Dystonic head tremor in paroxysmal dyskinesia in 17 dogs (2021-2023).

BACKGROUND: Dystonia is a common component of the movement disorder paroxysmal dyskinesia (PD) in dogs. However, the incidence of dystonic head tremor (DHT) in these dogs has not previously been evaluated. METHODS: The medical records of dogs presenting with PD between 2021 and 2023 were retrospectively reviewed, and those with available video footage and the presence of a head tremor were selected for further analysis. RESULTS: Seventeen of the 39 (43.6%) dogs diagnosed with PD that had video footage available manifested DHT. Poodle or Poodle-cross was the most commonly affected breed (7/17). DHTs were described as fine irregular head tremors accompanied by cervical dystonia (17/17), truncal (11/17) or head (10/17) sway, shifting limb (10/17) or single limb (6/17) dystonia, freezing (8/17), ataxia (6/17), ptyalism (5/17), falling (5/17), kyphosis (4/17) and prayer posture (4/17). Neurological examination and advanced imaging, when available, were within normal limits. LIMITATIONS: The limitations of the study include its retrospective nature, the lack of video recordings for all PD patients and the lack of electrophysiological evaluation of tremors and electroencephalography. CONCLUSIONS: DHT exists in dogs with PD; it has characteristic features, and it should be considered in differential diagnoses for dogs with head tremors.

Clinical characterisation of a novel paroxysmal dyskinesia in Welsh terrier dogs.

Breed specific paroxysmal dyskinesias are increasingly recognised in veterinary medicine. We aimed to characterise the phenomenology, clinical course and prevalence of a previously unreported paroxysmal dyskinesia in the Welsh terrier breed. Clinical records of five Welsh terriers with paroxysmal episodes were reviewed. Additionally, owners of Welsh terriers were invited to complete a questionnaire with the aim of characterising paroxysmal episodes in the wider breed population. Clinical examinations (n = 5) and diagnostic investigations (n = 3) of affected Welsh terriers were within normal limits, apart from mild-moderate ventriculomegaly on cranial magnetic resonance imaging (n = 3). The survey of Welsh terrier owners revealed episodes consistent with a paroxysmal dyskinesia in 41 (22.8%) of 177 respondents. Median age of onset was 59 months. Episodes were predominantly characterised by sustained hypertonicity with periods of limb flexion, abnormal head and body posture, with preserved consciousness. Episode duration ranged from 30 s to 30 min (median, 3 min 30 s), with frequency varying widely between dogs. Affected dogs demonstrated a stable to improving clinical course in most cases. This study investigated a previously unreported paroxysmal dyskinesia in Welsh terriers. Similar clinical signs within the breed were potentially consistent with an inherited cause, worthy of further investigation.

Phenotypic characterisation of paroxysmal dyskinesia in Sphynx cats.

OBJECTIVES: The aim of this study was to identify the phenotypic features of a paroxysmal dyskinesia observed in Sphynx cats. METHODS: The owners of affected Sphynx cats were invited to provide video footage of abnormal episodes for review. Those that demonstrated episodes consistent with paroxysmal dyskinesia were then invited to complete an online questionnaire designed to allow further characterisation. RESULTS: Ten Sphynx cats were included in the study. All affected cats were <4 years of age at the onset of the episodes (range 0.5-4.0). The episodes had a duration of <5 mins in 9/10 cats (range 0.5-10), while episode frequency was variable between and within individual cats. The episodes were characterised by impaired ambulation due to muscle hypertonicity, most commonly affecting the hips and pelvic limbs (9/10) and shoulders and thoracic limbs (8/10). The head and neck (6/10), tail (5/10), and back and abdomen (3/10) were also involved in some cats. Sudden movement, excitement and stress were identified as possible triggers for the episodes in three cats. Therapeutic intervention was not attempted in 7/10 cases, although two cats were reported to become free of the episodes while receiving acetazolamide. The two cats that were followed beyond 2 years from onset entered spontaneous remission. None of the owners believed that the abnormal episodes had affected the quality of life of their cat. CONCLUSIONS AND RELEVANCE: The phenotype of paroxysmal dyskinesia in Sphynx cats presented in this study appears to share similarities with paroxysmal kinesigenic dyskinesia described in human classification systems. Some cats appear to achieve episode freedom spontaneously. Subsequent research should focus on evaluating response to treatment and determining an underlying genetic cause.

