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

ABSTRACT

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.