Neuronal Ceroid Lipofuscinosis 4A (ARSG gene, American Staffordshire Terrier)

Neuronal ceroid lipofuscinosis 4A (NCL4A), currently known as lysosomal storage disease, is characterized by the accumulation of toxic substances inside neurons. Unlike other lipofuscinoses, it has a late onset, in adulthood. NCL4A is caused by a deficiency in arylsulfatase G enzyme activity.

Symptoms

The first symptoms of the disease appear between 3 and 5 years of age. The onset of the pathology is later and has a slower progression compared to other lipofuscinoses. Symptoms include lack of muscle coordination, tremors, abnormal eye movements, abnormal gait, and difficulty with balance and jumping. Unlike other lipofuscinoses, there are no visual disturbances.

Disease Management

Unfortunately, NCL4A has no cure and treatment is usually focused on alleviating the symptoms and improving the quality of life of the affected dog. Given the severity of the symptoms in some affected dogs, euthanasia is often resorted to. If you suspect that your dog has any symptoms related to NCL4A, you should see your veterinarian for evaluation.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by the accumulation of fluorescent lipofuscin granules in the lysosomes of neurons, resulting in early neuronal death and progressive neurodegeneration of the central nervous system. These diseases are caused by mutations in various genes, the age of onset of symptoms and progression vary with the specific form of the disease and the underlying mutation. The variant causing this type of lipofuscinosis is c.296G>A of the ARSG gene encoding for arylsulfatase G. Arylsulfatase G is an enzyme found in lysosomes and is involved in the degradation of substances such as steroids, carbohydrates, proteoglycans and glycolipids by hydrolysis of sulfate esters and sulfamates. When this enzyme does not function properly, the accumulation of substances that are toxic, especially to neurons, occurs. The c.296G>A mutation was identified in American Staffordshire Terrier dogs and the severity of NCL4A symptoms was found to be variable among affected dogs, showing that environmental factors other than genetics may be involved.

Most affected breeds

  • American Staffordshire Terrier

Bibliography

Abitbol M, Thibaud JL, Olby NJ,et al. A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14775-80.

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