Mucopolysaccharidosis: what is it, types, symptoms, treatment, prognosis

What is mucopolysaccharidosis?

Mucopolysaccharidoses (abbr. IPU)Is a group of hereditary metabolic diseases caused by the absence or malfunction of certain enzymes, necessary for the body to break down molecules called glycosaminoglycans, long chains of sugars (carbohydrates) in each of of our cells. These cells help build bones, cartilage, tendons, cornea, skin, and connective tissue. Glycosaminoglycans (formerly called mucopolysaccharides) are also found in the fluid that lubricates the joints.

Patients with mucopolysaccharidosis either do not produce enough of one of the 11 enzymes needed to break down these sugar chains into proteins and simpler molecules, or they produce enzymes that do not work properly way. Over time, these glycosaminoglycans accumulate in blood cells, the brain and spinal cord, and in connective tissues. The result is permanent, progressive cell damage that affects the appearance human, physical abilities, functioning of organs and systems and, in most cases, mental development. Symptoms can be similar or different for different types of disorder.

Mucopolysaccharidoses are classified within a broader group of diseases called lysosomal storage diseases. These are diseases in which a large number of molecules, which usually break down into smaller parts during intracellular compartments called lysosomes accumulate in harmful amounts in the cells and tissues of the body, especially in lysosomes. The main function of lysosomes is to digest non-functional cells and other materials (including bacteria and cellular debris).

Another lysosomal storage disease that is often confused with mucopolysaccharidosis is mucolipidosis. In this disease, in addition to smaller carbohydrates called sugars, an excessive amount of fatty substances known as lipids (another major component of living cells) accumulates. Patients with mucolipidosis may have common clinical features associated with mucopolysaccharidosis (certain facial features, bone abnormalities, and brain damage), however, these diseases various.

Signs and symptoms

Mucopolysaccharidoses have many common clinical features, but varying degrees of severity. These features may or may not be apparent at birth, but progress as glycosaminoglycan accumulation affects bones, skeletal structure, connective tissues, and organs. The age at which symptoms occur varies widely.

Neurological symptoms and complications can include damage to neurons (specialized nerve cells that send and receive signals throughout the body). Pain and impaired motor function (the ability to start and control muscle movement) can be the result of compression of nerves or nerve roots in the spinal cord or in the peripheral nerve system. The peripheral nervous system connects the brain and spinal cord to sensory organs such as the eyes, as well as other organs, muscles, and tissues throughout the body. People with MPS may have normal intelligence or have profound mental retardation, developmental delays, or severe behavioral problems. Many people have problems with hyperactivity, depression, speech and hearing impairment. Hydrocephalus, an excessive accumulation of cerebrospinal fluid in the brain, which can cause increased intracranial pressure, often found in some mucopolysaccharidoses.

Physical symptoms usually include rough facial features (including a flat bridge of the nose, thick lips, and an enlarged mouth and tongue), short stature with a disproportionate short torso (dwarfism), abnormal size and / or shape of bones (dysplasia) and other skeletal irregularities, thickened skin, enlarged organs, such how liver or spleen, hernias, urinary incontinence and excessive body hair. Short and often claw-like hands, progressive joint stiffness and carpal tunnel syndrome may restrict hand mobility and function. Recurrent respiratory infections, obstructive lung diseases and obstructive sleep apnea. Many patients also suffer from heart disease, often enlarged or damaged heart valves. People with MPS also have significantly shorter lifespans.

Types of mucopolysaccharidoses

Seven different clinical types and numerous subtypes of mucopolysaccharidoses have been identified. Although each mucopolysaccharidosis (MPS) is clinically different, most people experience a period of normal development followed by a decline in physical and / or mental function.

MPS I type historically divided into three broad groups based on the severity of symptoms - Gurler, Gurler-Scheie and Sheye (in descending order of severity). (Scheie syndrome was previously known as type V MPS before it was included in type I MPS.) Type I mucopolysaccharidosis can be viewed as a continuous spectrum diseases, with the most severely affected patients at one end and less severely affected (weakened) at the other, and between them a wide range of different degrees of severity. All people with MPS I lack or have insufficient levels of the enzyme alpha-L-iduronidase, which is required to break down glycosaminoglycans.

