Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy.

BACKGROUND: Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology. OBJECTIVES: To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause. METHODS: Clinical and postmortem evaluations, together with a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing. RESULTS: Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed. CONCLUSIONS: RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia-85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Novel MRI and histopathological findings in a young Bullmastiff cross dog with mitochondrial fission encephalopathy.

A 9-month-old male Bullmastiff cross dog was presented with a history of progressive proprioceptive ataxia and behavior changes. Neuroanatomical localization was multifocal with forebrain and vestibulo-cerebellum involvement. MRI identified moderate diffuse cerebral sulci widening, dilation of the ventricular system, and rounded, well-defined, bilaterally symmetrical T2W, FLAIR, and T2* hyperintense intra-axial lesions affecting the olivary nuclei. Histopathological examination was indicative of a primary mitochondrial disorder. This was confirmed following genetic analysis which identified mitochondrial fission encephalopathy with a homozygous frameshift variant in the MFF gene. This case report documents diagnostic imaging and histopathological findings not previously reported in dogs affected with mitochondrial fission encephalopathy, suggesting a different selective regional vulnerability of the neurons.

A TNR Frameshift Variant in Weimaraner Dogs with an Exercise-Induced Paroxysmal Movement Disorder.

BACKGROUND: Some paroxysmal movement disorders remain without an identified genetic cause. OBJECTIVES: The aim was to identify the causal genetic variant for a paroxysmal dystonia-ataxia syndrome in Weimaraner dogs. METHODS: Clinical and diagnostic investigations were performed. Whole genome sequencing of one affected dog was used to identify private homozygous variants against 921 control genomes. RESULTS: Four Weimaraners were presented for episodes of abnormal gait. Results of examinations and diagnostic investigations were unremarkable. Whole genome sequencing revealed a private frameshift variant in the TNR (tenascin-R) gene in an affected dog, XM_038542431.1:c.831dupC, which is predicted to truncate more than 75% of the open read frame. Genotypes in a cohort of 4 affected and 70 unaffected Weimaraners showed perfect association with the disease phenotype. CONCLUSIONS: We report the association of a TNR variant with a paroxysmal dystonia-ataxia syndrome in Weimaraners. It might be relevant to include sequencing of this gene in diagnosing humans with unexplained paroxysmal movement disorders. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Serum anti-GM2 and anti-GalNAc-GD1a ganglioside IgG antibodies are biomarkers for immune-mediated polyneuropathies in cats.

Recent work identified anti-GM2 and anti-GalNAc-GD1a IgG ganglioside antibodies as biomarkers in dogs clinically diagnosed with acute canine polyradiculoneuritis, in turn considered a canine equivalent of Guillain-Barré syndrome. This study aims to investigate the serum prevalence of similar antibodies in cats clinically diagnosed with immune-mediated polyneuropathies. The sera from 41 cats clinically diagnosed with immune-mediated polyneuropathies (IPN), 9 cats with other neurological or neuromuscular disorders (ONM) and 46 neurologically normal cats (CTRL) were examined for the presence of IgG antibodies against glycolipids GM1, GM2, GD1a, GD1b, GalNAc-GD1a, GA1, SGPG, LM1, galactocerebroside and sulphatide. A total of 29/41 IPN-cats had either anti-GM2 or anti-GalNAc-GD1a IgG antibodies, with 24/29 cats having both. Direct comparison of anti-GM2 (sensitivity: 70.7%; specificity: 78.2%) and anti-GalNAc-GD1a (sensitivity: 70.7%; specificity: 70.9%) antibodies narrowly showed anti-GM2 IgG antibodies to be the better marker for identifying IPN-cats when compared to the combined ONM and CTRL groups (P = .049). Anti-GA1 and/or anti-sulphatide IgG antibodies were ubiquitously present across all sample groups, whereas antibodies against GM1, GD1a, GD1b, SGPG, LM1 and galactocerebroside were overall only rarely observed. Anti-GM2 and anti-GalNAc-GD1a IgG antibodies may serve as serum biomarkers for immune-mediated polyneuropathies in cats, as previously observed in dogs and humans.

MRI ischemic and hemorrhagic lesions in arterial and venous territories characterize central nervous system intravascular lymphoma in dogs.

