Embark for Veterinarians

Applied Clinical Genetics Case Library
Case 6

  • 5-year-old
  • Spayed female
  • Pitbull Mix
History & Presenting Complaint
  • Dog stumbling. Abnormal gait. Has progressively gotten worse. 
  • They noticed one time when he went rigid and fell on his side, started vocalizing, frothing, and paddling for about 1-2 min. Episode occurred once as far as the owner knows.
  • Intracranial
    • Primary or idiopathic
      • Genetic causes
    • Symptomatic
      • Infectious encephalitis (viral, fungal, bacterial)
      • Noninfectious encephalitis (granulomatous meningoencephalitis, necrotizing meningoencephalitis)
      • Brain tumors
      • Vascular (stroke)
      • Head trauma
      • Degenerative diseases (storage diseases)
      • Malformation (cyst, hydrocephalus)
  • Extracranial
    • Hypoglycemia (insulinoma)
    • Encephalopathy (portosystemic shunt)
    • Hypocalcemia (hypoparathyroidism)
    • Toxin (ethylene glycol, metaldehyde, lead)
Physical Exam
  • Temp: 101.9 F; Pulse: 70 bpm; Respiration: 25/min; MM: pink/moist CRT: 2 sec; BCS: 5/9; Eyes: focal tremors; Ears: wnl; Mouth: wnl; LN’s: wnl; Cardio: wnl; Resp: wnl; Abd: wnl; GI: wnl; MS: wnl; CNS: ataxia (loss of balance, uncoordinated gait); Weight: 60 lbs (27 kg); Performed orthopedic and neurologic exam
  • Seizure. The following characteristics provide evidence that this was a seizure rather than syncope:
    • This is a middle-aged, rather than geriatric, patient
    • This dog is without a heart murmur
    • The dog has an abnormal gait
    • Does not have cyanotic mucous membranes
    • Does not have breathing issues
  • Seizure (intracranial vs. extracranial)
  • Abnormal gait (progressive)
  • Bloodwork-completely normal
  • MRI scan-completely normal
  • Spinal tap-completely normal
  • Seizure (intracranial)
  • NCL4A is the most likely diagnosis given the PE, normal blood work, MRI, and spinal tap combined with the genetic result.
  • Symptomatic and palliative care
    • There is currently no treatment for NCL4A. Enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy require more research to be available clinically. 
    • Since the disease has progressed to seizures, some medications may offer a temporary reduction in their frequency. However, the medications will eventually stop controlling the seizures.
    • Frank discussions about quality of life are likely warranted. However, survival time after the onset of clinical signs is usually two to four years.
    • Slings can be used to assist with dogs’ mobility, and caution should be taken to avoid falling hazards.
    • Watch to make sure the dog is able to eat without shaking or choking.
  • The owner is now monitoring this dog for quality of life but is grateful the genetic screening saved her from invasive procedures.
  • This variant was originally designated as an NCL even though no known human form of NCL had been shown to result from mutations in this gene. Subsequent analyses using a transgenic mouse model led to the reclassification of the canine disorder to the group of lysosomal storage diseases known as mucopolysaccharidoses. However, most veterinary resources still refer to the clinical disease as NCL4A.
  • NCL is definitively diagnosed via histopathology of central nervous system tissues after the affected dog is deceased. Histopathological brain examination shows severe cerebellar cortical abiotrophy and remodeling with loss of Purkinje cells with cytoplasmic storage material within remaining cells.