A newly described inherited disorder has appeared in curly-coated retrievers (CCR) (Gregory et al. 2007 JVIM 21:40-46). It is a metabolic disorder called glycogen storage disease type IIIa (GSD IIIa) that disrupts the intracellular storage and retrieval of glucose and causes disease primarily of liver and skeletal muscle. GSD IIIa is an autosomal recessive disorder due to deficient activity of the glycogen debranching enzyme (GDE).

The following description of clinical disease is based on observations and clinical testing of two affected dogs by their owners and local veterinarians. The dogs are five years old at this time. The affected litter mates, both female, were unremarkable until they were taken to the veterinarian for neutering, one at 6 months, and the other at 9 months. Presurgical blood tests revealed high levels of the liver (ALT, AST, and ALP) and muscle (creatine kinase, CK) enzymes in seemingly otherwise normal dogs. Recovery from surgery was uneventful but over the ensuing months and years the dogs were described as "sleeping a lot", lethargic, having delayed recovery from moderate exercise, and having episodes of hypoglycemic collapse that responded rapidly to oral administration of glucose-containing supplements. ALT, AST, and ALP activities have steadily increased, but CK activity has been intermittently normal or extremely elevated.  We continue to follow these dogs because late-onset sequellae in humans include skeletal muscle weakness and atrophy, hepatocellualr carcinoma, and cardiac failure. Further prognosis for the affected dogs is unknown.

 
Especially in the earliest months of life, the signs of GSD IIIa are sufficiently vague and nonspecific that we suspect some affected dogs have not been diagnosed. Other than the genetic test, the most likely finding that can alert a veterinarian to the dog’s problem is the elevation of liver leakage enzymes in serum. While muscle is also involved, the elevation of CK in serum has been a variable finding. Of course, many dogs have routine surgical procedures without presurgical blood tests, so the disorder may not be apparent until the dog has an episode of collapse or isn’t as active as expected, but these observations could completely escape a new CCR owner.

Liver and muscle biopsies revealed that all hepatocytes and intermittent skeletal muscle cells were swollen and full of glycogen, suggesting some form of glycogenosis. Enzyme measurements revealed lack of GDE activity and abnormal glycogen structure.  Further investigation in the Laboratory of Comparative Medical Genetics at Michigan State University revealed a mutation, a single base deletion, in the GDE gene, leading to undetectable enzyme production. This disease-causing change in the DNA sequence can be detected by polymerase chain reaction (PCR) amplification of a portion of genomic DNA obtained by simple cheek brushing or in a small sample of blood or semen.

Since this is an autosomal recessive disorder, for a puppy to inherit GSD IIIa, it must obtain one copy of the deleted gene from each of its parents; in other words, both parents of an affected dog are obligate carriers, and affected pups can only be produced when two carriers are mated. Therefore, GSD IIIa carrier testing is an effective preventative measure in a CCR breeding program. Among the ~160 CCR tested to date, carriers have been found in dogs from the US, Canada, New Zealand, Australia, and Finland. Carriers are entirely normal, both in their physical behavior and in blood tests, such as serum transaminase and CK activities. 

The carrier test can be used diagnostically, but it will be most useful for preventing the inadvertent production of GSD IIIa affected dogs or increasing the mutant allele frequency in the breed. GSD IIIa carrier testing is available from the Laboratory of Comparative Medical Genetics at the Michigan State University College of Veterinary Medicine. The GSD IIIa test costs $85.00/dog and we accept payment by personal check or money order made out to Michigan State University.  We do not accept credit cards or electronic forms of payment at this time.  Inquiries or requests for sample collection kits should be sent by email to fyfe@cvm.msu.edu. Sample submission instructions and forms can be downloaded via a link from http://www.mmg.msu.edu/faculty/fyfe.htm. Most owners prefer to submit cheek brush samples, but we can also use blood preserved in EDTA (0.3 cc in a purple top tube, refrigeration is not needed) or a similar volume of frozen semen. Please contact the laboratory ahead of submission if sending semen.