GM1-gangliosidosis

Definition

GM1-gangliosidosis is a lysosomal storage condition caused by a reduction or the absence in the amount of the enzyme, beta-galactosidase, in cells. This condition has been referred to by other names such as Norman-Landing disease, Gangliosidosis-GM1 beta-galactosidase-1 deficiency, Hurler-variant, pseudo-Hurler disease, Tay-Sachs disease with visceral involvement, and GLB1 deficiency.

Description

Lysosomes are structures found inside cells that contain specific proteins and enzymes that help digest or breakdown many of the complex biological substances found within the cells. After the lysosomes digest these substances, the remnants are then released from the cell. The role of the lysosome is to keep the inside of the cell clean and to help the cell function normally.

One of the lysosomal enzymes, beta-galactosidase, is necessary to digest a substance called GM1-ganglioside. When there is not enough beta-galactosidase within the lysosomes, GM1-ganglioside breaks down at a slower rate or not at all. Since GM1-ganglioside is not being digested as fast as it is being produced, GM1-ganglioside accumulates within the lysosomes. When too much GM1-ganglioside accumulates, the lysosomes stop functioning effectively, thereby causing the cell not to function properly.

When there are enough cells in an organ or organ system that stop functioning normally, the entire organ or organ system begins to experience problems. One of the first areas where GM1-ganglioside accumulates and causes problems is within the central nervous system. Other organs and systems in the body can also accumulate GM1-ganglioside; however, signs of the excessive accumulation are sometimes not immediately apparent.

There are three types of GM1-gangliosidoses; they are grouped according to the amount of beta-galactosidase detected in the individual's leukocytes (white blood cells) or skin cells, the individual's age when they start to show symptoms (called age of onset), and the specific symptoms that the individual exhibits. These types are labeled Type I, Type II, and Type III.

Genetic profile

All three types of GM1-gangliosidosis are inherited in an autosomal recessive manner. Symptoms of GM1-gangliosidosis occur when the pair of genes that produce beta-galactosidase (called GLB1) both contain a change, causing them not to work properly. When the GLB1 genes do not work properly, less or no beta-galactosidase is produced. Individuals with GM1-gangliosidosis inherit one of their non-working GLB1 genes from their mother and the other non-working GLB1 gene from their father. These parents are called carriers of GM1-gangliosidosis. When two people are known carriers for an autosomal recessive condition, like GM1-gangliosidosis, they have a 25% chance with each pregnancy to have a child affected with the disease.

The GLB1 gene is located on the short arm of chromosome 3, called 3p, in the region 21.33. This is written as 3p21.33. There have been over 20 mutations identified in the GLB1 gene that can cause the gene not to work properly. The most common type of mutation detected is a missense mutation. Typically, a gene is made up of DNA that codes for specific amino acids. It is the amino acids, when combined, that make a protein. When there is a missense mutation in a gene, the DNA code for a particular amino acid has been changed, often coding for a different amino acid. Changing the amino acid often changes the protein that is made. A change in the structure or production of a protein often alters its ability to function properly.

Most individuals with GM1-gangliosidosis are compound heterozygotes. This means that an individual with GM1-gangliosidosis has one GLB1 gene containing one mutation and his or her other GLB1 gene has a different mutation. Researchers do not believe that there is any correlation between specific mutations in the GLB1 gene and the severity of GM1-gangliosidosis. An exception to this is the discovery of mutations in the GLB1 gene that, instead of causing an individual to have GM1-gangliosidosis, cause the individual to have another condition called Morquio syndrome type B.

Demographics

GM1-gangliosidosis is a rare condition. It is estimated that approximately one in 100,000–200,000 live births is affected with this condition. Type I GM1-gangliosidosis is considered to occur more often than the other two types. There has also been an increased number of individuals living in Japan, Brazil, and Maltese Island diagnosed with all types of GM1-gangliosidosis. However, many researchers state that this condition is not more common in individuals of certain ethnic groups, although many of the individuals with Type III GM1-gangliosidosis are Japanese. Additionally, GM1-gangliosidosis occurs with equal frequency in males and females.

Signs and symptoms

GM1-gangliosidosis Type I

Type I GM1-gangliosidosis is also called infantile GM1-gangliosidosis or infantile type, and it is considered the most severe form of GM1-gangliosidosis. Infants with GM1-gangliosidosis Type I tend to have less than 1% of the normal amount of beta-galactosidase in their cells.

Some of the symptoms seen with Type I can be apparent at birth, but all infants with Type I will show characteristics of the condition before six months of age. All infants with Type I will reach a point where they fail to gain new skills and begin to regress and lose the skills they have learned.

Several of the initial symptoms seen in infants with Type I are caused by the storage of GM1-ganglioside in the cells of the infant's central nervous system. One sign of a problem with the central nervous system seen in some infants with Type I is the infant's inability to eat much food or formula because of a poor appetite and/or difficulties with sucking on a bottle or nipple. As a result, they tend to gain very little weight. Another sign of GM1-ganglioside storage in the central nervous system is muscle problems. Most of these infants will have low muscle tone, called hypotonia. These babies appear "floppy" or "loose." As the disease progresses, the infant presents with other central nervous system problems, such as an exaggerated reaction to sound, atrophy of the optic nerves, their bodies becoming rigid and stiff, developing tight joints (joint contractures), and experiencing seizures. Infants with Type I can also develop brain atrophy and/or areas of decreased amount of white matter in the brain.

In GM1-gangliosidosis Type I, GM1-ganglioside is also stored in the skeleton, causing visible changes on radiographs. Some of the more common bone changes are: differences with their vertebrae causing spine curvature, thicker skull, wider bones and hands, and wide, short fingers. Also, the growth of the bones tends to slow down or stop, causing infants with GM1-gangliosidosis Type I to appear smaller than expected for their age.

