and cat models of MPS I has occurred and may pave the way to human trials in the future.
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 I (MPS I), Hurler's disease, also gargoylism
Gargoyle
In architecture, a gargoyle is a carved stone grotesque, usually made of granite, with a spout designed to convey water from a roof and away from the side of a building thereby preventing rainwater from running down masonry walls and eroding the mortar between...
, is a 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 results in the buildup of glycosaminoglycans (formerly known as mucopolysaccharides) due to a deficiency of alpha-L iduronidase, an 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...
responsible for the degradation of mucopolysaccharides in lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s. Without this enzyme, a buildup of 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...
and dermatan sulfate
Dermatan sulfate
Dermatan sulfate is a glycosaminoglycan found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs....
occurs in the body. Symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s appear during childhood and early death can occur due to organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
damage.
MPS I is divided into three subtypes based on severity of symptoms. All three types result from an absence of, or insufficient levels of, the enzyme α-L-iduronidase. MPS I H or Hurler syndrome is the most severe of the MPS I subtypes. The other two types are MPS I S or Scheie syndrome
Scheie syndrome
Scheie syndrome ") is less severe version of Hurler's disease. It is a condition characterized by corneal clouding, facial dysmorphism, and normal lifespan but unlike Hurler's, disease has normal intellect and ....
and MPS I H-S or Hurler-Scheie syndrome.
Hurler syndrome is often classified as 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...
, and is clinically related to Hunter Syndrome
Hunter syndrome
Hunter syndrome, or mucopolysaccharidosis Type II, is a lysosomal storage disease caused by a deficient enzyme, iduronate-2-sulfatase . The syndrome is named after physician Charles A. Hunter , who first described it in 1917...
. Hunter is X-linked while Hurler is autosomal recessive.
It is named for Gertrud Hurler.
Prevalence
Hurler syndrome has an overall frequency of 1 per 100,000. The mucopolysaccharidoses as a whole have a frequency of 1 in every 25,000 births.Genetics
Iduronidase
Iduronidase is an enzyme involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. It is found in the lysosomes of cells.-Pathology:...
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...
protein product. , 52 different mutations in the IDUA gene have been shown to cause Hurler syndrome.
Because Hurler syndrome is an autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
disorder, affected persons have two non-working copies of the IDUA gene. If someone is born with one normal and one defective copy of the gene (s)he is called a carrier and will produce less α-L-iduronidase than an individual with two normal copies of the gene. The slightly reduced production of the enzyme in carriers, however, remains sufficient for normal function and the person should not show any symptoms of the disease.
Features
The condition is marked by progressive deterioration, hepatosplenomegalyHepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
, dwarfism
Dwarfism
Dwarfism is short stature resulting from a medical condition. It is sometimes defined as an adult height of less than 4 feet 10 inches , although this definition is problematic because short stature in itself is not a disorder....
and unique facial features. There is a progressive 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...
, with death frequently occurring by the age of 10 years.
Developmental delay is evident by the end of the first year, and patients usually stop developing between ages 2 and 4. This is followed by progressive mental decline and loss of physical skills. Language
Language
Language may refer either to the specifically human capacity for acquiring and using complex systems of communication, or to a specific instance of such a system of complex communication...
may be limited due to hearing loss 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...
. In time, the clear layers of the cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
become clouded and retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
s may begin to degenerate. 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...
(or similar compression of nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s elsewhere in the body) and restricted joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
movement are common.
Affected children may be large at birth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
and appear normal but may have inguinal (in the groin) or umbilical (where the umbilical cord
Umbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
passes through the abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
) hernias. Growth in height may be initially faster than normal, then begins to slow before the end of the first year and often ends around age 3. Many children develop a short body trunk and a maximum stature of less than 4 feet. Distinct facial features (including flat face, depressed nasal bridge, and bulging forehead) become more evident in the second year. By age 2, the ribs have widened and are oar-shaped. 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...
, 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...
and heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
are often enlarged. Children may experience noisy breathing and recurring upper respiratory tract and ear
Ear
The ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....
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...
s. Feeding may be difficult for some children, and many experience periodic bowel problems. Children with Hurler syndrome often die before age 10 from obstructive airway disease, respiratory infections, or cardiac complications.
Diagnosis
Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urineUrine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
). Enzyme assay
Enzyme assay
Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition.-Enzyme units:...
s (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis
Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
using amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
and chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
can verify if a fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
either carries a copy of the defective 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...
or is affected with the disorder. Genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.
Treatment
Enzyme replacement therapies are currently in use, BioMarin PharmaceuticalBioMarin Pharmaceutical
BioMarin Pharmaceutical Inc. is a biotechnology firm based in Novato, California. It has offices and facilities in the US, South America, Asia and Europe. BioMarin's core business and research is in enzyme replacement therapies...
provides therapeutics for mucopolysaccaradosis type I (MPS I), by manufacturing laronidase (Aldurazyme), commercialized by Genzyme
Genzyme
Genzyme Corporation is a fully owned subsidiary of Sanofi-Aventis. Before its acquisition, Genzyme was an American biotechnology company based in Cambridge, Massachusetts. In 2010, Genzyme was the world’s third-largest biotechnology company, employing more than 11,000 people around the world...
. Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain.
Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can be used as treatments for MPS. Abnormal physical characteristics, except for those affecting the skeleton and eyes, can be improved, and neurologic degeneration can often be halted. BMT and UCBT are high-risk procedures with high rates of morbidity and mortality. There is no cure for MPS I.
Gene Therapy
There is currently a great deal of interest in treating MPS I with gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
. This approach has been taken with retroviral, lentiviral, AAV
Adeno-associated virus
Adeno-associated virus is a small virus which infects humans and some other primate species. AAV is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of...
, and even nonviral vectors to deliver the iduronidase
Iduronidase
Iduronidase is an enzyme involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. It is found in the lysosomes of cells.-Pathology:...
gene. Successful treatment of the mouse, dog, and cat models of MPS I has occurred and may pave the way to human trials in the future.