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Dandy-Walker-Like Malformation (DWLM)
| Acronym: | DWLM |
| Gene: | VLDLR |
| Mutation: | c.1713delC |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
Dandy-Walker-Like malformation (DWLM) is a genetic disorder affecting the Eurasier dog breed. It is a result of abnormal brain development caused by a genetic mutation. The Eurasier dog breed originated in Germany in 1960 and was created by crossing the Samoyed, Chow Chow, and Wolfspitz dog breeds. Since the Eurasier are a young dog breed and have started with only a small number of dogs, the inbreeding rate was high which significantly increased the risk of obtaining puppies affected by recessively inherited disorders. The name of the disorder, Dandy-Walker-Like malformation (DWLM), comes from inherited brain malformation in humans, the Dandy-Walker syndrome (DWS). DWS was named after American neuroscientists, Walter Dandy and Arthur Earl Walker.
Brain malformation involves the cerebellum and the fluid-filled spaces around it. Cerebellum, also known as the little brain, plays an important role in motor control through the regulation of coordination, precision, and motor learning. Any disease that affects the cerebellum has an effect on coordination and can cause ataxia. The main characteristic of the disorder is cerebellar hypoplasia, enlargement of the fourth ventricle, and a very small or completely absent part of the brain that is located between two hemispheres, known as cerebellar vermis. The fourth ventricle is part of the ventricular system and it is one of the cavities filled with fluid within the brain it is a site of the common occurrence of a form of brain tumor-intracranial ependymoma tumor. Other examinations can also show the posterior midline area of the cerebellar cortex is responsible for the coordination of the muscles and cyst formation near the internal base of the skull. Visible symptoms may be vomiting, mental retardation, intracranial pressure seen as macrocephaly, prominent forehead, and irritability. All these abnormalities commonly result in problems with movement, coordination, intellect, mood, and other neurological functions. DWLM-affected dogs display a non-progressive form of cerebellar ataxia. The ataxia varies among dogs in its severity, from mild truncal sway, mild lack of movement coordination, subtle dysmetric gait, imbalance, and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Some affected dogs exhibit epileptic seizures.
Dandy-Walker-Linke malformation (DWLM) is caused by a mutation in the VLDLR gene. VLDLR gene is encoding for a transmembrane receptor VLDLR that belongs to the low-density lipoprotein receptor family (LDL). Together with another receptor, it has a role in the biochemical pathway that controls neuroblast migration in the cerebral cortex and cerebellum. A neuroblast is a cell that will develop into a neuron after this migration phase. When the VLDLR receptor is absent or unfunctional, neuroblast migration cannot occur, which results in an undeveloped central nervous system. The disorder is inherited in an autosomal recessive manner. Regarding the mutated gene, a dog can be clear, carrier, or affected. Healthy parents of an 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 Dandy-Walker-Linke malformation (DWLM). At conception, 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. In research conducted in Switzerland, 16% of tested dogs were heterozygous carriers. This high carrier rate proves the importance of DWLM genetic testing, in order to avoid obtaining affected puppies.
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:
Gerber M,Fischer A,Jagannathan V, Drögemüller M,Drögemüller C,Schmidt MJ et al. (2015): A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resemblinga Dandy-Walker-Like Malformation (DWLM). PLoS ONE10(2): e0108917.doi:10.1371/journal. pone.0108917.