International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification.

Movement disorders are a heterogeneous group of clinical syndromes in humans and animals characterized by involuntary movements without changes in consciousness. Canine movement disorders broadly include tremors, peripheral nerve hyperexcitability disorders, paroxysmal dyskinesia, and dystonia. Of these, canine paroxysmal dyskinesias remain one of the more difficult to identify and characterize in dogs. Canine paroxysmal dyskinesias include an array of movement disorders in which there is a recurrent episode of abnormal, involuntary, movement. In this consensus statement, we recommend standard terminology for describing the various movement disorders with an emphasis on paroxysmal dyskinesia, as well as a preliminary classification and clinical approach to reporting cases. In the clinical approach to movement disorders, we recommend categorizing movements into hyperkinetic vs hypokinetic, paroxysmal vs persistent, exercise-induced vs not related to exercise, using a detailed description of movements using the recommended terminology presented here, differentiating movement disorders vs other differential diagnoses, and then finally, determining whether the paroxysmal dyskinesia is due to either inherited or acquired etiologies. This consensus statement represents a starting point for consistent reporting of clinical descriptions and terminology associated with canine movement disorders, with additional focus on paroxysmal dyskinesia. With consistent reporting and identification of additional genetic mutations responsible for these disorders, our understanding of the phenotype, genotype, and pathophysiology will continue to develop and inform further modification of these recommendations.

A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.

A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.

Levetiracetam-responsive paroxysmal exertional dyskinesia in a Welsh Terrier.

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.

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

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.

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

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.

Phenotypic characterization of paroxysmal dyskinesia in Maltese dogs.

BACKGROUND: Paroxysmal dyskinesias (PDs) are a group of central nervous system diseases characterized by episodes of abnormal involuntary hyperkinetic movement without altered consciousness that increasingly have been recognized in dogs. OBJECTIVES: To present the phenotypical characterization, treatment, and outcome of a PD observed in Maltese dogs. ANIMALS: Client-owned Maltese dogs (n = 19) with presumed diagnosis of PD. METHODS: Data were collected retrospectively from medical records (2014-2019), and supporting information was added prospectively by using a questionnaire directed to the owners of the affected dogs. RESULTS: The episodes were characterized mainly by sudden dystonia of ≥1 limbs and generalized body tremors with preserved consciousness. The mean age of clinical onset was 5.4 years. Episode frequency varied widely both among and within individuals. Median episode duration was 4.5 minutes. Most episodes were stress- or exercise-induced. Acetazolamide was administered to 6 dogs, and 4 dogs experienced a decrease in episode frequency. In 7 dogs that received a gluten-free diet, 6 dogs became episode-free. In 4 dogs, the episodes stopped spontaneously and in 2 dogs no medication or specific diet was given and the episodes continued at the same frequency. CONCLUSIONS AND CLINICAL IMPORTANCE: Given the breed predisposition and regional distribution of the disease, additional research should focus on elucidating the underlying genetic cause doing so might advance both our understanding of the pathophysiology and treatment of this disease, not only in dogs, but also in humans. Regardless of the treatment protocol selected, prognosis appears fair to good.

Paroxysmal Dyskinesia in Border Terriers: Clinical, Epidemiological, and Genetic Investigations.

BACKGROUND: In the last decade, a disorder characterized by episodes of involuntary movements and dystonia has been recognized in Border Terriers. OBJECTIVES: To define clinical features of paroxysmal dyskinesia (PD) in a large number of Border Terriers and to study the genetics of the disease. ANIMALS: 110 affected and 128 unaffected client-owned Border Terriers. METHODS: A questionnaire regarding clinical characteristics of PD was designed at Utrecht University and the University of Helsinki. Thirty-five affected Border Terriers underwent physical examination and blood testing (hematology and clinical biochemistry). Diagnostic imaging of the brain was performed in 17 affected dogs and electroencephalograms (EEG) between episodes were obtained in 10 affected dogs. A genomewide association study (GWAS) was performed with DNA of 110 affected and 128 unaffected dogs. RESULTS: One hundred forty-seven questionnaires were included in the study. The most characteristic signs during episodes were dystonia, muscle fasciculations, and falling over. The majority of owners believed that their dogs remained conscious during the episodes. A beneficial effect of anti-epileptic therapy was observed in 29 of 43 dogs. Fifteen owners changed their dogs' diet to a hypoallergenic, gluten-free diet, and all reported reasonable to good improvement of signs. Clinical examinations and diagnostic test results were unremarkable. The GWAS did not identify significantly associated chromosome regions. CONCLUSIONS AND CLINICAL IMPORTANCE: The survey results and EEG studies provided further evidence that the observed syndrome is a PD rather than epilepsy. Failure to achieve conclusive results by GWAS indicates that inheritance of PD in Border Terriers probably is complex.