Children with MPS l often show no symptoms at birth, but they develop complications after the first year of life. Neurological symptoms can include hydrocephalus (excess accumulation of cerebrospinal fluid in the brain), an enlarged head, and corneal opacities as the child grows older. Other common neurological complications can include visual impairment and loss of vision, carpal tunnel syndrome or other nerve compression, and limitation of joint mobility.

• Children with less severe MPS l may have normal intelligence or mild to moderate intellectual disabilities or learning difficulties. Some children may have mental problems. During adolescence, respiratory problems, sleep apnea and heart diseases. People with the least severe MPS can survive to adulthood, while others on this spectrum can survive into their late teens or 20s.
• In the most severe form of MPS I (Hurler's syndrome), developmental delay is manifested by the end of the first year of life. Children usually stop developing between the ages of 2 and 4. This is followed by a progressive decline in mental capacity and loss of physical skills. The tongue may be limited due to hearing loss. Physical symptoms include stunted growth until the end of the first year of life, short stature, multiple skeletal abnormalities, hernias, distinct facial features, and enlarged organs. Some babies may find it difficult to feed. Children with severe MPS I often die before the age of 10 due to obstructive airway disease, respiratory infections, or heart complications.

MPS II type (also called hunter syndrome) is caused by a lack of the enzyme iduronate-2-sulfatase (which breaks down glycosaminoglycans, heparin sulfate and dermatan sulfate inside cells). Although it was once divided into two groups based on the severity of symptoms, type II mucopolysaccharidosis is also considered a continuous spectrum of diseases. MPS II is the only mucopolysaccharidosis in which only the mother can pass the defective gene to her son (the so-called X-linked recessive inheritance). The disease occurs almost exclusively in young men, although cases have been reported in women.

• Children with more severe MPS type II share many of the same neurological and physical features associated with severe MPS type I, but with milder symptoms. The disease usually begins between the ages of 2 and 4. Decreased development is usually seen between the ages of 18 and 36 months, followed by a progressive loss of skills. Other neurological symptoms may include increased intracranial pressure, joint stiffness, retinal degeneration, and progressive hearing loss. Whitish skin lesions can be found on the shoulders, back, and upper limbs. Death usually occurs at the age of 15 from diseases of the upper respiratory tract or cardiovascular failure.
• Children with less severe MPS II are often diagnosed in the second decade of life. Intelligence and social development are not affected. The physical disabilities in these children are less obvious and progress much more slowly, and skeletal problems may be less severe. Individuals with less severe MPS II can live to be 50 years of age or older, although respiratory and cardiac complications can contribute to premature death.

MPS type III (also called syndrome Sanfilippo) is characterized by severe neurological symptoms that include progressive dementia, aggressive behavior, hyperactivity, epilepsy, some deafness and loss of vision, and an inability to sleep for more than a few hours at a time. Mucopolysaccharidosis type III affects children differently and progresses faster in some children than in others. The early development of mental and motor skills may be somewhat delayed. In sick children, there is a marked decrease in learning ability between the ages of 2 and 6, followed by possible loss of language skills and partial or complete hearing loss. These children tend to first lose the learned words and then lose motor function. Some children may never learn to speak. As the disease progresses, children become more unstable on their legs, and most of them cannot walk by the age of 10.

The life expectancy of patients with type III MPS is extremely diverse. Most people with MPS III live into adolescence, and some live to be 20-30 years old.

There are four different subtypes of type III mucopolysaccharidosis, each of which is caused by a change in another enzyme required to completely break down the sugar chain of heparan sulfate. There is little clinical difference between these four types, but symptoms seem to be most severe and seem to progress faster in children with type A.

• MPS IIIA is caused by a missing or altered enzyme heparan N- sulfatase.
• MPS IIIB is caused by the absence or deficiency of the enzyme alpha N- acetylglucosaminidase.
• MPS IIIC results from the absence or alteration of the acetyl-CoA enzyme: alpha-glucosaminide acetyltransferase
• MPS IIID is caused by a lack or deficiency of an enzyme N- acetylglucosamine-6-sulfate.

