Test Detail

Inherited neurological disease caused by defects in inhibitory glycinergic neurotransmission in the brainstem and spinal cord. In response to sudden acoustic or tactile stimuli, puppies show generalised hypertonia and tremor, with consciousness preserved. Apnoea and neonatal death may occur. It is the canine equivalent of human hyperekplexia ("startle disease"). Molecular heterogeneity is notable: variants in SLC6A5 (presynaptic glycine transporter GlyT2) have been described in the Irish Wolfhound, the Spanish Greyhound (Galgo español) and the Bobtail, and a variant in GLRA1 (alpha-1 subunit of the postsynaptic glycine receptor) in the Miniature Australian Shepherd; Miniature American Shepherds and Australian Shepherds were only included in the screening of related breeds.

Affected breeds: Irish Wolfhound, Spanish Greyhound, Miniature Australian Shepherd and Bobtail/Old English Sheepdog. Gill et al. (2011) confirmed recessive inheritance in a litter of seven Irish Wolfhounds (two affected) and identified 13 carriers among related animals (PMID 21420493). In the Spanish Greyhound the variant appears private to a single family (not found in 34 unrelated greyhounds or in 659 dogs of other breeds). In the Miniature Australian Shepherd, 6 carriers were found among 127 dogs analysed in Germany; Miniature American Shepherds and Australian Shepherds were only included in the screening (PMID 37222814). In the Bobtail/Old English Sheepdog the SLC6A5 c.1322del variant has been described, with 3 additional carriers in the breed (PMID 40012122).

- Test breeding animals with the breed-specific panel before mating: SLC6A5 for the Irish Wolfhound, Spanish Greyhound and Bobtail; GLRA1 for the Miniature Australian Shepherd\n- Do not mate two carriers of the same variant: 25% risk of affected homozygotes in each litter\n- A carrier may be mated to a clear animal; offspring intended for breeding must be tested and clear animals preferably selected\n- If a puppy shows rigidity and tremor when handled, refer to neurology and request a genetic test before planning any mating of the parents\n- Do not repeat the parental mating after a confirmed case; inform the buyer of the status and record the result in the pedigree\n- Remember that the correct test depends on the breed: use the panel covering SLC6A5 and GLRA1 when the breed is among those at risk or there is mixed ancestry

Differential diagnosis with non-hyperekplectic tremors of the puppy (hypomyelination of the Weimaraner and the Springer Spaniel, familial myoclonus of the Labrador, dystonia/episodic falling of the CKS), with true seizures (consciousness is preserved in hyperekplexia) and with congenital myasthenia. The neonatal presentation of rigidity in response to touch and noise is highly suggestive. Phenytoin and, above all, clonazepam are useful in human hyperekplexia due to their GABAergic effect, but the response in the Miniature Australian Shepherd was poor; in the Irish Wolfhound and Spanish Greyhound, supportive symptomatic treatment should be considered. In a litter with several affected puppies, suspect recessive inheritance and do not repeat the mating.

1. Gill JL, Capper D, Vanbellinghen JF, et al. (2011) Startle disease in Irish wolfhounds associated with a microdeletion in the glycine transporter GlyT2 gene. Neurobiol Dis 43:184-189. PMID: 21420493
2. Murphy SC, Recio A, de la Fuente C, et al. (2019) A glycine transporter SLC6A5 frameshift mutation causes startle disease in Spanish greyhounds. Hum Genet 138:509-513. PMID: 30847549
3. Heinonen T, Flegel T, Müller H, et al. (2023) A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia. Hum Genet 142:1221-1230. PMID: 37222814
4. Boeykens F, Hermans M, Adant L, et al. (2025) A frameshift variant in the SLC6A5 gene is associated with startle disease in a family of Old English Sheepdogs. Anim Genet 56:e70003. PMID: 40012122