Tibetan Terrier Research Articles

Frequency, breed predispositions and other demographic risk factors for diagnosis of hypothyroidism in dogs under primary veterinary care in the UK

BackgroundHypothyroidism is a commonly diagnosed endocrinopathy in dogs. This study aimed to investigate the frequency and risk factors for diagnosis of hypothyroidism in UK primary-care practice. Dogs diagnosed with hypothyroidism were identified by searching electronic patient records of primary-care practices participating in VetCompass. A cohort study design estimated one-year (2016) period prevalence and incidence risk for hypothyroidism. Multivariable binary logistic regression models were used to evaluate associations between demographic risk factors and hypothyroidism.ResultsFrom 905,553 dogs, 2,105 dogs were recorded with diagnosed hypothyroidism in 2016; 359 incident and 1,746 pre-existing, giving an annual prevalence of 0.23% (95% CI 0.22–0.24) and annual incidence risk of 0.04% (95% CI 0.04–0.04). Multivariable logistic regression identified 24 predisposed and nine protected breeds. Standard Doberman pinscher (odds ratio [OR] = 17.02, 95% CI 12.8–22.64), Tibetan terrier (11.25, 95% CI 8.27–15.32) and boxer (10.44, 95% CI 8.66–12.58) breeds showed high predisposition. Pug (OR 0.29, 95% CI 0.09–0.89), Yorkshire terrier (OR 0.38, 95% CI 0.24–0.59), Shih-tzu (OR 0.38, 95% CI 0.23–0.64) and Jack Russell terrier (OR 0.40, 95% CI 0.29–0.54) were the most protected breeds. Overall, being a purebred dog, being insured, having bodyweight above the breed-sex mean, increasing age, being neutered and rising adult bodyweight also showed increased odds being a dog living with a diagnosis of hypothyroidism.ConclusionsSeveral strong breed predispositions for diagnosis of hypothyroidism were identified that can assist with disorder prioritisation in ongoing efforts to improve breed health. Other risk factors were also identified that can assist veterinary surgeons during clinical work-up of suspected cases. Identification of novel evidence for protected breeds provides useful information for research into genetic mechanisms.

Imaging diagnosis: CT findings in bilateral necrotising sialometaplasia of the mandibular salivary glands in a Tibetan Terrier

AbstractA 7‐year‐old female neutered Tibetan Terrier presented with a 2‐week history of bilateral mandibular swelling, lethargy, reduced appetite, pyrexia and right sided exophthalmos. Computed tomography (CT) identified severe bilateral enlargement and heterogenicity of the mandibular salivary glands, which contained multiple cavitary lesions. Cytology of both mandibular salivary glands confirmed necrotising sialometaplasia. The treatment with phenobarbitone, omeprazole and paracetamol was initiated. The patient made a dramatic improvement upon 3‐week follow up, with marked reduction in size of the mandibular salivary glands and resolution of clinical signs. To the authors’ knowledge, this is the first reported case describing the CT imaging features of necrotising sialometaplasia.

Veterinary drug therapies used for undesirable behaviours in UK dogs under primary veterinary care.

Undesirable behaviours (UBs) in dogs are common and important issues with serious potential welfare consequences for both the dogs and their owners. This study aimed to investigate the usage of drug therapy for UBs in dogs and assess demographic risk factors for drug-prescribed UBs within the dog population under primary-care veterinary care in the UK in 2013. Dogs receiving drug therapy for UB were identified through the retrospective analysis of anonymised electronic patient records in VetCompass™. Risk factor analysis used multivariable logistic regression modelling. The study population comprised 103,597 dogs under veterinary care in the UK during 2013. There were 413 drug-prescribed UBs recorded among 404 dogs. The prevalence of dogs with at least one UB event treated with a drug in 2013 was 0.4%. Multivariable modelling identified 3 breeds with increased odds of drug-prescribed UB compared with crossbred dogs: Toy Poodle (OR 2.75), Tibetan Terrier (OR 2.68) and Shih-tzu (OR 1.95). Increasing age was associated with increased odds of drug-prescribed UB, with dogs ≥ 12 years showing 3.1 times the odds compared with dogs < 3 years. Neutered males (OR 1.82) and entire males (OR 1.50) had increased odds compared with entire females. The relatively low prevalence of dogs with at least one UB event that was treated with a drug in 2013 could suggest that opportunities for useful psychopharmaceutical intervention in UBs may be being missed in first opinion veterinary practice. While bodyweight was not a significant factor, the 3 individual breeds at higher odds of an UB treated with a behaviour modifying drug all have a relatively low average bodyweight. The current results also support previous research of a male predisposition to UBs and it is possible that this higher risk resulted in the increased likelihood of being prescribed a behaviour modifying drug, regardless of neuter status.