Classification of involuntary movements in dogs: Paroxysmal dyskinesias.

Paroxysmal dyskinesias (PDs) are a group of hyperkinetic movement disorders characterised by circumscribed episodes of disturbed movement, superimposed on a background state in which such abnormality is absent. There is no loss of consciousness. Episodes can last seconds, minutes or hours, and the beginning and end of the movement disturbance are abrupt. Neurological examination is typically normal between episodes. PDs are associated with a broad spectrum of clinical presentations, encompassing various aetiologies. In humans, three main groups of PDs are distinguished, based on precipitating events rather than phenomenology: (1) paroxysmal kinesigenic dyskinesia (PKD); (2) paroxysmal nonkinesigenic dyskinesia (PNKD); and (3) paroxysmal exertion-induced dyskinesia (PED). In recent years, there has been an expansion of the spectrum of manifestations of PD due to the identification of genes associated with PD in humans (PRRT1, MR-1, SLC2A1 and KCNMA1) and dogs (BCAN and PIGN). The precise pathophysiological mechanism underlying the clinical manifestations of these reported mutations remains to be elucidated. Progress is also being made in the field of immunology, and links to gluten hypersensitivity in Border terriers with so-called canine epileptoid cramping syndrome (CECS) have been reported. This review aims to synthesise a classification scheme for veterinary PDs by reviewing human systems and applying them to veterinary examples. However, it is anticipated that genetic advancement will greatly aid in future stratification and therapy for PDs in dogs. Therefore, classification systems should be viewed as works in progress that should be modified as necessary.

A homozygous PIGN missense mutation in Soft-Coated Wheaten Terriers with a canine paroxysmal dyskinesia.

Hereditary paroxysmal dyskinesias (PxD) are a heterogeneous group of movement disorders classified by frequency, duration, and triggers of the episodes. A young-adult onset canine PxD has segregated as an autosomal recessive trait in Soft-Coated Wheaten Terriers. The medical records and videos of episodes from 25 affected dogs were reviewed. The episodes of hyperkinesia and dystonia lasted from several minutes to several hours and could occur as often as >10/day. They were not associated with strenuous exercise or fasting but were sometimes triggered by excitement. The canine PxD phenotype most closely resembled paroxysmal non-kinesigenic dyskinesia (PNKD) of humans. Whole genome sequences were generated with DNA from 2 affected dogs and analyzed in comparison to 100 control canid whole genome sequences. The two whole genome sequences from dogs with PxD had a rare homozygous PIGN:c.398C > T transition, which predicted the substitution of an isoleucine for a highly conserved threonine in the encoded enzyme. All 25 PxD-affected dogs were PIGN:c.398T allele homozygotes, whereas there were no c.398T homozygotes among 1185 genotyped dogs without known histories of PxD. PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors a variety of proteins including CD59 to the cell surface. Flow cytometry of PIGN-knockout HEK239 cells expressing recombinant human PIGN with the c.398T variant showed reduced CD59 expression. Mutations in human PIGN have been associated with multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1). Movement disorders can be a part of MCAHS1, but this is the first PxD associated with altered GPI anchor function.

Natural history of canine paroxysmal movement disorders in Labrador retrievers and Jack Russell terriers.

