NORD gratefully acknowledges Maria Fuller, Associate Professor, Genetics and Molecular Pathology, SA Pathology, Australia, for assistance in the preparation of this report.
Sialidosis, also known as mucolipidosis type I, is a rare inherited metabolic disorder characterized by a deficiency of the enzyme neuraminidase (sometimes referred to as sialidase). Deficiency of neuraminidase results in the abnormal accumulation of toxic materials in the body. Sialidosis is divided into two types (i.e., type I and type II). Sialidosis type I usually becomes apparent during the second decade of life with the development of sudden involuntary muscle contractions (myoclonus), distinctive red spots (cherry-red macules) in the eyes, and sometimes additional neurological findings. Sialidosis type II is usually more severe than sialidosis type I. Type II often begins during infancy or later during childhood and is characterized by cherry-red macules, mildly coarse facial features, skeletal malformations and mild cognitive impairment. Sialidosis is inherited as an autosomal recessive trait.
Sialidosis belongs to a group of diseases known as the lysosomal storage disorders (LSDs). Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as complex molecules composed of a sugar attached to a protein (glycoproteins). In sialidosis patients, low levels or inactivity of the neuraminidase enzyme leads to the abnormal accumulation these compounds in the cells with unwanted consequences. Sialidosis is also classified as one of the mucolipidoses, a subgroup of the LSDs.
The age of onset, symptoms, progression and severity of sialidosis vary greatly from one person to another. Sialidosis type I is a milder form of the disorder than sialidosis type II and has later onset. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Individuals with sialidosis type I may develop symptoms anywhere from childhood to young adulthood, with most people developing symptoms during the second or third decade of life. Such individuals develop normally until problems with walking (gait disturbances) or vision abnormalities require medical attention. Symptoms of sialidosis type I include the development of distinct red spots in the eyes known as cherry-red macules. Cherry red macules are spots that form on the retina, the thin membrane that lines the back of the eyes. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. Affected individuals may experience loss of clarity of vision (visual acuity) and may develop impaired color vision and night blindness. Rapid, involuntary eye movements (nystagmus) and clouding (opacity) of the cornea may also occur.
In addition to walking difficulties and vision problems, additional symptoms may be associated with sialidosis type I. Such symptoms include seizures, abnormally heightened reflexes (hyperreflexia), an inability to coordinate voluntary movements (ataxia), and sudden, involuntary twitching or jerking of muscle (myoclonus). Intelligence is usually unaffected in sialidosis type I.
Sialidosis type II is generally more severe than sialidosis type I and is often further subdivided into congenital and infantile forms. Some researchers have proposed including a juvenile form, but other researchers believe that these individuals may have galactosialidosis. In the congenital form, symptoms are present at birth. In the infantile form symptoms usually develop shortly after birth.
Children with sialidosis type II may develop an abnormally enlarged liver (hepatomegaly) and/or spleen (splenomegaly), a specific assortment of bone deformities known as dysostosis multiplex, coarse facial features, delays in reaching developmental milestones, and cognitive impairment. Bone deformities associated with dysostosis multiplex include premature closure (fusion) of the fibrous joints (sutures) between certain bones of the skull, a thickened skullcap (calvaria), an enlarged skull, widely spaced teeth, thickened collarbones (clavicles), and abnormalities of the ribs, pelvic bones, certain long bones and other bones of the body.
Distinctive “coarse” facial features associated with sialidosis type II may include a high forehead, flattened bridge of the nose, a long groove on the upper lip (long philtrum), upturned nostrils (anteverted nares), and puffy eyelids. Some affected children may have overgrowth of the gums (gingival hypertrophy) and an abnormally large tongue (macroglossia).
As with sialidosis type I, affected children may also develop clouding (opacity) of the lenses or corneas of the eyes, and sudden, involuntary twitching or jerking of muscles. Cherry-red macules may also develop in children with sialidosis type II.
Additional symptoms have been reported in some individuals with sialidosis type II including hearing loss, vision loss, facial swelling due to the accumulation of fluid (facial edema), seizures, an inability to coordinate voluntary movements (ataxia), and heart abnormalities. As children with sialidosis type II age, they may exhibit short stature.
Infants with the congenital form may also develop a serious condition in which abnormal amounts of fluid accumulate in various areas of the body (hydrops fetalis). Some infants may experience fluid accumulation in the abdomen (ascites) before birth. The congenital form of sialidosis type II is rapidly progressive and often can cause life-threatening complications early during infancy.
Sialidosis is caused by mutations of the NEU1 gene. This gene mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the NEU1 gene is located on the short arm (p) of chromosome 6 (6p21.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The NEU1 gene contains instructions for creating (encoding) an enzyme known as neuraminidase (alpha-neuraminidase) which is necessary for the proper breakdown (metabolism) of certain glycoproteins, substances that play various vital roles in the body. Glycoproteins are proteins that contain oligosaccharides, which are long sugar chains. Without proper levels of functional neuraminidase, oligosaccharides abnormally accumulate in and damage various tissues and organs of the body. Mutations of the NEU1 gene result in the lack of production of the neuraminidase enzyme or the production of a defective, inactive form of the enzyme.
Sialidosis affects males and females in equal numbers. The exact incidence of sialidosis in the general population is unknown. One estimate places the incidence at 1 in 4.2 million individuals in the Australian population. Another estimate placed the incidence at 1-4 individuals per 200,000 of the general population. Because rare disorders like sialidosis often go unrecognized or misdiagnosed, determining the true frequency of sialidosis in the general population is difficult.
A diagnosis of sialidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. An examination of urine may reveal increased levels of oligosaccharides. A urine test is usually followed up by blood tests and a skin biopsy (surgical removal and microscopic study of skin tissue). These tests can reveal low levels of the enzyme alpha-neuraminidase in blood and skin tissue.
For families with a previous history of sialidosis, prenatal diagnosis is available through amniocentesis. During amniocentesis, samples of fluid surrounding the fetus are removed. Fetal tissue samples may be obtained during a procedure known as chorionic villus sampling. Certain cells (fibroblasts) are cultured grown in the laboratory and evaluated for alpha-neuraminidase activity.
There is no specific therapy for sialidosis. Treatment is directed toward the specific symptoms that are apparent in each individual. Anti-seizure medications (anti-convulsants) may be used to treat myoclonic seizures, but are not always effective.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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