Dwarfism in Tibetan Terrier dogs with an LHX3 mutation.

Canine pituitary dwarfism in German Shepherd and related dog breeds has been reported to be associated with a 7-bp deletion mutation in intron 5 of the LHX3 gene. This mutation is transmitted as an autosomal recessive trait that results in dwarf dogs with significantly smaller stature and abnormal haircoat, and potentially early death. Phenotypically, affected adult dogs are proportionally dwarfs. These dwarfs also have a soft, woolly puppy coat that fails to transition into the typical adult hair coat, and marked hair loss occurs in some dogs. We report a similar manifestation of dwarfism in Tibetan Terriers with the same LHX3 mutation. Dwarf Tibetan Terrier puppies were born physically normal but failed to gain weight or to grow at the same rate as their normal littermates. The 7-bp deletion mutation of the LHX3 gene was identified in both alleles of 3 Tibetan Terrier dwarfs from 3 litters, which were biologically related. All parents of these dogs are carriers, confirming transmission of dwarfism in an autosomal recessive manner. Recognition and detection of this mutation will help in guiding future breeding plans to eventually eliminate this trait from Tibetan Terriers.

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds

BackgroundCanine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes.MethodsThe 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together.ResultsFive dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM.ConclusionsNovel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified.

Brain MRI findings in a dog with late onset epileptic seizure after portosystemic shunt attenuation

A female Tibetan terrier aged five years and six months presented 23 months after portosystemic shunt attenuation due to generalised tonic–clonic epileptic seizure activity. Repeat MRI of the brain showed...

Bodyweight at Birth and Growth Rate during the Neonatal Period in Three Canine Breeds.

Simple SummaryThe 349 recognized canine breeds differ greatly in bodyweight and, therefore, in birthweight and neonatal growth. The weight and growth of puppies are easily measurable, and are possible early indicators of problems. Low birthweight has been linked to neonatal mortality based on results obtained by grouping breeds according to their adult bodyweight. Breed-specific ranges of birthweight and growth would allow for the identification of puppies at risk. Our aim was to evaluate the birthweight and early growth of healthy puppies of three breeds in a breed-specific manner. Birthweight, expressed as percentage of mothers’ bodyweight, showed that puppies of a large breed are born smaller than puppies of a small breed. Puppies of a large breed gain weight slower than puppies of a small breed. Sex has no impact on birthweight, whereas litter size influences birthweight and weight gain. Based on our procedure, we considered 29 of 213 puppies to be of a low birthweight, whereas 160 of 213 might have been considered of a low birthweight if using the classical criteria (based on breed groups). This shows the importance of breed-specific evaluations of birthweight. Further research is needed on the importance of breed-specific evaluations for early growth.Weight at birth (bBW) and early weight gain have been linked to the risk of neonatal mortality. Pups are described to be of low bBW if weighing less than one standard deviation (SD) below the mean. Most studies classified breeds according to their expected adult bodyweight. Our aim was to evaluate the breed specificity of these parameters. We assessed the bBW of 213 puppies of Bernese Mountain Dog (BMD), Tibetan Terrier (TT), and Lhasa Apso (LA) breeds, as well as the neonatal growth rate of 133 puppies of BMD and TT. BMD puppies were born relatively smaller than puppies of TT and LA (p ≤ 0.0001) and gained less weight than TT puppies during the first 14 days (p ≤ 0.05). Litter size had a significant impact on bBW and daily gain until the onset of the third week for BMD (p < 0.0001 and p = 0.0005, respectively) and TT (p = 0.0003 and p = 0.0064, respectively). When using bBW means and SD specifically assessed according to breed, 29 out of the 213 neonates of our study were judged as being of low bBW, whereas, when using the classical criteria (based on breed groups), the number of low bBW pups was 160 of 213. These results suggest that evaluations of bBW and neonatal growth should be performed in a breed-specific manner.