Delineation of the typical disease progression in canine paroxysmal dyskinesia (PD) may assist in evaluating therapeutic agents during clinical trials. Our objective was to establish the natural disease course in a group of dogs diagnosed with PD that received no medication. Fifty-nine dogs (36 Labradors, 23 JRTs) with clinically confirmed PD and a follow-up of ≥3 years were retrospectively reviewed. Dogs with PD had a young onset, were triggered by startle or sudden movements, and had a male bias (75%) with the majority being entire sample population. Twenty-one dogs (36%) had at least one event comprising cluster episodes. Episode duration and frequency varied dramatically, even within an individual. Median follow-up was 7 years. No concurrent disease was identified in any dog that was investigated. The natural history was self-limiting with 32% entering remission and an improvement in 75%. Episodes reduced in terms of frequency and duration in Labradors and JRTs respectively. Remission was lower in dogs with cluster episodes than those without. These findings suggest that the diagnostic yield of advanced neuroimaging techniques in dogs with video footage and historical data supporting PD, without neurological deficits, is low. The presence of cluster episodes is of predictive value for the prognosis of canine PD. Future research should be cautious in reporting treatment response for PD without first considering the spontaneous remission rate and improvements in untreated dogs documented in this study.

Paroxysmal dyskinesia suspected as canine epileptoid cramping syndrome in a young Yorkshire terrier dog.

A 9-month-old intact female Yorkshire terrier dog was presented with episodic partial seizure-like cramping of the limbs. The patient's episodes began six months previously; the interval between episodes became shorter, and the duration of the episodes increased. Various tests including neurologic examination, blood examination, abdominal radiography, ultrasonographic examination, angiographic computed tomography (CT) and brain magnetic resonance imaging (MRI) detected no remarkable changes. After these tests were conducted, the patient's condition was suspected to be canine epileptoid cramping syndrome (CECS), which could be a form of paroxysmal dyskinesia (PD), and as a trial therapy, Science Diet k/d (Hill's Pet Nutrition, Topeka, KS, U.S.A.) was prescribed. The clinical signs were dramatically reduced after diet therapy, and we diagnosed the patient with CECS. This is the first case report of CECS in a Yorkshire terrier dog.

Characterization and mode of inheritance of a paroxysmal dyskinesia in Chinook dogs.

BACKGROUND: Paroxysmal dyskinesias are episodes of abnormal, involuntary movement or muscle tone, distinguished from seizures by the character of the episode and lack of seizure activity on ictal EEG. HYPOTHESIS: Paroxysmal dyskinesia is an inherited, autosomal recessive disorder in Chinook dogs. ANIMALS: Families of Chinook dogs with paroxysmal dyskinesia. METHODS: Pedigrees and medical histories were reviewed for 299 Chinook dogs. A family of 51 dogs was used for analysis. Episodes were classified as seizures, paroxysmal dyskinesia, or unknown, and segregation analysis was performed. RESULTS: Paroxysmal dyskinesia was identified in 16 of 51 dogs and characterized by an inability to stand or ambulate, head tremors, and involuntary flexion of 1 or multiple limbs, without autonomic signs or loss of consciousness. Episode duration varied from minutes to an hour. Inter-ictal EEGs recorded on 2 dogs with dyskinesia were normal. Three dogs with dyskinesia also had generalized tonic-clonic seizures. One of 51 dogs had episodes of undetermined type. Phenotype was unknown for 6 of 51 dogs, and 28 dogs were unaffected. Segregation was consistent with an autosomal recessive trait. CONCLUSIONS AND CLINICAL IMPORTANCE: This movement disorder is prevalent in the Chinook breed, and consistent with a partially penetrant autosomal recessive or polygenic trait. Insufficient evidence exists for definitive localization; episodes may be of basal nuclear origin, but atypical seizures and muscle membrane disorders remain possible etiologies. The generalized seizures may be a variant phenotype of the same mutation that results in dyskinesia, or the 2 syndromes may be independent.

Medico-geographical aspects of some nervous diseases of animals.

Illustrating with some examples of animal diseases appearing to be less important like the cerebellar hypoplasy of cats, pig chorea, louping ill and scrapie, the author wants to enlighten the significance of medico-geographical investigations concerning the distribution of nervous diseases of animals. He is supplying data to confirm the fact that many diseases of central nervous system of animals - after having detected their nosology and distribution more extensively - would come much more into prominence from public and animal health aspect too.