Intravascular lymphoma (IVL) is characterized by the proliferation of large malignant lymphocytes within the lumen of blood vessels. This retrospective, multi-center, case series study aimed to describe the MRI features of confirmed central nervous system IVL in dogs and compare them with histopathological findings. Medical record databases from seven veterinary centers were searched for cases of histologically confirmed IVL. Dogs were included if an MRI was performed. The MRI studies and histopathology samples were reviewed to compare the MRI changes with the histopathological findings. Twelve dogs met the inclusion criteria (12 brains and three spinal cords). Imaging of the brains revealed multifocal T2-weighted/FLAIR hyperintense and T1-weighted iso-hypointense lesions, with variable contrast enhancement; areas of abnormal diffusion both in arterial and venous territories in diffusion-weighted imaging; and meningeal enhancement. On gradient echo images (GRE), the changes comprised tubular susceptibility artifacts, consistent with the "susceptibility vessel sign", and additional variably sized/shaped intraparenchymal susceptibility artifacts. Spinal cord lesions presented as fusiform T2-weighted hyperintensities with scattered susceptibility artifacts on GRE and variable parenchymal and meningeal contrast enhancement. On histopathology, subarachnoid hemorrhages and neuroparenchymal areas of edema and necrosis, with or without hemorrhage, indicating ischemic and hemorrhagic infarctions, were found. These lesions were concurrent with severely dilated meningeal and parenchymal arteries and veins plugged by neoplastic lymphocytes and fibrin. Due to the unique angiocentric distribution of IVL, ischemic and hemorrhagic infarcts of variable chronicity affecting both the arterial and venous territories associated with thrombi formation can be detected on MRI.

Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy.

Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1:c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from 'encephalopathy due to defective mitochondrial and peroxisomal fission 2'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'.

MRI features of canine hemangiosarcoma affecting the central nervous system.

Hemangiosarcoma is the most common metastatic tumor involving the brain in dogs but detailed published descriptions of the magnetic resonance imaging (MRI) features are lacking. The objective of this multi-center, retrospective case series study was to describe MRI characteristics of canine hemangiosarcoma affecting the central nervous system (CNS). Medical records of seven referral institutions were retrospectively reviewed. Dogs were included if they had a histopathologically confirmed diagnosis of hemangiosarcoma affecting the CNS and undergone an MRI of the brain and/or vertebral column. Lesions were independently evaluated by two observers. Twenty dogs met the inclusion criteria and one dog had both intracranial and intramedullary hemangiosarcoma. Consistent MRI features included heterogeneous (17/21) lesions in all sequences with mainly mixed signal intensity (12/21), presence of susceptibility artifact on T2*w (15/16), associated moderate to severe perilesional edema (21/21), and moderate to strong (20/21) heterogeneous (14/21) or ring-like (6/21) contrast enhancement. Intracranial hemangiosarcoma was frequently multiple and intra-axial, affecting consistently the telencephalon and no differences in MRI features were found between primary and metastatic hemangiosarcoma. This is the first MRI description of primary intracranial hemangiosarcoma and primary intracranial epithelioid hemangiosarcoma. Vertebral hemangiosarcomas were segmental poorly marginated polyostotic and highly aggressive lesions invading the thoracic vertebral canal and paraspinal tissues. Epidural hemangiosarcomas were single and well-marginated lesions in the thoracolumbar and/or lumbar region. Intramedullary hemangiosarcomas were cervical, metastatic in origin, and frequently (3/4) accompanied by intracranial lesions. These described MRI features will aid early identification of hemangiosarcoma guiding subsequent diagnostics and therapeutics.

Vertebral vascular canal dysplasia in French and English Bulldogs: Clinical, CT, and MRI characteristics and prevalence.