Additionally, infants with Type I usually develop certain characteristic facial features. The facial features typically seen in infants with Type I include frontal bossing, ears that are set lower on the head than normal, thicker skin, hair on forehead and neck, an elongated space between the nose and mouth, and an enlarged tongue. Children with these facial changes are often described as appearing "coarse." Coarse facial features can also be seen in infants and children who have other types of storage disorders.

Other characteristics of GM1-gangliosidosis Type 1 include an enlarged spleen and liver (called hepatosplenomegaly), cardiomyopathy (which has only been described in caucasian patients), and an enlargement of the cells in the bone marrow. Additionally, infants with Type I have cherry-red spots in the macula of their retinas, and several develop corneal clouding.

GM1-gangliosidosis Type II

GM1-gangliosidosis Type II is also referred to as the juvenile type. In children with Type II, the amount of beta-galactosidase in the cells is approximately 1–5% of normal.

There are no symptoms that are specific to GM1-Gangliosidosis Type II. Signs of Type II often appear late in infancy or in early childhood. Although each individual with Type II may present differently, several children with Type II have been reported to have difficulty walking and/or developed seizures. The bone changes seen in Type I may or may not occur in children with Type II. Furthermore, children with Type II do not have macular cherry-red spots, enlarged spleen or liver, or the facial changes.

GM1-gangliosidosis Type III

Individuals with GM1-gangliosidosis Type III are also labeled as having the adult or chronic type of this condition. Individuals with Type III tend to have approximately 10% of the normal amount of beta-galactosidase in their cells. The age when symptoms begin to appear in individuals with Type III is extremely variable. There have been reports of individuals with Type III exhibiting symptoms as early as three years of age to as late as 30 years old. The symptoms slowly worsen over many years.

Individuals with GM1-gangliosidosis Type III tend to experience some symptoms related to the storage of GM1-ganglioside in their central nervous system; however, these symptoms are not as severe as those seen in infants with Type I. The signs of GM1-ganglioside storage can be different in each person affected with the GM1-gangliosidosis Type III, but many individuals with Type III have been reported to have signs of dystonia . Other neurological symptoms in Type III can include difficulty or unusual method of walking (ataxia), mild mental delays, and slurred speech. Often the ataxia and slurred speech are some of the first symptoms to appear.

Individuals with Type III also have GM1-ganglioside storage in bone cells, but bone changes are considered milder than those seen in Type I. Often the vertebrae of individuals with Type III tend to have a flattened appearance and/or the presence of other mild vertebral changes. On CT or MRI examinations, mild brain atrophy with signs of storage in the basal ganglia can be present in some individuals with Type III. Also, some individuals with Type III have experienced corneal clouding. However, the macular cherry-red spots, facial changes, and differences in the bones are not seen in individuals with GM1-gangliosidosis Type III.

Diagnosis

The diagnosis of GM1-gangliosidosis in an individual can be made by measuring the amount of beta-galactosidase in either skin cells or in leukocytes. Additionally, prenatal testing to determine if a fetus is affected with GM1-gangliosidosis prior to its delivery can be accomplished by measuring the amount of beta-galactosidase on cultured cells from an amniocentesis or chorionic villus sampling (CVS). Amniocentesis is a procedure used to remove some of the fluid, which contains fetal cells, from around the fetus. CVS is used to obtain cells from the placenta. With both of these procedures, the cells collected are stimulated to multiply so that there are enough cells to perform certain analyses, in this case measuring the amount of beta-galactosidase.

Both of these procedures have their own risks, benefits, and limitations.

X rays can detect bone changes and organ enlargement. However, in early stages of the condition, bone differences may not have developed or the organs may not yet be enlarged. Also, a CT scan and/or MRI can identify brain changes, such as cerebral atrophy or a loss of myelin in the white matter of the brain. An eye examination can detect any macular cherry-red spots or other changes.

Analysis of the amount of beta-galactosidase in an individual's cells cannot be used to determine if the person is a carrier of GM1-gangliosidosis. This is because the range for the amount of beta-galactosidase seen in carriers of this condition overlaps with the range of the amount of beta-galactosidase seen in individuals who are not carriers.

Treatment and management

There is no cure for GM1-gangliosidosis. Most of the treatments revolve around trying to alleviate some of the symptoms, such as helping infants with Type I to eat and devices that can help with problems walking in individuals with Type III. Additionally, there is ongoing research into gene therapy for GM1-gangliosidosis to infuse genes that produce beta-galactosidase into the body.

Prognosis

In Type I GM1-gangliosidosis, the child dies within a few years after the symptoms begin, typically by age two. In Type II GM1-gangliosidosis, the prognosis is variable. Some individuals have died during childhood and others have lived many years after symptoms began. In Type III GM1-gangliosidosis, no decrease in life span has been reported.

Resources

BOOKS

Suzuki, Yoshiyuki, Hitoshi Sakuraba, and Akihiro Oshima. "Beta-Galatosidase Deficiency (Beta-Galactosidosis): GM1 Gangliosidosis and Morquio B Disease." In The Metabolic and Molecular Bases of Inherited Disease, edited by Charles R. Scriver, et al. New York: McGraw Hill, 1995, pp. 2785-2823.

ORGANIZATIONS

Association for Neuro-Metabolic Disorders. 5223 Brookfield Lane, Sylvania, OH 43560-1809. (419) 885-1497.

WEBSITES

Lysosomal Storage Disease: A Family Source Book. <http://mcrcr2.med.nyu.edu/murphp01/lysosome/hgd.htm>.

Online Mendelian Inheritance in Man. National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov/Omim/>.

Sharon A. Aufox, MS, CGC