Population structure and genetic history of Tibetan Terriers

BackgroundTibetan Terrier is a popular medium-sized companion dog breed. According to the history of the breed, the western population of Tibetan Terriers includes two lineages, Lamleh and Luneville. These two lineages derive from a small number of founder animals from the native Tibetan Terrier population, which were brought to Europe in the 1920s. For almost a century, the western population of Tibetan Terriers and the native population in Tibet were reproductively isolated. In this study, we analysed the structure of the western population of Tibetan Terriers, the original native population from Tibet and of different crosses between these two populations. We also examined the genetic relationships of Tibetan Terriers with other dog breeds, especially terriers and some Asian breeds, and the within-breed structure of both Tibetan Terrier populations.ResultsOur analyses were based on high-density single nucleotide polymorphism (SNP) array (Illumina HD Canine 170 K) and microsatellite (18 loci) genotypes of 64 Tibetan Terriers belonging to different populations and lineages. For the comparative analysis, we used 348 publicly available SNP array genotypes of dogs from other breeds. We found that the western population of Tibetan Terriers and the native Tibetan Terriers clustered together with other Asian dog breeds, whereas all other terrier breeds were grouped into a separate group. We were also able to differentiate the western Tibetan Terrier lineages (Lamleh and Luneville) from the native Tibetan Terrier population.ConclusionsOur results reveal the relationships between the western and native populations of Tibetan Terriers and support the hypothesis that Tibetan Terrier belongs to the group of ancient dog breeds of Asian origin, which are close to the ancestors of the modern dog that were involved in the early domestication process. Thus, we were able to reject the initial hypothesis that Tibetan Terriers belong to the group of terrier breeds. The existence of this native population of Tibetan Terriers at its original location represents an exceptional and valuable genetic resource.

Genetic diversity and population structure of the Sapsaree, a native Korean dog breed

BackgroundThe Sapsaree is a breed of dog (Canis familiaris) native to Korea, which became perilously close to extinction in the mid-1980s. However, with systematic genetic conservation and restoration efforts, this breed was rescued from extinction and population sizes have been gradually increasing over the past few decades. The aim of this study was to ascertain novel information about the genetic diversity, population structure, and demographic history of the Sapsaree breed using genome-wide single nucleotide polymorphism data. We characterized the genetic profile of the Sapsaree breed by comparison with seven foreign dog breeds with similar morphologies to estimate genetic differentiation within and among these breeds.ResultsThe results suggest that Sapsarees have higher genetic variance compared with the other breeds analyzed. The majority of the Sapsarees in this study share a discrete genetic pattern, although some individuals were slightly different, possibly as a consequence of the recent restoration process. Concordant results from analyses of linkage disequilibrium, effective population size, genetic diversity, and population structural analyses illustrate a relationship among the Sapsaree and the Tibetan breeds Tibetan terrier and Lhasa Apso, and a small genetic introgression from European breeds. The effective population size of the Sapsaree has contracted dramatically over the past generations, and is currently insufficient to maintain long-term viability of the breed’s genetic diversity.ConclusionsThis study provides novel insights regarding the genetic diversity and population structure of the native Korean dog breed Sapsaree. Our results suggest the importance of a strategic and systematic approach to ensure the genetic diversity and the authenticity of the Sapsaree breed.

Unilateral otitis externa induced by a plastic foreign body

A nine-year-old, male, neutered Tibetan terrier was evaluated for unilateral otitis externa associated with the history of a dog bite injury to the pinna five years prior. Examination findings of...

Identification of the mutation causing progressive retinal atrophy in Old Danish Pointing Dog.

Progressive retinal atrophy (PRA) is a common cause of blindness in many dog breeds. It is most often inherited as a simple Mendelian trait, but great genetic heterogeneity has been demonstrated both within and between breeds. In many breeds the genetic cause of the disease is not known, and until now, the Old Danish Pointing Dog (ODP) has been one of those breeds. ODP is one of the oldest dog breeds in Europe. Seventy years ago the breed almost vanished, but today a population still exists, primarily in Denmark but with some dogs in Germany and Sweden. PRA has been diagnosed in ODP since the late 1990s. It resembles late onset PRA in other dog breeds, and it is inherited as an autosomal recessive trait. In the present study, we performed whole-genome sequencing and identified a single base insertion (c.3149_3150insC) in exon 1 of C17H2orf71. This is the same mutation previously found to cause PRA in Gordon Setters and Irish Setters, and it was later found in Tibetan Terrier, Standard Poodle and the Polski Owczarek Nizinny. The presence of the mutation in such a diverse range of breeds indicates an origin preceding creation of modern dog breeds. Hence, we screened 262 dogs from 44 different breeds plus four crossbred dogs, and can subsequently add Miniature Poodle and another polish sheepdog, the Polski Owczarek Podhalanski, to the list of affected breeds.