The authors have observed a vertebral anomaly in French and English Bulldogs and termed this anomaly "vertebral vascular canal dysplasia (VVCD)." No previously published descriptions of this anomaly were found. The aims of this retrospective, multi-institutional, observational study were to (1) describe the clinical, CT, and MRI characteristics of VVCD, and (2) estimate the prevalence and describe the characteristics of VVCD in a group of French and English Bulldogs. For descriptions of the anomaly, medical records and imaging studies of nine clinical cases with VVCD from several countries were reviewed. For estimation of prevalence, imaging studies of French and English Bulldogs from the United Kingdom (UK) and Italy were reviewed. All clinical case dogs had ≥5 thoracic vertebrae with VVCD affecting >50% of vertebral body height (VBH). The prevalence of VVCD involving ≥1 thoracic vertebra in the UK population (CT identified) of English Bulldogs and French Bulldogs was, respectively, 83.3% (30/36) and 68.3% (28/41). English Bulldogs had significantly more thoracic vertebrae with VVCD than French Bulldogs (P = < 0.01). The prevalence of VVCD in ≥1 thoracic vertebra in the Italian population (MRI identified) of English Bulldogs and French Bulldogs was, respectively, 21.7% (5/23) and 6.6% (7/106). Vertebral vascular canal dysplasia was observed in normal as well as in malformed vertebrae (e.g., hemivertebrae). Findings from the current study introduced descriptions of VVCD that can be used as background for future studies.

Can MRI differentiate between ring-enhancing gliomas and intra-axial abscesses?

Gliomas of the brain may appear as expansile ring-enhancing masses in MRI studies, mimicking the appearance of intra-axial abscesses. The aims of this study were to compare the MRI features of ring-enhancing gliomas and intra-axial brain abscesses in dogs and cats and to identify the characteristics that might help differentiate them. For this multicenter, retrospective, and observational study, the inclusion criteria were as follows: (a) a definitive diagnosis of glioma or abscess based on cytological or histopathological examination following CSF collection or surgical biopsy/necropsy, respectively; (b) MRI study performed with a high- or low-field MRI scanner, including a same plane T1W pre- and postcontrast, a T2W and a T2 FLAIR sequence in at least one plane. If available, delayed T1W postcontrast, T2*W GE, DWI/ADC, and SWI sequences were also evaluated. Sixteen patients were diagnosed with ring-enhancing gliomas, and 15 were diagnosed with intra-axial abscesses. A homogenous signal on T1W (P = 0.049) and T2W (P = 0.042) sequences, a T2W (P = 0.005) or T2*W GE (P = 0.046) peripheral hypointense halo, and an even enhancing capsule (P = 0.002) were significantly associated with brain abscesses. A progressive central enhancement on delayed T1W postcontrast sequences was correlated with ring-enhancing gliomas (P = 0.009). The combination of the following features was suggestive of brain abscess: homogeneous T1W or T2W signal intensity, a T2W or T2*W GE peripheral hypointense halo and an evenly enhancing capsule. Central progression of enhancement on delayed T1W postcontrast sequences was suggestive of glioma.

Magnetic resonance imaging findings and clinical management of suspected intracranial hypovolemia after transfrontal craniotomy in a dog.

OBJECTIVE: To report the diagnosis and clinical management of a case of suspected intracranial hypovolemia (IH) in a dog after resection of a large fronto-olfactory chordoid meningioma. STUDY DESIGN: Clinical case report. ANIMAL: One 8-year-old border collie with forebrain neurological signs caused by a fronto-olfactory extra-axial mass diagnosed by using MRI. METHODS: The dog underwent bilateral transfrontal craniotomy for excision of the mass by using ultrasonic aspiration. Immediate postsurgical MRI revealed complete gross resection with no evidence of early-onset complications such as edema, hemorrhage, mass effect, or pneumoencephalus. However, diffuse symmetric meningeal thickening and contrast enhancement were noted. No complications were noted during surgery or while under anesthesia. RESULTS: Neurological deterioration was observed postoperatively. No abnormalities were detected systemically. Thus, early MRI-confirmed findings and neurological deterioration were suspected to be caused by IH. Conservative treatment consisting of bed rest, gabapentin, and intravenous theophylline was then initiated in addition to steroids, antiepileptic drugs, and antibiotics. A gradual neurological improvement was observed, and the dog was discharged completely ambulatory with moderate proprioceptive ataxia 15 days after surgery. CONCLUSION: The clinical and MRI-confirmed findings reported here are consistent with IH, a well-described syndrome in man. This is the first report of a dog with MRI-confirmed findings consistent with IH describing subsequent response to medical management. CLINICAL SIGNIFICANCE: Intracranial hypovolemia after craniotomy should be considered when there is neurological deterioration and characteristic MRI-confirmed findings.

