Cell differentiation involves activation of mutually exclusive genetic programs The shape of our nose, the color of our skin, the movement of our gut, all depend on an extraordinary cell type called neural crest cells, which originate during embryogenesis. Since their discovery in 1868 (1), neural crest cells, which are present in all vertebrates, have fascinated developmental biologists (2). One of the amazing features of neural crest cells is their extraordinary multipotency: They form cartilage, muscle, neurons, glia, pigment cells, adrenal cells, and so on. (3). No other embryonic cell type can differentiate into so many different kinds of cells. However, how this multipotency is achieved is not understood. On page 971 of this issue, Soldatov et al. (4) clarify some of the mechanisms that explain how the multiplicity of cell types is generated by neural crest cells.

/pdf/cell-fate-decisions-during-development-4o4tdi9ngv.pdf

Cell fate decisions during development.

A hereditary movement disorder in Soft coated wheaten terriers (SCWT) has been associated with a mutation in PIGN which encodes an enzyme involved in synthesis of glycosylphosphatidylinositol (GPI). The objective of this study was to describe and classify the clinical phenotype and assess therapeutic response. Twenty-five SCWT and related dogs homozygous for PIGN:c.398C>T with paroxysmal dyskinesia were available for inclusion. Medical records and video recordings of 17 dogs were evaluated in a retrospective case series. Affected dogs had episodes of involuntary, hyperkinetic movements and dystonia. Median age of onset was 2.5 years. A typical episode consisted of rapid, irregular hyperflexion and extension of the pelvic limbs with some degree of truncal dystonia. A mild episode consisted of spontaneous flexion of one pelvic limb while walking which could resemble a lameness. Episodes lasted several minutes to several hours and occurred up to 10 times/day or more. They were not associated with exercise or fasting but were sometimes triggered by excitement or stress. Acetazolamide therapy improved nine of 11 dogs, in seven cases abolishing episodes. Five of 17 dogs treated with other agents had mild improvement with clonazepam (n = 2), levetiracetam (n = 1), or phenobarbital (n = 2). Paroxysmal dyskinesias must be differentiated from seizure disorders since they often respond to different therapies. The SCWT phenotype consisted predominantly of hyperkinesia, and can respond dramatically to acetazolamide. GPI anchors proteins to the cell surface including carbonic anhydrase IV which modulates synaptic pH in the brain. Altered activity of this enzyme may be the target of acetazolamide therapy.

Phenotypic characterization of PIGN-associated paroxysmal dyskinesia in Soft-coated wheaten terriers and preliminary response to acetazolamide therapy.

A 5-and-a-half-year old, 9-kg, spayed, female Welsh Terrier presented with a 12 month history of paroxysmal exertion-induced dyskinesia (PED) characterized by recurrent episodes of involuntary hyperkinetic movements, abnormal muscle tone, and contractions triggered by exercise. A single episode occurred within 2 hours after exercise, lasted from 7 to 10 minutes, and resolved without treatment. The owner sought treatment for the dog when the episodes began to last longer (20-30 minutes), and occurred as long as 2.5 to 8 hours after exercise. Diazepam administered intranasally at the start of an episode promptly alleviated the symptoms. Maintenance therapy with levetiracetam proved effective, such that the dog was gradually returned to exercise. However, attempts to wean the dog off the drug resulted in reoccurrence. Although the pathophysiology of PED is not fully understood, the clinical presentation and the positive response to antiepileptic therapy highlight the overlap between disease pathways in epilepsy and PED in dogs.

Levetiracetam-responsive paroxysmal exertional dyskinesia in a Welsh Terrier.

BACKGROUND
Autoimmune mechanisms represent a novel category for causes of seizures and epilepsies in humans, and LGI1-antibody associated limbic encephalitis occurs in cats.


HYPOTHESIS/OBJECTIVES
To investigate the presence of neural antibodies in dogs with epilepsy or dyskinesia of unknown cause using human and murine assays modified for use in dogs.


ANIMALS
Fifty-eight dogs with epilepsy of unknown cause or suspected dyskinesia and 57 control dogs.


METHODS
Serum and CSF samples were collected prospectively as part of the diagnostic work-up. Clinical data including onset and seizure/episode type were retrieved from the medical records. Screening for neural antibodies was done with cell-based assays transfected with human genes for typical autoimmune encephalitis antigens and tissue-based immunofluorescence assays on mouse hippocampus slices in serum and CSF samples from affected dogs and controls. The commercial human und murine assays were modified with canine-specific secondary antibody. Positive controls were from human samples.


RESULTS
The commercial assays used in this study did not provide unequivocal evidence for presence of neural antibodies in dogs including one dog with histopathologically proven limbic encephalitis. Low titer IgLON5 antibodies were present in serum from one dog from the epilepsy/dyskinesia group and in one dog from the control group.


CONCLUSION AND CLINICAL IMPORTANCE
Specific neural antibodies were not detected using mouse and human target antigens in dogs with epilepsy and dyskinesia of unknown origin. These findings emphasize the need for canine-specific assays and the importance of control groups.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jvim.16744

Investigation of the presence of specific neural antibodies in dogs with epilepsy or dyskinesia using murine and human assays.

Background To our knowledge, this is the first description of long-term nutritional management in a dog with paroxysmal dyskinesia. Case summary An obese 9-year-old, male entire, German Spitz was presented for dietary management after being diagnosed with calcium oxalate urolithiasis and suspected pancreatitis. Since he was seven years old, the dog has had a history of neurological signs, which were thought to be epileptic seizures. He was treated with phenobarbital and potassium bromide and was clinically controlled. For his nutritional advice, aiming to minimize one of the most important risk factors for the diseases, a weight loss program was started and successfully executed. However, 10 months later, the dog restarted presenting neurological episodes at a high frequency (3x/week). Based on videos and the characteristics of the neurological signs, the dog was diagnosed with paroxysmal dyskinesia. To investigate the role of gluten intake on this patient's neurological signs, a dietary trial with a commercial hypoallergenic diet (gluten-free; hydrolyzed protein) was followed. During the 3 months of the dietary trial, four neurologic episodes related to food indiscretion occurred. Upon the decrease in neurological episodes, the anti-seizure drugs were slowly discontinued. During this period, the dog presented only two neurologic episodes that were related to the days that the anti-seizure drugs were decreased. For 4 months the dog remained episode-free. However, a change in the dog's diet to another gluten-free diet (higher fat) led the dog to vomit and experience another neurologic episode. Once the dog was back to the previous gluten-free diet, it clinically improved, and no other clinical signs were reported by the client during the next 5 months. Conclusion Although a relationship between gluten and paroxysmal dyskinesia cannot be confirmed, the dog's improvement after the nutritional management and the removal of the anti-seizure therapy is supportive of dietary association.

/pdf/long-term-nutritional-management-of-an-obese-german-spitz-2qymioce.pdf

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

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>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.

/pdf/mitochondrial-pck2-missense-variant-in-shetland-sheepdogs-4cuy8ju7op.pdf

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

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