Neuronal Ceroid Lipofuscinosis 1 ( PPT1 gene)

Neuronal ceroid lipofuscinosis 1 (NCL1) is a rare, severe genetic disorder characterized by the accumulation of a fatty pigment called lipofuscin in nerve cells of the brain and other tissues, resulting in progressive neurological degeneration.

Symptoms

Symptoms of NCL1 usually manifest between 6 months and 2 years of age, and include behavioral changes such as anxiety, restlessness or aggression, ataxia, loss of vision, sensitivity to light, and seizures. As the disease progresses, affected dogs may develop muscle weakness and atrophy, loss of appetite and weight, cognitive impairment and dementia-like symptoms, as well as breathing and swallowing difficulties.

Disease Management

There is currently no cure for NCL1 in dogs, and treatment focuses on symptom management to improve the animal's quality of life. Medications may be used to control seizures and anxiety. It may also be necessary to provide therapy to maintain mobility and improve coordination, as well as nutritional support to prevent malnutrition. It is essential to work closely with a veterinarian to develop a personalized treatment plan tailored to the specific needs of the affected dog.

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 several genes, the age of onset of symptoms and progression vary with the specific form of the disease and the underlying mutation. NCL1, in particular, is caused by mutations in the PPT1 (palmitoyl-protein thioesterase 1) gene and can affect various breeds. The PPT1 gene produces an enzyme that PPT1 catalyzes the palmitoylation reaction, a modification that occurs in certain proteins conferring them the ability to interact with membranes or other hydrophobic proteins. The PPT1 enzyme, in neurons, is localized in axons and synaptic vesicles. The mutation analyzed here was first associated with the disease in a study by Sanders et al. The researchers detected a single-base insertion in the PPT1 gene sequence (c.736_737insC) in NCL1-affected Dachshund dogs. This change affects an essential residue for the correct functioning of the enzyme and results in a total loss of its activity.

Most affected breeds

Dachshund
Italian Cane Cors

Bibliography

Kolicheski A, Barnes Heller HL, Arnold S,et al. Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis. J Vet Intern Med. 2017 Jan;31(1):149-157.

Sanders DN, Farias FH, Johnson GS,et al. A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Mol Genet Metab. 2010 Aug;100(4):349-56.