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INHERITED MONOGENIC DISEASES

           

Salla disease

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.

Some 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 lysosomal free sialic acid storage disease can vary greatly from one individual to another. Only a handful of people with intermediate lysosomal free sialic acid storage 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.

WHAT IS SALLA DISEASE ABOUT?

Salla disease, as written before, is an inherited metabolic disease. An abnormal accumulation of sialic acid in the lysosomes of distinct tissues provoked by a defect in the transporter of sialic acid (sialin) located on the lysosome membrane. This transporter is in charge of guaranteeing the movement of the free sialic acid (N-acetylneuraminic acid) out of the lysosomes.

SALLA DISEASE CONCEPTS

Metabolic diseases:

Congenital metabolic diseases or inherited metabolic diseases are a large group of disorders that result from the absence or abnormality of an enzyme or its cofactor which interrupts a metabolic pathway causing an accumulation or deficiency of a specific metabolite.

Metabolic diseases are considered rare and the majority of them have an incidence of 1 in 100,000 births. In most cases, metabolic disorders are caused by individual mutations, deletions or other genetic changes. Nonetheless, one enzyme can be composed of multiple subunits codified by different genes and can catalyze more than one metabolic reaction. In addition, defects in different enzymes can cause a similar clinical phenotype.

The onset and severity of the disorder can be influenced by changes in nutrition, fasting, dehydration, intercurrent diseases, medicines, extenuating activity, childbirth, trauma or surgery.

Sialic acid storage disorders:

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. The function of sialin is to transport sialic acid out of lysosomes.

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. Although these disorders comprise a spectrum of disease severity, they have historically been divided into three clinical phenotypes/subtypes: infantile free sialic acid storage disease (ISSD), the most severe form; salla disease, the mildest form; and intermediate lysosomal free sialic acid storage 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.

The gene that causes the disorder (SLC17A5) is located on chromosome 6, where several mutations have been described.

Biologically speaking, a diagnosis of the illness can be obtained from urine excretion or from free siatic acid storage in the fibroblasts, trophoblasts or amincytes.

SALLA DISEASE SYMPTOMS

Symptoms of infantile free sialic acid storage disease (ISSD) are usually apparent at birth or early in infancy; some infants may be born prematurely. 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 can include malformation (dysplasia) near 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 TREATMENT

There is no specific treatment for any of the 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 anticonvulsants.

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 counselling is recommended for affected individuals and their families.

SALLA DISEASE CARRIER

This type of inheritance requires the presence of two copies of a pathogenic variant in the gene for a person to have the genetic disease. Both parents must be carriers of a pathogenic variant in the gene in order to be at risk to have an affected child. The child must inherit a pathogenic variant from each carrier parent in order to be affected. There is a 1 in 4 chance that a baby will inherit two mutated copies of the gene and be affected when both parents are carriers. There are generally no signs or symptoms associated with being a carrier for salla disease. However, the risk to have a child affected with salla disease is increased. Testing of reproductive partners is recommended for carriers of salla disease.

These conditions are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

SALLA DISEASE PREVALENCE

Free sialic acid storage disease is a very rare disorder and it can affect males and females in equal numbers. The exact frequency of these disorders in the general population is unknown. Salla disease has been reported in approximately 150 individuals, mainly from Finland and Sweden. Individuals with molecularly proven salla disease have been identified outside of Finland and Sweden. The prevalence of the SLC17A5 pathogenic variant p. Arg39Cys is high in the founder region of north-eastern Finland, where the Carrier frequency is in the range of 1:100. Ninety-five percent of individuals of Finnish heritage with salla disease have the p. Arg39Cys pathogenic variant. The prevalence of other SLC17A5 pathogenic variants appears to be independent of the geographic origin or ethnicity of affected individuals; their presence has been documented in more than 30 individuals from several countries throughout the world. Infantile free sialic acid storage disease (ISSD) has been identified in only a few dozen infants worldwide. A few individuals have been identified as having intermediate severe salla disease.

SALLA DISEASE – GENE OR REGION STUDIED

Free sialic acid storage disorders occur because of changes (mutations) of the SLC17A5 gene and are inherited in an autosomal recessive pattern. The SLC17A5 gene provides instructions for producing a protein called sialin that is located mainly on the membranes of lysosomes, compartments in the cell that digest and recycle materials. Sialin moves a molecule called free sialic acid, which is produced when certain proteins and fats are broken down, out of the lysosomes to other parts of the cell. Free sialic acid means that the sialic acid is not attached (bound) to other molecules. Researchers believe that sialin may also have other functions in brain cells, in addition to those associated with the lysosomes, but these additional functions are not well understood.

GENE OR REGION STUDIED


  • SLC17A5

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