Clinical conundrum: Hindlimb paraparesis

James Guillem, of the Veterinary Referral Centre in Surrey, invites Companion readers to consider a Tibetan Terrier with hindlimb paresis that was seen while he was a rotating intern at the Willows Veterinary Centre and Referral Service.

Small Intestinal Lymphatic Hypoplasia in Three Dogs with Clinical Signs of Protein-losing Enteropathy

Intestinal lymphatic hypoplasia (ILH) is a rare but well-documented cause of protein-losing enteropathy (PLE) in human infants. To our knowledge, this condition has not been reported previously in veterinary medicine. Here we report the clinical and histopathological findings in three dogs that presented with clinical signs of PLE. The onset of PLE was early in an 18-month-old Great Pyrenees, while the other two dogs, a pug and a Tibetan terrier, had a later onset at 4 and 12 years of age, respectively. The presence of intestinal lymphatic and blood vessels was assessed by immunohistochemistry for human prospero homeobox 1 (prox-1), a lymphatic endothelial nuclear transcription factor and human von Willebrand factor (vWf), a marker of vascular endothelial cells, respectively. Small intestinal specimens taken from each dog showed severe mucosal oedema with a lack of prox-1 labelling of villous lacteals, dilated and tortuous vWf immunoreactive villous arterial and capillary blood vessels, and variable lamina propria mixed inflammatory cell infiltrates. Other histological features of ILH included club-shaped villi that were lined by low cuboidal epithelium or epithelial cells with cytoplasmic pallor and microvacuolar change, extrusion zone epithelial inversion and thin and inconspicuous villous longitudinal smooth muscles. While ILH is an uncommon diagnosis, it should be considered as a differential in dogs with clinical signs of PLE. The cause of canine ILH is unknown; however, a congenital abnormality with early or late onset of clinical signs is suspected. Diagnosis of ILH can be challenging; however, immunohistochemical labelling of lymphatic endothelial cells with prox-1 is essential for making this diagnosis.

Canine intrathoracic sarcoma with ultrastructural characteristics of human synovial sarcoma \u2013 case report

BackgroundCanine joint sarcomas, designated synovial sarcomas, are uncommon malignant mesenchymal neoplasms that occur in the large joints of the extremities of middle-aged, large-breed dogs. We report the diagnosis of an intrathoracic sarcoma with ultrastructural characteristics reminiscent of human synovial sarcoma in a dog.Case presentationA 7-year-old female spayed Tibetan terrier crossbred dog was presented for acute severe labored breathing and diagnosed with an intrathoracic neoplastic mass. The neoplasm resulted in the accumulation of substantial amounts of viscous pleural fluid that led to dyspnea. The neoplastic mass consisted of interweaving bundles of large pleomorphic mesenchymal cells, supported by an alcian blue positive myxomatous matrix. The neoplastic cells were immunohistochemically negative for cytokeratin and CD18. Transmission electron microscopy indicated that the neoplastic cells had desmosome junctions, short microvilli-like structures and ample amounts of rough endoplasmic reticulum resembling type B-like synoviocytes and synovial sarcoma as reported in people. Despite complete surgical excision of the neoplastic mass, clinical signs recurred after a month and led to the euthanasia of the dog.ConclusionCurrently, there are no immunohistochemical markers specific for synovial sarcoma. Canine neoplasms with transmission electron microscopy characteristics resembling type B-like synoviocytes should be considered similar to the human sarcomas that carry the specific translocations between chromosomes X and 18.

Self assessment: acute-onset vomiting in a Tibetan Terrier

Self assessment: acute-onset vomiting in a Tibetan Terrier

Characteristics of urolithiasis in the dog population of Hungary from 2001 to 2012

The objective of this study was to describe the epidemiology of canine urolithiasis in Hungary in order to determine the annual incidence of urolithiasis and to identify breeds at risk for different types of urolithiasis. Data of a total of 2,543 canine uroliths analysed in the laboratory of the Budapest Urolith Centre were evaluated retrospectively from 2001 to 2012. Logistic regression was used to assess odds ratios for the proportion of each affected breed compared to those of crossbreeds. The annual incidence of urolithiasis was evaluated by the number of submissions compared to the estimated number of dogs in the population from which the samples originated. Epidemiologic data revealed a relatively high and increasing proportion of struvite urolithiasis. Statistical analysis of breed predispositions resulted in the detection of breeds not having been reported at risk (e.g. Bernese Mountain dog - struvite, Bichon Frise, Bolognese, Tibetan Terrier - purine, French Bulldog - cystine). Conflicting results were revealed for some other breeds previously described as being affected by certain types of urolithiasis (Chihuahua, Pekingese, Shih Tzu, English Cocker Spaniel). Regardless of the type of urolithiasis, its average cumulative incidence in the dog population of Hungary was found to be 1.76/10,000/year.

