The role of genetic testing for specific disease: 2 Case studies

The Emerging role of Genetic testing:  Two recent case studies


Case #1:  Degenerative Myelopathy


A couple of years ago while I was working at the CSU VTH as clinical neurologist, a second opinion case came my way.  This was a 10 yr old Corgi diagnosed here in Grand Junction with a slowly progressive T3-L3 myelopathy (clinical localization) rendering the dog unable to walk—not paralyzed, but a non-ambulatory paraparesis as we say.  The owner told me the dog had spinal MRI and spinal surgery, but was no better, in fact still getting worse…was there anything she still might be able to do for her dog? I reviewed the records and the MRI and was puzzled at the management of the case.  The records clearly stated that the dog had a “T3-L3 myelopathy”, but only had MRI of the lumbar spine, leaving a whole section of spinal cord that could have been affected, unexamined—mistake #1.  The MRI did reveal a mild type II disk bulge at L5-6 and the dog had decompressive surgery at that site.  But signs consistent with T3-L3 myelopathy cannot be caused by a disk at L5-6…not to mention that this disk herniation was not severe enough to cause significant clinical signs.  The L5-L6 disk bulge was not causing the dog’s signs, but had been operated nonetheless—mistake #2. And this was a Corgi!  A breed commonly affected by Degenerative Myelopathy!  And a breed for which the disease has been linked to a genetic mutation that could be tested for; for about $65. This had not been done—mistake #3.


Contrast this case to a very similar case I saw last month.  Princess is an 8.5 yr German Shepherd dog with slowly progressive pelvic ataxia and paraparesis with CP deficits both pelvic limbs.  Her neuro exam suggests a T3-L3 myelopathy.  MRI of her entire thoracolumbar spine identified moderate disk herniations causing spinal cord deviation and mild to moderate and chronic appearing cord compression at T12-13 and T13-L1, and a very large disk herniation at L7-S1.  Although the L-S disk herniation was most severe, it is least likely to be contributing to her pelvic ataxia (T3-L3 signs).  Princess is also a breed commonly affected with Degenerative myelopathy (DM).  Is Princess’ progressive pelvic ataxia due to the disk problems at T12-L1 or does she have degenerative myelopathy?  Will surgery at T12-L1 help Princess or represent unnecessary cost, risk and morbidity?  Without biopsy of the spinal cord (not possible), there is no way to definitively know.  Here is what we did. 


First we submitted a sample for genetic testing to see if Princess carried the gene mutations linked to DM; this would take about 2 weeks.  In that time I put her on a tapering course of prednisone.  Most dogs with compressive myelopathy, regardless of cause (tumor, disk, other), will typically show significant clinical improvement on prednisone.  Of course this evaluation is somewhat flawed as it is highly subjective, but the temporally linked improvement is often obvious.  Princess did not have obvious improvement in her rear limb function.  Her DM genetic test identified her as a homozygous carrier of two copies of the gene mutation; she was likely to be affected or become affected by DM in her lifetime.


So although I cannot say definitively that she has DM, her neuro exam, failure to improve on prednisone and her genetic test results make this conclusion highly probable.  More importantly, spinal surgery at the thoracolumbar sites will probably NOT help her and would subject her to significant risk of getting worse.


To do surgery (or not) at LS is a different question. It may alleviate low back discomfort and may preserve or restore some lower motor neuron mediated strength in her legs, improving her QUALITY of life, but is unlikely to help her pelvic ataxia. 


Genetic testing for DM, although imperfect, has an important role in case management.  It’s affordable and easy to do.


Case #2:  Centronuclear Myopathy of Labradors


Griz, a 6-month M Labrador retriever was also a case I saw last month.  Griz’s complaints included a stiff and stilted bunny-hopping gait, abnormal fatigue with activity, hunching of the lumbar spine and difficulty putting on weight.  His routine lab work was unremarkable including a normal serum CK.  Despite the stiff gait and hunching lumbar spine, Griz’s neuro exam suggested a peripheral neuromuscular problem (diminished generalized muscle mass, diminished patella and withdrawal reflexes, and normal proprioceptive responses).  Griz was acquired from a breeder in Texas (a veterinarian in fact).  There were no such abnormalities in the pedigree and no effected littermates from Griz’s litter.


Neuropathy and Myopathy are generally uncommon, and commonly missed conditions due to relative rarity.  Differentials in a young dog with signs of neuromuscular disease include inherited disease, infectious inflammatory like Toxoplasma and neospora, toxins (rare), CNS storage disease and other conditions mimicking neuromyopathic disease like myasthenia gravis and polyarthritis.  A diagnostic workup for a case like this can be extensive and expensive, including joint fluid analysis, serologic testing, organic acid assays, electrodiagnostics and nerve and muscle biopsy.  All of this was discussed with owner who was committed to finding an answer if possible.  Normal serum CK made a category of inherited myopathies similar to human muscular dystrophy unlikely (they are typically associated with very high serum CK levels).  The referring veterinarian had already ordered and run the genetic test for Exercise induced collapse in Labs and it was negative for the mutation.  Centronuclear myopathy of labs is another inherited myopathy resulting from genetic mutation and a test has been developed to detect the mutation if present.  A simple cheek swab kit for about $65 ordered and performed by the owner confirmed the condition; Griz had two pairs of the mutated gene associated with the condition. 


The test kit allowed us to make a specific diagnosis and spared Griz and the owner a long, invasive and often unfruitful (non specific) series of tests.  Not a good outcome, but easily and inexpensively discovered.  Dogs can live a long life with Centronuclear myopathy although they are handicapped and prone to life-threatening complications like megaesophagus and aspiration pneumonia.  The owners had bought Griz as a hunting dog prospect, so they have re-homed him with a relative who will love him and understands his handicap.  Additionally, Griz’s owners have contacted owners of Griz’s littermates as well as the breeder and informed them that their dogs may be carriers of the mutation and should be tested if breeding is to be considered. Hopefully this will put an end to this disease in this line of dogs.