Lumbosacral intervertebral disk extrusions in 13 dogs.

OBJECTIVE: To describe the clinical presentation, magnetic resonance imaging (MRI) findings, and outcome of dogs treated surgically for lumbosacral intervertebral disk extrusion (IVDE). STUDY DESIGN: Retrospective study. ANIMALS: Thirteen dogs. METHODS: Records and MRI studies of dogs with intraoperatively confirmed lumbosacral IVDE were reviewed. MRI features of thoracolumbar IVDE were applied to all cases. Postoperative outcome was subjectively assessed as excellent, good, or poor. RESULTS: All dogs had an acute or subacute onset of lumbosacral pain and nerve root signature. Seven dogs had neurological deficits. MRI revealed lateralized herniated disk material and partial to complete disk degeneration in all cases; the extradural material extended cranial and/or caudally from the disk space in 10 cases. All dogs underwent L7-S1 dorsal laminectomy and removal of extruded disk material. In six dogs, surgery was complicated by inflammatory changes, including one case of epidural steatitis. On reexamination 4-6 weeks postsurgery, outcome was judged as excellent in 11 dogs and poor in the remaining 2 due to contralateral nerve root signature in one case and nonambulatory paraparesis and urinary incontinence in the case with steatitis. CONCLUSION: Lumbosacral IVDE in dogs was characterized by acute/subacute onset of lumbosacral pain and nerve root signature and lateralized and often dispersed extradural material over a degenerated L7-S1 intervertebral disk on MRI. Early decompressive dorsal laminectomy generally resulted in excellent clinical outcome. CLINICAL SIGNIFICANCE: Observation of these clinical and imaging features in dogs should prompt clinical suspicion of lumbosacral IVDE.

Clinical signs, MRI findings and outcome in dogs with peripheral vestibular disease: a retrospective study.

BACKGROUND: Vestibular dysfunction is relatively common in dogs, with a prevalence of 0.08% reported in primary veterinary care in the UK. There are several studies investigating how to differentiate between peripheral and central vestibular disease but only limited information regarding the possible underlying causes for peripheral vestibular dysfunction in dogs. This study therefore aimed to describe the clinical signs, magnetic resonance imaging findings (MRI), underlying causes and outcome in a large population of dogs diagnosed with peripheral vestibular disease. RESULTS: One hundred eighty-eight patients were included in the study with a median age of 6.9 years (range 3 months to 14.6 years). Neurological abnormalities included head tilt (n = 185), ataxia (n = 123), facial paralysis (n = 103), nystagmus (n = 97), positional strabismus (n = 93) and Horner syndrome (n = 7). The most prevalent diagnosis was idiopathic vestibular disease (n = 128), followed by otitis media and/or interna (n = 49), hypothyroidism (n = 7), suspected congenital vestibular disease (n = 2), neoplasia (n = 1) and cholesteatoma (n = 1). Long-term follow-up revealed persistence of head tilt (n = 50), facial paresis (n = 41) and ataxia (n = 6) in some cases. Recurrence of clinical signs was observed in 26 dogs. Increasing age was associated with a mild increased chance of diagnosis of idiopathic vestibular syndrome rather than otitis media and/or interna (P = 0.022, OR = 0.866; CI 0.765-0.980). History of previous vestibular episodes (P = 0.017, OR = 3.533; CI 1.251-9.981) was associated with an increased likelihood of resolution of the clinical signs whilst contrast enhancement of cranial nerves VII and/or VIII on MRI (P = 0.018, OR = 0.432; CI 0.251-0.868) was associated with a decreased chance of resolution of the clinical signs. CONCLUSIONS: Idiopathic vestibular disease is the most common cause of peripheral vestibular dysfunction in dogs and it is associated with advanced age. Incomplete recovery from peripheral vestibular disease is common, especially in dogs presenting with cranial nerve enhancement on MRI but less so if there is previous history of vestibular episodes.

Clinical features and MRI characteristics of presumptive constrictive myelopathy in 27 pugs.

