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Neuroaxonal Dystrophy (NAD) in Spanish Water Dog
| Acronym: | NAD |
| Gene: | TECPR2 |
| Mutation: | c.4009C>T |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
Neuroaxonal Dystrophy Spanish Water Dog Type (NAD) is a neurodegenerative disorder affecting Spanish Water Dog. In general, neuroaxonal dystrophies represent a group of heterogeneous inherited neurodegenerative diseases. Different forms of NAD share characteristic pathologic features, but they vary in the clinical and neurological signs, the progression of the disease, and lesion distribution among but also within species. Except as a result of inherited genes, NAD-like findings were also associated with aging and toxic to metabolism conditions. They have been recognized in several species, such as dogs, cats, horses, sheep, and humans. Neuroaxonal dystrophy-affected dog breeds except for Spanish Water Dog are Rottweiler, German Shepherd, Jack Russell Terrier, Collie Sheepdog, Papillon, and Chihuahua.
In numerous neurodegenerative disorders, including Huntington’s, Alzheimer’s, Parkinson’s disease, etc., impairment of autophagy is considered the main mechanism of these disorders’ development. Autophagosomes sequestrate damaged organelles and long-lived proteins and further degradation and subsequent release of amino acids and other molecules into the cytoplasm. Autophagy is essential for the metabolic homeostasis of neurons. The first clinical signs in affected Spanish Water Dogs appear between six and eleven months of age. Mild head tilt, generalized mild cerebellar ataxia with hypermetria of the thoracic limbs, and absence of decreased patellar reflex are present. Symptoms recognized by owners are gait abnormalities, incontinence alone, uncontrolled defecation, and behavioral changes, such as dullness, nervousness, and vocalization. Other signs affected dogs exhibit are compulsory pacing varying in its severity, proprioceptive deficits, decreased menace, visual deficits, involuntary eye movement (nystagmus), and a decrease in muscle tone. Pathomorphological findings are restricted to the central nervous system. Brain examination revealed neuronal loss and swollen axons, and spheroids.
Newborn affected pups usually exhibit acute respiratory distress, stereotypical positioning of limbs, scoliosis, arthrogryposis (multiple joint contractures), pulmonary hypoplasia (incomplete development of the lungs), and respiratory failure. Diagnosing Neuroaxonal Dystrophy takes into consideration differential diagnosis, which includes cerebellar hypoplasia, abiotrophy, hypomyelogenesis, and inflammatory or infectious disease (viral, rickettsia, protozoal, fungal, or immune-mediated). Due to the severity of the disorder and its progressive nature, it is often required to euthanize the affected dog due to humane reasons.
Neuroaxonal Dystrophy Spanish Water Dog Type (NAD) is caused by a mutation in the TECPR2 gene. Immunohistochemistry and the ultrastructural findings showed that this gene involves in the regulation of autophagosome accumulation in the autophagic pathways. The disorder is inherited as an autosomal recessive disorder. Healthy parents of the affected puppy are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes have no symptoms. Dogs homozygous for the mutation will display the symptoms of the Neuroaxonal Dystrophy Spanish Water Dog Type (NAD). At conception, when mating two carrier dogs, each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Results Reported As
Test Result |
Interpretation of test result |
CLEAR |
Tested mutation was not detected in animal with „clear“ result. Animal tested as clear has wild-type allele in homozygous state (i.e. two pairs of healthy alleles). It will not develop disease caused by tested mutation.* It will pass only wild-type allele to its offspring. |
CARRIER |
Tested mutation was detected in animal with „carrier“ result. Animal tested as carrier has one wild-type and one mutation allele, it is in heterozygous state. It will not develop disease caused by tested mutation.* It can pass wild-type or mutation allele to its offspring. |
AFFECTED |
Tested mutation was detected in animal with „affected“ result. Animal tested as affected has two copies of mutation alleles affecting the gene. It is likely the animal will experience a genetic disorder due to this mutation.** It will pass only mutation allele to its offspring. |
*Test excludes only tested mutation but not possible unknown mutations or factors that can lead to similar condition/symptoms.
** Potential unknown mutations or multiple other factors can possibly affect the likelihood of experiencing a genetic disorder.
References:
Hahn K, Rohdin C, Jagannathan V, Wohlsein P, Baumgärtner W, Seehusen F, et al. (2015): TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs. PloS ONE 10 (11): e0141824. doi:10.1371/journal.pone.0141824
Diaz, J. V., et al. (2007.): Neuroaxonal Dystrophy in Dogs: Case Report in 2 Litters of Papillon Puppies. J Vet Intern Med 2007;21:531–534.