Free sialic acid storage disease

Alternate names

Sialic acid storage disease; N-Acetylneuraminic acid storage disease (former); NANA storage disease (former); Lysosomal Free Sialic Acid Storage Disorders

Definition

Free sialic acid storage diseases are inherited conditions that lead to progressive neurological damage.

Types

There are three forms of free sialic acid storage diseases; an infantile form, an intermediate severe form and Salla disease.

• The infantile form is the most severe, with symptoms appearing before birth or soon after.
• Salla disease is the least severe with symptoms that start in the first year of life and progress slowly through adulthood.
• The intermediate severe form is less severe than the infantile form, but more severe than Salla disease.

Epidemiology

Sialic acid storage disease is a very rare disorder. ISSD has been identified in only a few dozen infants worldwide. Salla disease occurs mainly in Finland and Sweden and has been reported in approximately 150 people. A few individuals have been identified as having intermediate severe Salla disease.

Cause

Mutations in the SLC17A5 gene cause all forms of sialic acid storage disease. This 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. Approximately 20 mutations that cause sialic acid storage disease have been identified in the SLC17A5 gene. Some of these mutations result in sialin that does not function normally; others prevent sialin from being produced. In a few cases, sialin is produced but not routed properly to the lysosomal membrane.

Gene mutations

SLC17A5 gene mutations that reduce or eliminate sialin activity result in a buildup of free sialic acid in the lysosomes. It is not known how this buildup, or the disruption of other possible functions of sialin in the brain, causes the specific signs and symptoms of sialic acid storage disease.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The symptoms of free sialic acid storage disease may be different from person to person. Some people may be more severely affected than others, even people who have the same form. Not everyone with free sialic acid storage disease will have the same symptoms.

Infants with the most severe form of free sialic acid storage disease have symptoms that usually appear before or at the time of birth. The signs and symptoms of infantile free sialic acid storage disease include:

• Abnormal fluid buildup before birth (hydrops fetalis)
• Fluid in the stomach (ascites)
• Low muscle tone (hypotonia)
• Enlarged liver and spleen (hepatosplenomegaly)
• Coarse facial features
• Seizures
• Failure to gain weight
• Severe developmental delay and intellectual impairment
• Bone abnormalities
• Enlarged heart (cardiomegaly)
• Kidney damage

The symptoms of Salla disease, the least severe form of free sialic acid storage disease, usually appear in the first year of life and may include:

• Low muscle tone (hypotonia)
• Developmental delay and intellectual impairment
• Seizures
• Abnormal movements
• Uncontrolled or uncoordinated movements (ataxia)
• Stiff or rigid muscles (spasticity)
• Involuntary, writhing movement (athetosis)

• Some coarsening of facial features
• Loss of motor and speech skills

Very few people have been diagnosed with the intermediate severe form of free sialic acid storage disease. The severity of the signs and symptoms of this condition tend to fall between the other two forms.

Diagnosis

Less Severe FSASD Including Salla Disease[1].

Clinical findings

• Truncal ataxia and hypotonia apparent at approximately one year of age
• Developmental delay
• Growth deficiency (short stature)
• Intellectual disability
• Spasticity
• Facial coarsening (variable and not always present)

Imaging findings on brain MRI examination

• Hypomyelination of the basal ganglia
• Hypoplasia of the corpus callosum

Severe FSASD Including Infantile Free Sialic Acid Storage Disease (ISSD) Clinical findings

• Nonimmune hydrops fetalis (24%)
• Hepatosplenomegaly
• Failure to thrive
• Severe developmental delay
• Cardiomegaly
• Club feet
• Increasingly coarse facial features
• Neurologic deterioration
• Early death
• Imaging findings on skeletal survey (ISSD) include skeletal dysostosis.

FSASD Including Less Severe and Severe Forms Laboratory findings

• Free sialic acid. Sialic acids are a family of negatively charged sugars, one of which, N-acetylneuraminic acid, is elevated in lysosomes in free sialic acid storage disorders.
• Urinary excretion of free sialic acid, measured by the fluorimetric thiobarbituric acid assay, thin-layer chromatography or mass spectrometry, is elevated about tenfold in individuals with Salla disease and about 100-fold in individuals with ISSD. HPLC/tandem mass spectrometry is also able to detect free sialic acid in urine .

The diagnosis of a free sialic acid storage disorder is established in a proband by identification of biallelic pathogenic variants in SLC17A5 on molecular genetic testing.

Treatment

Management is symptomatic and supportive: standard treatment of seizures; feeding therapy and provision of adequate nutrition; rehabilitation to optimize mobility and communication; supplementation of calcium and vitamin D for low bone density; family and social support.

Prognosis

All forms of free sialic acid storage disease are progressive, meaning the symptoms get worse over time. The infantile form is rapidly progressive and children with this form typically only live until early childhood. Life expectancy for the less severe form of free sialic acid storage disease appears to be shortened, although affected individuals have lived into their seventies.

NIH genetic and rare disease info

• NIH info on Free sialic acid storage disease

Free sialic acid storage disease is a rare disease.

Free sialic acid storage disease Resources
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