Constrictive myelopathy has been described in pugs with paraparesis and is characterized by fibrous connective and granulation tissue within the dura mater causing spinal cord compression and focal gliosis. An association between constrictive myelopathy and caudal articular process (CAP) dysplasia is suspected; however, some studies have reported CAP dysplasia as an incidental finding. The imaging appearance of constrictive myelopathy is currently limited to a small number of cases. The aim of this multicenter, retrospective, descriptive study was to detail the magnetic resonance imaging (MRI) characteristics and to correlate these with clinical signs of presumptive constrictive myelopathy in pugs. Medical databases from five veterinary referral hospitals were reviewed to identify pugs with pelvic limb ataxia and paresis, that had a complete record of signalment, neurological examination, and MRI of the thoracolumbar spinal cord. The exclusion criteria were pugs with other conditions, such as unequivocal subarachnoid diverticula, hemivertebrae causing vertebral canal stenosis, intervertebral disc extrusions/protrusions, and multifocal/diffuse lesions. Twenty-seven pugs met the inclusion criteria. All cases were ambulatory with paraparesis and ataxia. Nearly 60% were incontinent. Magnetic resonance imaging revealed a focal myelopathy in all cases showing one or more of the following lesions: CAP dysplasia (25/27), focal subarachnoid space irregular margination (26/27) with circumferential or dorsal contrast enhancement (10/12), and a symmetric V-shaped ventral extradural lesion (23/27). This study describes specific MRI features of pugs with presumptive constrictive myelopathy, which authors hypothesize to be a consequence of chronic micro-motion. Our results may help in diagnosing and subsequently treating this condition, which may warrant vertebral stabilization.

Imaging characteristics and treatment of a penetrating brain injury caused by an oropharyngeal foreign body in a dog.

A 4-year-old Border collie was presented with one episode of collapse, altered mentation, and a suspected pharyngeal stick injury. Magnetic resonance imaging (MRI) and computed tomography showed a linear foreign body penetrating the right oropharynx, through the foramen ovale and the brain parenchyma. The foreign body was surgically removed and medical treatment initiated. Complete resolution of clinical signs was noted at recheck 8 weeks later. Repeat MRI showed chronic secondary changes in the brain parenchyma. To the authors' knowledge, this is the first report of the advanced imaging findings and successful treatment of a penetrating oropharyngeal intracranial foreign body in a dog.

IMAGING DIAGNOSIS-MAGNETIC RESONANCE IMAGING AND HISTOPATHOLOGICAL FEATURES OF A SKULL BASE CHORDOMA IN A CAT.

An 8-year-old domestic short-haired cat was presented with anorexia, lethargy, ataxia and one episode of consciousness loss. A midline vertically orientated, biconcave, extra-axial mass originating from the basioccipital bone was detected on magnetic resonance images of the head. The mass was T1W iso- to hypointense when compared with normal grey matter, T2W hyperintense with small areas of isointensity and heterogeneously enhanced with contrast. Multiple signal voids were observed on T2* images. Histopathological evaluation confirmed a chordoma. To the authors' knowledge this is the first report of the imaging characteristics of a chordoma affecting the skull base in a cat.

Vertebral venous system abnormalities identified with magnetic resonance imaging in sighthounds.

In humans, abnormalities of the vertebral venous system are considered rare but significant causes of radiculopathy and myelopathy. Published information on abnormalities of the canine vertebral venous system is currently lacking. Aims of this retrospective descriptive study were to characterize magnetic resonance imaging (MRI) abnormalities of the vertebral venous system in a population of sighthounds, report prevalence of vertebral venous system abnormalities within that population and explore possible clinical significance. Our hospital database was searched over the period of 2002-2013 for sighthounds with MRI studies of the vertebral column. Medical records and MRI studies for included dogs were retrieved and findings were recorded by a single observer. A total of 92 sighthounds were sampled. Eleven cases (prevalence 12%) showed abnormal enlargement of the internal vertebral venous plexus (10/11 unilaterally, 1/11 bilaterally), external vertebral venous plexus (7/11 cases unilaterally), and/or intervertebral veins (8/11 unilaterally, 2/11 bilaterally, and 1/11 unilaterally and bilaterally at different sites). The majority of the abnormalities were right sided and the most common location for abnormalities was C6/7. Of the 11 cases, nine did not have a definitive diagnosis. Seven of those nine cases had an abnormality in a neuroanatomical localization that could wholly or partly explain the clinical signs. Findings indicated that, while the prevalence of vertebral venous system abnormalities was low in this sample of sighthounds, the majority of dogs with these abnormalities had clinical signs that matched the location of the abnormalities. Further prospective research is needed to investigate potential underlying aetiologies for vertebral venous system abnormalities in dogs and clarify their clinical significance.

