A NECAP1 Nonsense Variant is Associated With Leukoencephalomyelopathy With Oligodendroglial Dysplasia in a Belgian Malinois With Spinocerebellar Ataxia.

A 7-month-old Belgian Malinois puppy was presented for progressively worsening ataxia and episodes of aggression. General physical examination was unremarkable, and neurological examination revealed ambulatory tetraparesis, spinocerebellar ataxia, thoracic limb pseudo-hypermetria, exaggerated head movements, bilateral vestibular signs and a bilateral divergent strabismus. A magnetic resonance imaging (MRI) of the brain and cervical spinal cord revealed a generalized cerebral atrophy. The dog woke up from anesthesia in a severe episode of disorientation and aggression, wherefore he was euthanized. Histopathology of the brain revealed diffuse and widespread oligodendroglial dysplasia with myelinated fibers disorganization. A disease-associated nonsense variant in NECAP1 (NC_049248.1:g.8636271G>A on chromosome 27), introducing a stop codon at codon 48 (XM_038576681.1:c.142C>T (p.Arg48*)) and truncating the only isoform by 83%, was identified by whole genome sequencing (WGS). The variant segregated in the affected family with a recessive mode of inheritance, but was not present in 158 undiagnosed Belgian Malinois from the Belgian population. The exact same variant, as well as another NECAP1 variant (c.301 + 1G>A), have been associated with early onset epileptic encephalopathy (EOEE) in humans, a disease that is characterized by intractable epileptic seizures and profound global developmental delay in young children. In conclusion, a previously unreported leukoencephalomyelopathy with oligodendroglial dysplasia causes spinocerebellar ataxia and abnormal behavior in Belgian Malinois.