Genetics of Salla Disease: Mutations, Inheritance and Gene Therapy

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Salla disease is a rare autosomal recessive lysosomal storage disorder characterized by defective sialic acid metabolism. It falls under the broader category of sialic acid storage disorders (SASD) and is caused by mutations in the SLC17A5 gene, which encodes the sialin transporter protein. This transporter is responsible for the export of free sialic acid (N-acetylneuraminic acid) from lysosomes. Mutations in SLC17A5 lead to an abnormal accumulation of sialic acid within lysosomes, affecting multiple organ systems, particularly the central nervous system.

Sialic acids are important for cell signaling, immune function, and neural development, and their proper export allows cells to recycle them for glycoprotein and glycolipid synthesis. Defective transport impairs cellular function, particularly in the nervous system, leading to severe neurodevelopmental and metabolic disorders.

Genetic Basis of Salla Disease

SLC17A5 Gene and Its Role

The SLC17A5 (a.k.a AST) gene, located on chromosome 6q14-q15, encodes sialin, a protein essential for transporting sialic acid out of lysosomes.

In Salla disease, mutations in SLC17A5 impair this transport, leading to accumulation of sialic acid inside cells and subsequent cellular dysfunction. The disease follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit two defective copies of the SLC17A5 gene—one from each parent.

Common Mutations in SLC17A5

Several mutations in SLC17A5 have been linked to Salla disease, with the most common being:

c.115C>T (p.R39C): A prevalent mutation in Finnish populations, often associated with classical Salla disease.
c.850C>T (p.Q284X): A nonsense mutation leading to a truncated, non-functional sialin protein.
c.1408G>A (p.G470R): A missense mutation affecting protein stability.

Clinical Manifestations

The severity of Salla disease varies based on the residual function of the mutated sialin transporter. There are two primary forms:

Classical Salla Disease (CSD) – Milder form, primarily observed in Finnish populations, presenting with early-onset hypotonia, delayed motor development, progressive neurological deterioration, and intellectual disability.
Infantile Sialic Acid Storage Disorder (ISSD) – A more severe neonatal-onset form, often leading to fatal multi-organ involvement and profound neurodevelopmental impairment within infancy.

Diagnosis and Genetic Testing

Diagnosis of Salla disease is confirmed through:

Urinary Free Sialic Acid Testing – Elevated free sialic acid in urine is a hallmark of the disease.
Molecular Genetic Testing – Identification of SLC17A5 mutations through next-generation sequencing (NGS) or Sanger sequencing.
Brain MRI – May reveal characteristic white matter abnormalities, indicative of leukoencephalopathy.

Genetic Counseling and Inheritance

As an autosomal recessive disorder, parents of an affected child are typically carriers (heterozygous), each having one defective copy of SLC17A5. Carrier parents have a 25% chance of passing the disease to their offspring with each pregnancy, a 50% chance that the child will be an asymptomatic carrier, and a 25% chance of being unaffected.

Also learn about other autosomal recessive disorders:

Cystic Fibrosis

Genetic counseling is highly recommended for families with a history of Salla disease, especially in high-risk populations such as those of Finnish descent.

Potential Therapeutic Approaches

A 2023 study compared two methods, the CRISPR-Cas9-mediated homology-directed repair (HDR) and adenine base editing (ABE), to correct the SLC17A5 c.115C>T (p.Arg39Cys) variant in human fibroblasts. While HDR showed minimal correction with a high rate of undesired mutations, ABE achieved significant correction without detectable errors, effectively reducing free sialic acid levels and offering a glimpse of hope that one day this methodology could be applied to help affected individuals as well.

Learn more about the groundbreaking usage of Gene Editing to cure genetic conditions

Currently, there is no cure for Salla disease, and treatment focuses on symptom management and supportive care, including:

Physical therapy for motor function support.
Speech and occupational therapy for developmental delays.
Seizure management with antiepileptic medications.
Future gene therapy prospects – Research into gene therapy and targeted molecular treatments may provide potential interventions in the future.

Conclusion

Salla disease is a rare lysosomal storage disorder caused by mutations in the SLC17A5 gene, leading to defective sialic acid transport and progressive neurological impairment. While currently incurable, early diagnosis, genetic counseling, and supportive therapies can improve quality of life for affected individuals. Advances in molecular genetics continue to offer hope for future treatments, highlighting the importance of ongoing research in the field of lysosomal storage diseases.