MPS IV type (also called Morquio syndrome) has two subtypes, which arise from the absence or lack of enzymes N- acetylgalactosamine-6-sulfatase (type A) or beta-galactosidase (type B), required to break down the sugar chain of keratan sulfate. Clinical signs are similar for both types, but less pronounced in type IVB MPS. Onset between ages 1 and 3. Neurological complications include compression of the spinal nerve and nerve root as a result of extreme, progressive skeletal changes, as well as hearing loss and corneal opacity.

Physical growth slows down and often stops at age 8. Among the many skeletal abnormalities seen in people with Morquio syndrome, bones that stabilize the connection between the head and neck can be deformed (odontoid hypoplasia) and a surgical procedure called cervical fusion can be life-saving to kid. Other skeletal changes include a protruding sternum, a curved spine from side to side and back to front, and a deformity of the knee joint (when the knees bend over and touch each other). Restricted breathing, joint stiffness, and heart disease are also common. Children with more severe MPS type IV can live no more than 20-30 years.

MPS VI type (also called Maroto-Lamy syndrome) is caused by insufficient enzyme N- acetylgalactosamine-4-sulfatase. Type VI MPS has various severe symptoms. Although children usually have normal intellectual development, they share many of the general physical symptoms found in severe mucopolysaccharidosis type I. In addition to many of the neurological complications seen in other MPS disorders, people with type VI MPS there is a thickening of the dura mater (the membrane that surrounds and protects the brain and spinal cord), which can lead deafness. Eye problems include corneal opacity, glaucoma (a group of diseases that damage the optic nerve), swelling of the optic nerve or disc, and degeneration of the optic nerve.

Growth is normal in children at first, but stops abruptly by age 8. Skeletal changes are progressive and this limits movement. Nearly all children suffer from some form of heart disease, usually with valve dysfunction.

MPS VII type (also called Sly syndrome) - one of the least common forms of mucopolysaccharidosis. The disease is caused by a deficiency of the enzyme beta-glucuronidase. In its rarest form, Type VII MPS causes dropsy of the fetus, in which an excessive amount of fluid is retained in the body. Survival in these cases is usually several months or less. Most children with type VII MPS are less severely affected. Neurologic symptoms may include mild to moderate mental retardation by age 3 years, hydrocephalus, pinched nerve, some loss of vision, joint stiffness, and limitation of movement. In addition to skeletal problems, some people may have recurrent seizures in the first years of life. pneumonia. Most children with MPS type VII survive into adolescence or adolescence.

MPS IX type occurs as a result of hyaluronidase deficiency. This is an extremely rare type of mucopolysaccharidosis. Movement and intelligence are not affected. Symptoms include soft tissue nodules located around the joints with episodes of painful swelling of the tissue masses and pain that subsides spontaneously within 3 days. Other signs include mild facial changes, short stature, multiple soft tissue masses, and some bone erosion seen on pelvic x-rays.

Causes and risk factors

All MPS disorders result from a deficiency or malfunction of a certain lysosomal an enzyme needed to break down dermatan sulfate, heparan sulfate, or keratan sulfate, separately or together. Failure to break down these mucopolysaccharides leads to their accumulation in cells, tissues and organs throughout the body. All of these disorders are inherited in an autosomal recessive manner, with the exception of Hunter syndrome (MPS type 2), which is an X-linked recessive disorder.

Genetic diseases are defined by abnormal changes in the enzyme gene for each disease, one of which is passed on from the father and the other from the mother. Recessive genetic disorders occur when a person inherits an abnormal gene for the same trait from each parent. If a person receives one normal gene and one gene for the disease, they will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents of passing on the defective gene and therefore giving birth to a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents and be genetically normal for this trait is 25%.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Women have two X chromosomes, but one of the X chromosomes is turned off and all genes on that chromosome are inactivated. A woman who has an abnormal gene on one of her X chromosomes is a carrier of the disorder. Female carriers usually do not show symptoms of the disease, since it is usually the X chromosome with the abnormal gene disabled. Men have one X chromosome, and if they inherit the X chromosome containing the disease gene, they will develop the disease. Men with X-linked disorders pass the disease gene on to all of their daughters who will be carriers. Males cannot pass the X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to the male offspring.

Affected populations

The prevalence of all forms of mucopolysaccharidosis is estimated at 1 in 25,000 births. However, due to the fact that mucopolysaccharidoses, especially mild forms of diseases, often remain unrecognized, these diseases are underdiagnosed or diagnosed incorrectly, which makes it difficult to determine their true frequency among the general population.

