Mitochondrial PCK2 Missense Variant in Shetland Sheepdogs with Paroxysmal Exercise-Induced Dyskinesia (PED)

Abstract

<jats:p>Four female Shetland Sheepdogs with hypertonic paroxysmal dyskinesia, mainly triggered by exercise and stress, were investigated in a retrospective multi-center investigation aiming to characterize the clinical phenotype and its underlying molecular etiology. Three dogs were closely related and their pedigree suggested autosomal dominant inheritance. Laboratory diagnostic findings included mild lactic acidosis and lactaturia, mild intermittent serum creatine kinase (CK) elevation and hypoglycemia. Electrophysiological tests and magnetic resonance imaging of the brain were unremarkable. A muscle/nerve biopsy revealed a mild type II fiber predominant muscle atrophy. While treatment with phenobarbital, diazepam or levetiracetam did not alter the clinical course, treatment with a gluten-free, home-made fresh meat diet in three dogs or a tryptophan-rich, gluten-free, seafood-based diet, stress-reduction, and acetazolamide or zonisamide in the fourth dog correlated with a partial reduction in, or even a complete absence of, dystonic episodes. The genomes of two cases were sequenced and compared to 654 control genomes. The analysis revealed a case-specific missense variant, c.1658G&gt;A or p.Arg553Gln, in the PCK2 gene encoding the mitochondrial phosphoenolpyruvate carboxykinase 2. Sanger sequencing confirmed that all four cases carried the mutant allele in a heterozygous state. The mutant allele was not found in 117 Shetland Sheepdog controls and more than 500 additionally genotyped dogs from various other breeds. The p.Arg553Gln substitution affects a highly conserved residue in close proximity to the GTP-binding site of PCK2. Taken together, we describe a new form of paroxysmal exercise-induced dyskinesia (PED) in dogs. The genetic findings suggest that PCK2:p.Arg553Gln should be further investigated as putative candidate causal variant.</jats:p>

Long-term nutritional management of an obese German Spitz with paroxysmal dyskinesia, calcium oxalate urolithiasis, and suspected pancreatitis—A case report

“…As stated before, the use of the serological tests (immunologic response against transglutaminase and gliadin) would have been a good option to ensure that the dog was being exclusively fed a gluten-free diet ( 6 ), however, since the dog was not tested before the start of the diet, testing the dog at this moment would be unreliable. Nonetheless, the increase in the fat intake from 3.1 to 3.5 g/kg 0.75 could have been the cause of the vomiting and subsequently, the associated stress ( 5 , 28 , 29 , 36 ) could have triggered the neurologic signs. The same symptoms were also noticed when the dog was hospitalized with suspected pancreatitis, presenting a PD episode after remaining episode-free for 2 years.…”

Biallelic pathogenic variants in the mitochondrial form of phosphoenolpyruvate carboxykinase cause peripheral neuropathy

“…A study of dogs with paroxysmal dyskinesia has recently implicated a heterozygous variant in the GTP-binding domain of PCK2 as causative. 11 One possible avenue for future studies is investigating whether the clearance of GTP in the mitochondrial matrix by PCK may be important for the maintenance of neuronal health.…”

A novel mutation in PCK2 gene causes primary angle-closure glaucoma

“…PCK2 also is associated with lung cancer by promoting tumorigenesis through its gluconeogenic function [ 18 ]. Due to its gluconeogenic function, PCK2 deficiency is expected to disrupt glucose homeostasis and result in hypoglycemia related-disorder [ 19 ]. The non-synonymous somatic variant in PCK2 was identified in hepatocellular carcinoma tissue, suggesting that PCK2 was associated with hepatocellular carcinoma [ 20 ].…”