Spinocerebellar ataxia in the Bouvier des Ardennes breed is caused by a KCNJ10 missense variant

Abstract

Background In Belgian Malinois, a KCNJ10 variant causes progressive spinocerebellar degeneration. Hypothesis/Objectives Describe the clinical, diagnostic, pathological and genetic features of spinocerebellar degeneration in the Bouvier des Ardennes breed. Animals Five affected Bouvier des Ardennes puppies with spinocerebellar ataxia (SCA), 8 healthy related dogs, and 63 healthy unrelated Bouvier des Ardennes. Methods Sequential case study. Results Clinical signs started at 6 weeks of age in 1 puppy with severe signs of cerebellar disease, and at 7 to 10 weeks of age in the 4 remaining puppies with milder signs of spinocerebellar disease. The first puppy displayed severe intention tremors and rapidly progressive generalized hypermetric ataxia, whereas the 4 others developed a milder progressive SCA. Euthanasia after progression to nonambulatory status was performed by 8 weeks of age in the first puppy, and before 11 months of age in the 4 remaining puppies. Histopathology revealed cerebellar spongy degeneration and a focal symmetrical demyelinating myelopathy. All cases were homozygous for KCNJ10 XM_545752.6:c.986T>C(p.(Leu329Pro)), which is pathogenic for SCA with (or without) myokymia, seizures or both (SAMS) and spongy degeneration and cerebellar ataxia (SDCA) 1 in Belgian Malinois dogs. All sampled parents were heterozygous and none of the healthy dogs were homozygous for this recessive variant. This variant has an allele frequency of 15% in the 63 healthy dogs studied. Conclusions and Clinical Importance Inherited spinocerebellar degeneration also affects the Bouvier des Ardennes breed and is caused by a KCNJ10 variant. It can present with a spectrum of severity grades, ranging from severe cerebellar to milder spinocerebellar signs.

Phenotypic and genetic aspects of hereditary ataxia in dogs

“…SAMS and SDCA1 are associated with the exact same autosomal recessive KCNJ10 missense variant (XM_038448705.1:c.986T>C (p.[Leu329Pro])) in both Malinois Shepherd and Bouvier des Ardennes dogs. The fact that the same variant was found in both breeds is likely explained by the fact that some Malinois Shepherd dogs were used to expand the Bouvier des Ardennes bloodlines after this breed nearly became extinct at the beginning of the 20th century 21 …”

“…Hereditary ataxias have been recognized since the 1940s in the Smooth Haired Fox Terrier breed in Sweden 79 and since the 1970s in the Jack Russell Terrier breed in the United Kingdom 80 . Since, several reports have been published in the Jack and Parson Russell Terrier breeds, 14,81–86 Smooth Haired and Toy Fox Terrier breeds, 15,87,88 Malinois Shepherd breed, 18,19 as well as in the Patterdale Terriers 16 and Bouvier des Ardennes breed 21 . One affected Dachshund is reported 17 …”

“…In the SAMS phenotype, the SCA is milder at first and progresses more slowly, resulting in a nonambulatory status by 5 to 6 months of age in Malinois Shepherds and 7 to 11 months of age in Bouvier des Ardennes dogs (Movie S4). Myokymia, neuromyotonia, and seizures can also be part of this picture, and the main abnormal findings on neurological examination are absent menace responses and patellar reflexes 18,21 . In SDCA1, the severity of the SCA is more pronounced at onset and progresses faster (Movie S5).…”

“…Myokymia, neuromyotonia, and seizures have not been reported in SDCA1, and neurological examination can also show delayed proprioception. On histopathology, main lesions include spongy degeneration of the cerebellar nuclei, granular cell layer, cerebellar white matter, vestibulocochlear tract, and reticular formation, as well as a bilateral symmetrical demyelinating myelopathy targeting the dorsolateral spinocerebellar tracts 18,19,21,89 . SAMS and SDCA1 are associated with the exact same autosomal recessive KCNJ10 missense variant (XM_038448705.1:c.986T>C (p.[Leu329Pro])) in both Malinois Shepherd and Bouvier des Ardennes dogs.…”

“…80 Since, several reports have been published in the Jack and Parson Russell Terrier breeds, 14,[81][82][83][84][85][86] Smooth Haired and Toy Fox Terrier breeds, 15,87,88 Malinois Shepherd breed, 18,19 as well as in the Patterdale Terriers 16 and Bouvier des Ardennes breed. 21 One affected Dachshund is reported. 17 The SCA has a juvenile onset (2-6 months of age in most breeds)…”