The neuronal ceroid lipofuscinoses: Opportunities from model systems.

The neuronal ceroid lipofuscinoses are a group of severe and progressive neurodegenerative disorders, generally with childhood onset. Despite the fact that these diseases remain fatal, significant breakthroughs have been made in our understanding of the genetics that underpin these conditions. This understanding has allowed the development of a broad range of models to study disease processes, and to develop new therapeutic approaches. Such models have contributed significantly to our knowledge of these conditions. In this review we will focus on the advantages of each individual model, describe some of the contributions the models have made to our understanding of the broader disease biology and highlight new techniques and approaches relevant to the study and potential treatment of the neuronal ceroid lipofuscinoses. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease.

A proposed radiographic classification scheme for congenital thoracic vertebral malformations in brachycephalic "screw-tailed" dog breeds.

Congenital vertebral malformations are common in brachycephalic "screw-tailed" dog breeds such as French bulldogs, English bulldogs, Boston terriers, and pugs. The aim of this retrospective study was to determine whether a radiographic classification scheme developed for use in humans would be feasible for use in these dog breeds. Inclusion criteria were hospital admission between September 2009 and April 2013, neurologic examination findings available, diagnostic quality lateral and ventro-dorsal digital radiographs of the thoracic vertebral column, and at least one congenital vertebral malformation. Radiographs were retrieved and interpreted by two observers who were unaware of neurologic status. Vertebral malformations were classified based on a classification scheme modified from a previous human study and a consensus of both observers. Twenty-eight dogs met inclusion criteria (12 with neurologic deficits, 16 with no neurologic deficits). Congenital vertebral malformations affected 85/362 (23.5%) of thoracic vertebrae. Vertebral body formation defects were the most common (butterfly vertebrae 6.6%, ventral wedge-shaped vertebrae 5.5%, dorsal hemivertebrae 0.8%, and dorso-lateral hemivertebrae 0.5%). No lateral hemivertebrae or lateral wedge-shaped vertebrae were identified. The T7 vertebra was the most commonly affected (11/28 dogs), followed by T8 (8/28 dogs) and T12 (8/28 dogs). The number and type of vertebral malformations differed between groups (P = 0.01). Based on MRI, dorsal, and dorso-lateral hemivertebrae were the cause of spinal cord compression in 5/12 (41.6%) of dogs with neurologic deficits. Findings indicated that a modified human radiographic classification system of vertebral malformations is feasible for use in future studies of brachycephalic "screw-tailed" dogs.

Vertebral and spinal malformations in small brachycephalic dog breeds: Current knowledge and remaining questions.

Small brachycephalic dog breeds, such as the French bulldog, English bulldog and pug have become increasingly popular. These breeds are predisposed to a variety of vertebral and spinal malformations, including hemivertebra, caudal articular process dysplasia, transitional vertebra, cranial thoracic vertebral canal stenosis, spinal arachnoid diverticulum and meningeal fibrosis. Recent studies have provided new insights into the prevalence, anatomical characteristics, pathophysiology and treatment of these conditions. Thoracic hemivertebra, caudal articular process dysplasia, transitional vertebra, and cranial thoracic vertebral canal stenosis occur commonly in neurologically normal dogs. Although the clinical relevance of these vertebral anomalies has therefore been questioned, severe kyphosis and hemivertebra in pugs have been associated with an increased likelihood of neurological signs. Meningeal fibrosis is characterised by the formation of dense intradural fibrotic adhesions, constricting the spinal cord. This condition has been heavily associated with the pug breed. It is in pugs further common to observe multiple concurrent spinal disorder in association with chronic progressive pelvic limb gait abnormalities. This clinical presentation has been referred to as 'pug dog thoracolumbar myelopathy' and potential genetic risk factors have recently been identified. Despite our increased knowledge, many questions remain currently unanswered. This review discusses our current understanding and controversies surrounding vertebral and spinal malformations in small brachycephalic dog breeds.