Paroxysmal movement disorder of the Shetland Sheepdog (Sheltie) triggered by exercise and stress. The episodes combine generalised ataxia with hypermetria, muscle hypertonia of the four limbs, dystonia and mild tremor, with normal or mildly altered mental state, and last from minutes to several hours. It has been associated with a heterozygous variant in PCK2, which encodes mitochondrial phosphoenolpyruvate carboxykinase.

Affected breed: Shetland Sheepdog. Published cases are infrequent and concentrated in related females; the true population frequency is not reliably known.

- Generalised ataxia with hypermetria\n- Muscle hypertonia of the four limbs and dystonia\n- Mild tremor and, in severe episodes, inability to walk\n- Normal or mildly reduced mental state\n- Triggered by exercise, excitement, stress and, in some cases, heat\n- Duration of minutes to hours\n- Mild lactacidaemia and lactaturia with hypoglycaemia and intermittent CK elevation

Sheltie PED was described as a new form of exercise-induced paroxysmal dyskinesia in four related females. Nessler and colleagues (2020) performed whole-genome sequencing of two cases versus 654 controls and found an exclusive missense variant, PCK2:c.1658G>A (p.Arg553Gln), in the heterozygous state in the four cases and absent in more than a thousand controls. The affected arginine is highly conserved and lies close to the GTP-binding site of the enzyme. The authors propose autosomal dominant inheritance with haploinsufficiency during energy demand.

- Identify carriers of the PCK2:c.1658G>A variant before breeding\n- Avoid mating carrier animals with each other because of the suspected dominant inheritance\n- Consider environmental management (stress control, avoiding intense exercise and heat) in affected animals\n- Consider a gluten-free diet rich in tryptophan or seafood and treatment with acetazolamide or zonisamide, which have been associated with partial reduction of episodes\n- Do not replace genetic prevention with clinical management

Differential diagnosis with other canine paroxysmal dyskinesias (episodic falling in the CKCS due to BCAN, PxD in the SCWT due to PIGN) and with motor epilepsy. The video of the episode and the exercise-stress association are indicative. The PCK2 variant is considered a candidate and not a definitive diagnosis: it should be interpreted together with the clinical picture. The response to a gluten-free diet in some cases suggests additional mechanisms to be investigated.

1. Nessler J et al. 2020. Mitochondrial PCK2 missense variant in Shetland Sheepdogs with paroxysmal exercise-induced dyskinesia (PED). Genes (Basel) 11:774. PMID: 32660061
2. OMIA:002868-9615 - Dyskinesia, paroxysmal, PCK2-related. https://omia.org/OMIA002868/9615/