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Infantile free sialic acid storage disease
This severe condition typically presents in infancy, causing significant developmental delays, muscle weakness, and often affecting multiple organ systems. It is inherited in an autosomal recessive manner.
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Overview
Infantile free sialic acid storage disease (ISSD) is a very rare genetic condition belonging to a group known as lysosomal storage disorders. Lysosomes are compartments within cells that break down and recycle waste materials. In ISSD, there is a problem with transporting a molecule called sialic acid out of the lysosomes, leading to its build-up. This accumulation of sialic acid can disrupt normal cell function, particularly in the brain, muscles, and other organs [PMID:17918077].
The condition is present from birth, though symptoms typically become noticeable during infancy. It is considered the most severe form of free sialic acid storage disorders, with a rapid progression of symptoms. While it is a rare disease, understanding its genetic basis is crucial for diagnosis and potential future therapies.
Symptoms & clinical features
Infants with ISSD often show signs from early life, with symptoms worsening over time. Common features include severe developmental delay, meaning children do not reach expected milestones such as sitting, crawling, or speaking at typical ages. Muscle weakness, known as hypotonia, is also frequently observed, leading to difficulties with movement and feeding.
Other symptoms can include an enlarged liver and spleen (hepatosplenomegaly), skeletal abnormalities, and distinct facial features such as a broad nasal bridge and widely spaced eyes [PMID:17918077]. Respiratory problems and recurrent infections are also common, contributing to the serious nature of the condition. In some cases, fluid accumulation in the abdomen (ascites) may be present.
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Affected organs
Infantile free sialic acid storage disease can affect multiple organ systems due to the widespread accumulation of sialic acid. The brain is significantly impacted, leading to severe neurological symptoms and profound developmental delay. The skeletal system can also be affected, resulting in bone abnormalities.
Other organs commonly involved include the liver and spleen, which may become enlarged. The lungs and respiratory system can also be compromised, contributing to breathing difficulties. Additionally, the kidneys may show signs of dysfunction, and the heart can sometimes be affected.
Risks & severity
ISSD represents the most severe end of the spectrum of free sialic acid storage disorders. The condition typically manifests in infancy, often within the first six months of life, and is characterised by progressive deterioration. The prognosis is generally poor, with affected individuals often not surviving beyond early childhood due to complications such as respiratory failure or infections [PMID:17918077].
While exact prevalence figures are not well established due to its rarity, ISSD is considered a very rare disorder. The severity and early onset mean that comprehensive medical care is required from diagnosis to manage symptoms and support affected infants.
Genetic causes
Infantile free sialic acid storage disease is caused by pathogenic variants in the *SLC17A5* gene. This gene provides instructions for making a protein called sialin, which acts as a transporter. Sialin is located in the membrane of lysosomes and is responsible for moving free sialic acid out of these cellular recycling centres.
When variants in *SLC17A5* impair the function of the sialin protein, sialic acid cannot be efficiently transported out of the lysosomes. This leads to an excessive build-up of free sialic acid within the lysosomes of cells throughout the body [PMID:19302196]. This accumulation is toxic to cells, disrupting their normal processes and leading to the diverse range of symptoms observed in ISSD.
- SLC17A5 solute carrier family 17 member 5The SLC17A5 gene provides instructions for producing the sialin protein, which is essential for transporting free sialic acid within cells and is associated with conditions like Infantile free sialic acid storage disease.
Inheritance pattern
Infantile free sialic acid storage disease is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the *SLC17A5* gene - one from each parent - to develop the condition. People who have only one altered copy of the gene are called carriers. Carriers typically do not show any symptoms of the disorder themselves because their one working copy of the gene can compensate.
When two carriers have children together, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies of the gene and be affected by ISSD. There is a 50% (1 in 2) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two working copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of infantile free sialic acid storage disease often begins with clinical suspicion based on an infant's symptoms and developmental trajectory. If ISSD is suspected, biochemical tests can be performed to measure the level of free sialic acid in urine or blood. Elevated levels suggest the condition [PMID:19302196].
Confirmation of the diagnosis is typically achieved through genetic testing, which looks for pathogenic variants in the *SLC17A5* gene. This testing is usually requested by a paediatrician or a clinical geneticist. In the UK, genetic testing for lysosomal storage disorders is available through the NHS Genomic Medicine Service, often following referral to a regional clinical genetics centre. Relevant NHS R-codes would be used for this diagnostic pathway.
Management & lifestyle
There is currently no cure for infantile free sialic acid storage disease, and management focuses on providing supportive care to alleviate symptoms and improve the quality of life for affected infants and their families. This involves a multidisciplinary team of specialists, including paediatricians, neurologists, geneticists, and physiotherapists.
Care often includes nutritional support, management of respiratory issues, and physical therapy to help with muscle weakness. Regular monitoring for complications such as infections or organ enlargement is also important. Families can access support and guidance through their clinical genetics team and genetic counsellors, who can provide information about the condition and support networks.
UK care pathway
In the UK, if infantile free sialic acid storage disease is suspected, a child would typically be referred by their GP or paediatrician to a specialist paediatric service or a regional clinical genetics centre. Here, a geneticist or genetic counsellor would assess the child and family, coordinate diagnostic tests, and explain the implications of a diagnosis. Genetic testing for this condition falls under the NHS Genomic Medicine Service (GMS) pathways, with specific R-codes used to guide testing. Genetic counsellors play a vital role in providing information, emotional support, and discussing inheritance patterns and family planning.
Frequently asked questions
What is sialic acid?
Sialic acid is a type of sugar molecule that is important for many bodily functions, especially in the brain and immune system. In infantile free sialic acid storage disease, it builds up inside cell compartments called lysosomes because it cannot be properly transported out.
Is there a treatment for infantile free sialic acid storage disease?
Currently, there is no cure for infantile free sialic acid storage disease. Treatment focuses on managing the symptoms and providing supportive care to help improve the child's comfort and quality of life.
How common is infantile free sialic acid storage disease?
Infantile free sialic acid storage disease is a very rare condition. Exact prevalence figures are not well established, but it is considered one of the rarest lysosomal storage disorders.
If I am a carrier, does that mean I will develop symptoms later?
No, if you are a carrier for infantile free sialic acid storage disease, you typically will not develop symptoms of the condition yourself. Carriers have one working copy of the *SLC17A5* gene, which is usually enough to prevent the build-up of sialic acid.
Can future pregnancies be tested for infantile free sialic acid storage disease?
Yes, for families where the genetic cause of ISSD has been identified, prenatal diagnosis is available for future pregnancies. This involves testing during pregnancy to determine if the unborn baby has inherited the condition.
References
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- Stone DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis. Advances in pediatrics. 1999. PMID: 10645471
- Chapleau A, Mirchi A, Tran LT. Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease. Pediatric neurology. 2023. PMID: 37713976
- Kleta R, Aughton DJ, Rivkin MJ. Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children. American journal of medical genetics. Part A. 2003. PMID: 12794688
- Lemyre E, Russo P, Melançon SB. Clinical spectrum of infantile free sialic acid storage disease. American journal of medical genetics. 1999. PMID: 10069709
- Berra B, Gornati R, Rapelli S. Infantile sialic acid storage disease: biochemical studies. American journal of medical genetics. 1995. PMID: 7573152
- Blom HJ, Andersson HC, Seppala R. Defective glucuronic acid transport from lysosomes of infantile free sialic acid storage disease fibroblasts. The Biochemical journal. 1990. PMID: 2363700
- Barmherzig R, Bullivant G, Cordeiro D. A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease. Pediatric neurology. 2017. PMID: 28662915