NORD gratefully acknowledges William A. Gahl, MD, PhD, Clinical Director, National Human Genome Research Institute; Head, Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Free sialic acid storage disorders are a group of related disorders characterized by the abnormal accumulation of sialic acid in various cells and tissues of the body. These disorders are generally broken down into three subtypes: infantile free sialic acid storage disease (ISSD), the most severe form; Salla disease, the mildest form; and intermediate Salla disease which is less severe than ISSD, but more serious than Salla disease. The specific symptoms associated with these disorders can vary greatly. All the disorders are characterized by some degree of degeneration of nerve cells (neurodegeneration) and cognitive impairment. Free sialic acid storage disorders occur because of mutations of the SLC17A5 gene and are inherited in an autosomal recessive fashion.
Free sialic acid storage disorders belong to a larger group of diseases known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Low levels or inactivity of a transport protein known as sialin leads to the abnormal accumulation (storage) of free sialic acid in the tissues of affected individuals. Sialin normally helps transport sialic acid out of lysosomes.
The symptoms and severity of free sialic acid storage disorders are highly variable. Some individuals will develop severe, life-threatening complications; others will have milder findings. The more severe cases usually exhibit symptoms within six months of birth or even before birth; milder cases may become apparent later during infancy or childhood. These disorders represent a spectrum of disease; affected individuals may not have all of the symptoms discussed below.
INFANTILE FREE SIALIC ACID STORAGE DISEASE (ISSD)
Symptoms of this form of ISSD are usually apparent at birth or early in infancy. Some infants may be born prematurely. Other infants may appear normal at birth, but develop symptoms as they grow older. Affected infants may have fluid accumulation in the abdominal cavity (ascites), abnormal enlargement of the liver and spleen (hepatosplenomegaly), and coarse facial features. Some infants have diminished muscle tone (hypotonia), and may be referred to as “floppy babies”.
Affected infants may also fail to gain weight and grow at the normal rate for age and sex (failure to thrive), may experience significant delays in attaining developmental milestones (developmental delays) or may lose milestones that have been previously acquired. Cognitive deficits and seizures may occur.
Skeletal abnormalities in infants with ISSD may include malformation (dysplasia) of the ends of the long bones (metaphyses), clubbed feet, abnormally short thigh bones (femurs), malformation (dysplasia) of the hip and underdevelopment of certain bones of the fingers and toes (phalanges).
ISSD eventually progresses to cause life-threatening complications such as serious respiratory infections and abnormal enlargement of the heart (cardiomegaly). Some infants develop nephrotic syndrome, in which damage to the kidneys causes them to leak large quantities of protein into the urine. Nephrotic syndrome can cause swelling in the arms and legs, around the eyes or in other areas due to fluid accumulation (edema). Additional symptoms may include a swollen abdomen, unintended weight gain and high blood pressure.
Salla disease is the mildest form of the free sialic acid storage disorders. The specific symptoms and severity of the disorder can vary from one individual to another. Although Salla disease can cause life-threatening complications, some individuals have lived into their 70s. Affected infants appear normal at birth, but may develop symptoms during the first year of life. Such symptoms include diminished muscle tone (hypotonia), rapid, involuntary eye movements (nystagmus), and difficulty coordinating voluntary movements (ataxia). Affected infants often exhibit delays in reaching developmental milestones (developmental delays) such as sitting, walking or talking.
Approximately two-thirds of children with Salla disease eventually learn to walk. Some degree of speech impairment is usually present. Affected infants may learn single words or small sentences, but this ability may be lost as they age. The ability to produce speech is affected more severely than the ability to understand speech. Affected children exhibit some degree of cognitive impairment as well.
In some cases, individuals with Salla disease may not develop symptoms until later in childhood when a variety of neurological findings become apparent. These include seizures, involuntary muscles spasms that result in slow, stiff movements of the legs (spasticity), and repetitive, involuntary, writhing movements of the arms and legs (athetosis). Some individuals who previously developed the ability to walk or talk may lose these skills (regression). Some individuals may experience a gradual coarsening of facial features.
INTERMEDIATE SALLA DISEASE
The severity of intermediate Salla disease can vary greatly from one individual to another. Only a handful of people with intermediate Salla disease have been reported in the medical literature. The symptoms are similar to those of ISSD and Salla disease, but less severe than ISSD and more severe than Salla disease.
Free sialic acid storage disorders are caused by mutations of the SLC17A5 gene. The mutations are inherited in an autosomal recessive fashion.
Recessive genetic disorders occur when an individual inherits an abnormal gene for the same disease from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass a 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 disease is 25 percent. The risk is the same for males and females.
The SLC17A5 gene is located on the long arm of chromosome 6 (6q14-q15). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual as DNA. Human 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 6q14-q15” refers to bands 14-15 on the long arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SLC17A5 gene contains instructions for producing (encoding) a protein called sialin that is required to transport free sialic acid from inside lysosomes. Sialic acid is a sugar produced when lysosomes break down certain sugar-containing proteins (glycoproteins) or fats (glycolipids). In sialic acid storage disorders, deficient levels of functioning sialin result in the accumulation (storage) of free sialic acid in lysosomes.
Free sialic acid storage disorders affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. Salla disease has been reported in more than 150 individuals, most from Finland and Sweden. Free sialic acid storage diseases may go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
A diagnosis of a free sialic acid storage disorder may be suspected based upon identification of characteristic signs and symptoms. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history (including family history) and specialized tests that detect elevated levels of free sialic acid in certain cells and tissues or in urine.
Molecular genetic testing (which can identify a mutation in the SLC17A5 gene) is available on a clinical basis to confirm the diagnosis.
Diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS). During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes) to detect elevated levels of free sialic acid.
There is no specific treatment for free sialic acid storage disorders. Treatment is directed toward the specific symptoms that are apparent in each individual. Seizures are treated by generally accepted standards such as the use of medications (anti-convulsants).
Early intervention is important in ensuring that children with free sialic acid storage disorders reach their highest potential. Services that may be beneficial include special education, physical therapy to improve strength and coordination, speech therapy, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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