Estimates for specific types of mucopolysaccharidosis range from: 1 in 100,000 for Hurler's syndrome; 1 in 500,000 for Scheie syndrome; 1 in 115,000 has Hurler-Scheie syndrome; 1 in 70,000 with Sanfilippo syndrome; 1 in 200,000 with Morquio syndrome; and fewer than 1 in 250,000 people have Sly syndrome. Hunter's syndrome occurs predominantly in men. In extremely rare cases, the disease has been reported in women. The incidence of Hunter syndrome is estimated at 1 in 100,000–150,000 newborn boys.

More than 40 different lysosomal storage diseases.

Diagnostics

Clinical examination and tests to detect excessive excretion of mucopolysaccharides in the urine are the first steps in the diagnosis of MPS disease. For a definitive diagnosis, enzyme tests (testing of various cells or blood in culture for enzyme deficiencies) are required. Prenatal diagnosis using amniocentesis and chorionic villus sampling can confirm whether the fetus is affected. Genetic counseling can help parents with a family history of MPS determine if they carry a mutated gene for the disorder.

Standard treatments

There is currently no cure for these disorders. Medical care is aimed at treating systemic diseases and improving the quality of human life. Dietary changes will not prevent the disease from progressing.

Surgery can help drain excess cerebrospinal fluid from the brain and release nerves and nerve roots that have been compressed by skeletal and other abnormalities. Corneal transplantation can improve vision in people with significant corneal opacity. Removing the tonsils and adenoids can improve breathing in people with obstructive airway disorders and sleep apnea. Some people may need to surgically insert an endotracheal tube to make breathing easier.

Enzyme replacement therapy is currently used to treat MPS I, MPS II, MPS IVA, MPS VI and MPS VII types, and is also tested for other disorders associated with mucopolysaccharidoses. Enzyme replacement therapy involves the intravenous administration of a solution containing an enzyme that is not present in the body. It does not treat the neurological manifestations of the disease, but has proven to be effective in reducing non-neurological symptoms and pain.

Bone marrow transplantation (BMT) and cord blood transplantation (CBCT) have had limited success in the treatment of mucopolysaccharidosis. Abnormal physical signs, with the exception of those affecting the skeleton and eyes, can be improved, but neurological outcomes vary. BMT and TPK are high-risk procedures and are usually performed only after careful examination and consultation with family members.

Physical therapy and daily exercise can delay joint problems and improve mobility.

Forecast

Patients with Hurler's syndrome usually die between the ages of 5-10. The life expectancy of patients with Scheye syndrome may be nearly normal. Patients can live up to the fifth or sixth decade of life and have healthy offspring. For patients with Hunter and Sanfilippo syndromes, death usually occurs by the time of puberty. In the classic form of Morquio's syndrome, people also do not live long, usually death occurs at the age of 20-40 years. In patients with severe Maroto-Lamy syndrome, death usually occurs in early adulthood.

- Mucopolysaccharidosis type I (Hurler's syndrome).

Patients with Hurler's syndrome have a poor prognosis. Children with this condition have significant progressive physical and mental disabilities. Death can occur in late childhood, early adolescence, or adulthood.

- Mucopolysaccharidosis type II (Hunter's syndrome).

Life expectancy in the early (severe) form is 10-20 years; for the late form (mild form) - 20-60 years.

- Mucopolysaccharidosis type III (Sanfilippo syndrome).

Severe lethargy is the most important clinical problem. Patients may have IQs below 50. Severe cases lead to death before the patient reaches 20 years of age.

- Mucopolysaccharidosis type IV (Morquio syndrome).

Bone abnormalities are a serious problem. Small vertebrae at the top of the neck can damage the spinal cord, which can lead to paralysis. Death can result from heart complications.

- Mucopolysaccharidosis type VI (Maroto-Lamy syndrome).

Life expectancy is between the second and third decade of life, with patients dying from heart failure. Patients may die earlier from cardiac or neurological complications, depending on the severity of the disease.

- Mucopolysaccharidosis type VII (Sly syndrome).

In mild cases, patients have been reported to live up to 19-20 years. Life expectancy is reduced as a result of frequent upper respiratory tract infections, neurodegenerative complications, and gastrointestinal abnormalities.