Mucopolysaccharidosis

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs (formerly called mucopolysaccharides) are also found in the fluids that lubricate joints.

Individuals with mucopolysaccharidosis either do not produce enough of one of the eleven enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these GAGs collect in the cells, blood and connective tissues. The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning.

The mucopolysaccharidoses are part of the lysosomal storage disease family, a group of genetic disorders that result when the lysosome organelle in animal cells malfunctions. The lysosome can be thought of as the cell's recycling center because it processes unwanted material into other substances that the cell can utilize. Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival. Lysosomal disorders like mucopolysaccharidosis are triggered when a particular enzyme exists in too small an amount or is missing altogether.

Signs and symptoms

thumb|right|A child with an unspecified MPS disorder, showing characteristic facial features

thumb|right|Corneal clouding in a 30-year-old male with MPS-VI. Several other MPS disorders may also present with corneal clouding.

The mucopolysaccharidoses share many clinical features but have varying degrees of severity. These features may not be apparent at birth but progress as storage of GAGs affects bone, skeletal structure, connective tissues, and organs. Neurological complications may include damage to neurons (which send and receive signals throughout the body) as well as pain and impaired motor function. This results from compression of nerves or nerve roots in the spinal cord or in the peripheral nervous system, the part of the nervous system that connects the brain and spinal cord to sensory organs such as the eyes and to other organs, muscles, and tissues throughout the body.

Depending on the mucopolysaccharidosis subtype, affected individuals may have normal intellect or have cognitive impairments, may experience developmental delay, or may have severe behavioral problems. Many individuals have hearing loss, either conductive (in which pressure behind the eardrum causes fluid from the lining of the middle ear to build up and eventually congeal), neurosensory (in which tiny hair cells in the inner ear are damaged), or both. Communicating hydrocephalus—in which the normal reabsorption of cerebrospinal fluid is blocked and causes increased pressure inside the head—is common in some of the mucopolysaccharidoses. Surgically inserting a shunt into the brain can drain fluid. The eye's cornea often becomes cloudy from intracellular storage, and glaucoma and degeneration of the retina also may affect the patient's vision.

Physical symptoms generally include coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and other skeletal irregularities, thickened skin, enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly), hernias, and excessive body hair growth. Short and often claw-like hands, progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function. Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea. Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.

Another lysosomal storage disease often confused with the mucopolysaccharidoses is mucolipidosis. In this disorder, excessive amounts of fatty materials known as lipids (another principal component of living cells) are stored, in addition to sugars. Persons with mucolipidosis may share some of the clinical features associated with the mucopolysaccharidoses (certain facial features, bony structure abnormalities, and damage to the brain), and increased amounts of the enzymes needed to break down the lipids are found in the blood.

Genetics

thumb|right|Mucopolysaccharidosis has an autosomal recessive pattern of inheritance.

It is estimated that 1 in 25,000 babies born in the United States will have some form of the mucopolysaccharidoses. Approximately 1 in 100,000 newborns will experience severe mucopolysaccharidosis type I, while approximately 1 in 500,000 newborns will experience attenuated mucopolysaccharidosis type I. Most mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.

Diagnosis

Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (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.

Types

Seven distinct clinical types and numerous subtypes of the mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) differs clinically, most patients generally experience a period of normal development followed by a decline in physical and/or mental function. (Note: MPS-V and MPS-VIII are no longer in use as designations for any disease.)

Overview table

{|class="wikitable" style="text-align: left;"

|+ Main mucopolysaccharidoses

! style="width: 5em" | Type

! style="width: 13em" | Common name Other names

! style= | OMIM

! style="width: 5em" | Gene

! style="width: 4em" | Locus

! style="width: 12em" | Deficient enzyme

! style="width: 10em" | Accumulated products

! style= | Symptoms

! style= | Incidence

| MPS IH

| Hurler syndrome

| rowspan="3" | IDUA

| rowspan="3" | 4p16.3

| rowspan="3" | α-L-iduronidase

| rowspan="3" | Heparan sulfate Dermatan sulfate

| rowspan="3" | Intellectual disability, micrognathia, coarse facial features, macroglossia, retinal degeneration, corneal clouding, cardiomyopathy, hepatosplenomegaly

| rowspan="3" | 1:100,000

| MPS IH/S

| Hurler–Scheie syndrome

| MPS IS

| Scheie syndrome Formerly: Mucopolysaccharidosis type V

| MPS II

| Hunter syndrome

| IDS

| Xq28

| Iduronate sulfatase

| Heparan sulfate Dermatan sulfate

| Intellectual disability (similar, but milder, symptoms to MPS I). This type exceptionally has X-linked recessive inheritance

| 1:100,000-1:150,000 males – 1:50,000

| MPS IIIB

| Sanfilippo syndrome B NAGLU deficiency

| NAGLU

| 17q21.2

| N-acetylglucosaminidase

| MPS IIIC

| Sanfilippo syndrome C

| HGSNAT

| 8p11.21

| Heparan-α-glucosaminide N-acetyltransferase

| MPS IIID

| Sanfilippo syndrome D

| GNS

| 12q14.3

| N-acetylglucosamine 6-sulfatase

| MPS IVA

| Morquio syndrome A

| GALNS

| 16q24.3

| Galactose-6-sulfate sulfatase

| Keratan sulfate Chondroitin 6-sulfate

| rowspan="2" | Severe skeletal dysplasia, short stature, motor dysfunction

| rowspan="2" | 1 in 75,000 The disorder results from hyaluronidase deficiency. Symptoms included nodular soft-tissue masses located around joints, with episodes of painful swelling of the masses and pain that ended spontaneously within 3 days. Pelvic radiography showed multiple soft-tissue masses and some bone erosion. Other traits included mild facial changes, acquired short stature as seen in other MPS disorders, and normal joint movement and intelligence.

Treatment

Currently there is no cure for these disorders. Medical care is directed at treating systemic conditions and improving the person's quality of life. Physical therapy and daily exercise may delay joint problems and improve the ability to move.

Changes to the diet will not prevent disease progression, but limiting milk, sugar, and dairy products has helped some individuals experiencing excessive mucus.

Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. Sleep studies can assess airway status and the possible need for nighttime oxygen. Some patients may require surgical insertion of an endotrachial tube to aid breathing. Surgery can also correct hernias, help drain excessive cerebrospinal fluid from the brain, and free nerves and nerve roots compressed by skeletal and other abnormalities. Corneal transplants may improve vision among patients with significant corneal clouding.

Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain. Currently BioMarin Pharmaceutical produces enzyme replacement therapies for MPS type I and VI. Aldurazyme is an enzymatic replacement therapy for alpha-L-iduronidase produced by BioMarin for use in Type I MPS. In May 2005, galsulfase (under the name Naglazyme), a recombinant enzyme replacement therapy also produced by Biomarin was approved for MPS VI (Marateaux-Lamy syndrome). In July 2006, the United States Food and Drug Administration approved a synthetic version of I2S produced by Shire Pharmaceuticals Group, called Elaprase, as a treatment for MPS type II (Hunter syndrome). Vestronidase alfa (Mepsevii) is a recombinant human lysosomal beta glucuronidase for MPS VII (Sly syndrome) approved in the United States in November 2017 (Ultragenyx).

Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success in treating the mucopolysaccharidoses. Abnormal physical characteristics, except for those affecting the skeleton and eyes, may be improved, but neurologic outcomes have varied. BMT and UCBT are high-risk procedures and are usually performed only after family members receive extensive evaluation and counseling.