Breed differences in development of anti-insulin antibodies in diabetic dogs and investigation of the role of dog leukocyte antigen (DLA) genes

Administration of insulin for treatment of diabetes mellitus in dogs can stimulate an immune response, with a proportion of animals developing anti-insulin antibodies (AIA). For an IgG antibody response to occur, this would require B cell presentation of insulin peptides by major histocompatibility complex (MHC) class II molecules, encoded by dog leukocyte antigen (DLA) genes, in order to receive T-cell help for class switching. DLA genes are highly polymorphic in the dog population and vary from breed to breed. The aim of the present study was to evaluate AIA reactivity in diabetic dogs of different breeds and to investigate whether DLA genes influence AIA status.Indirect ELISA was used to determine serological reactivity to insulin in diabetic dogs, treated with either a porcine or bovine insulin preparation. DLA haplotypes for diabetic dogs were determined by sequence-based typing of DLA-DRB1, -DQA1 and -DQB1 loci. Significantly greater insulin reactivity was seen in treated diabetic dogs (n=942) compared with non-diabetic dogs (n=100). Relatively few newly diagnosed diabetic dogs (3/109) were found to be AIA positive, although this provides evidence that insulin autoantibodies might be involved in the pathogenesis of the disease in some cases. Of the diabetic dogs treated with a bovine insulin preparation, 52.3% (182/348) were AIA positive, compared with 12.6% (75/594) of dogs treated with a porcine insulin preparation, suggesting that bovine insulin is more immunogenic. Breeds such as dachshund, Cairn terrier, miniature schnauzer and Tibetan terrier were more likely to develop AIA, whereas cocker spaniels were less likely to develop AIA, compared with crossbreed dogs. In diabetic dogs, DLA haplotype DRB1*0015--DQA1*006--DQB1*023 was associated with being AIA positive, whereas the haplotype DLA-DRB1*006--DQA1*005--DQB1*007 showed an association with being AIA negative. These research findings suggest that DLA genes influence AIA responses in treated diabetic dogs.

Successful medical treatment for globe penetration following tooth extraction in a dog

A five-year-old entire male Tibetan Terrier was referred for left-sided periorbital swelling and blepharospasm 4 days following ipsilateral maxillary tooth extraction. Examination of the left eye revealed mild exophthalmos, pain on retropulsion, and absent menace response and pupillary light reflexes. Examination of the posterior segment was not possible owing to the anterior segment pathology. Differential diagnoses considered were iatrogenic globe penetration and peribulbar abscess/cellulitis. Ocular ultrasound was consistent with a penetrating wound to the globe. Treatment with systemic prednisolone and marbofloxacin, and topical atropine sulfate 1%, prednisolone acetate, and brinzolamide was started. Marked clinical improvement allowed visual confirmation of the perforation. Oral prednisolone was tapered over the following 10 weeks. At final re-examination (10 months), the patient was visual, and fundic examination revealed an additional chorioretinal scar, most likely an exit wound that was obscured by vitreal debris on initial examinations. Neither scar was associated with retinal detachment. To the authors' knowledge, this is the first reported case of successful medical management of iatrogenic globe penetration following exodontic procedures.

Ehrlichia canis infection in a dog with no history of travel outside the United Kingdom

A two-year-old female neutered Tibetan terrier was referred following a one-month history of lethargy, inappetence and pancytopenia, which had been poorly responsive to immunosuppressive and fluoroquinolone treatment. The dog was diagnosed with pure red cell aplasia and was found to be positive for Ehrlichia canis by both antibody titre measurement and polymerase chain reaction. The dog lived in London and had not travelled outside the UK. The dog was treated with doxycycline, prednisolone and ciclosporin, but died as a result of gastrointestinal tract haemorrhage. To the authors' knowledge, this represents the first reported case of Ehrlichia canis in a dog in the UK with no previous travel history.

A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies.