Cleo Schwarz

A 7-month-old intact male Cavalier King Charles Spaniel was presented for persistent glucosuria despite normoglycemia, failure to thrive, chronic diarrhea, and cerebellar ataxia. Fanconi syndrome was diagnosed, but the neurologic abnormalities were not fully explained. As a consequence of the early onset Fanconi syndrome, a hereditary process was suspected. Whole genome sequencing identified a private hemizygous SINE-like insertion into the ATP7A gene, at the end of intron 13, near the start of exon 14. In humans, variants in ATP7A are associated with Menkes disease, a disorder of copper metabolism associated with a spectrum of clinical signs including progressive neurodegeneration and connective tissue abnormalities. Clinically affected dogs with variants in ATP7A have not been reported previously. Although this case appears to represent a mild phenotypic presentation of Menkes-like disease, it raises the possibility that copper disorders aside from copper-associated hepatitis might exist in dogs. Further genetic screening and phenotypic characterization of rare genetic variants associated with copper metabolism would be beneficial to expand our knowledge of copper disorders in dogs and allow potential early intervention and modeling for metabolic diseases in humans.

We identified a dwarfism syndrome in six Rottweiler dogs characterized by reduced height and body weight; limb deformities, shortening of the tail and abnormally thick skin in puppies; developmental delays, pain and non‐goitrous hypothyroidism. Histological examination of the thyroid gland revealed severe chronic diffuse bilateral atrophy with loss of thyroid follicles and lack of colloid. Pedigree analysis suggested an autosomal recessive transmission. Whole genome sequencing of an affected dog and filtering for private variants against 1539 control genomes identified a homozygous nonsense variant in the TG gene encoding thyroglobulin, NM_001048104.1:c.3694C>T. The variant was predicted to introduce a premature stop codon truncating 55% of the wild‐type open reading frame, NP_001041569.1:p.(Arg1232*). The TG glycoprotein is the precursor to the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4). TG deficiency leads to comparable phenotypes in human patients, cattle and goats. Genotyping six affected and 87 control Rottweiler dogs confirmed the expected genotype–phenotype association, with all affected dogs being homozygous for the mutant allele and control dogs being either heterozygous or homozygous wild‐type. All four obligate carriers were heterozygous and among the 74 unrelated control dogs without known relationships to cases we found a 5.4% carrier frequency. Correct co‐segregation in the available families was also observed. Taken together, this study provides an initial clinical and pathological characterization of an inherited dwarfism syndrome in Rottweilers and identifies a TG variant as a causal genetic defect. The results enable genetic testing to avoid unintentional risk matings.

Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar ataxia, hypermetria, and absent menace response. The MRI revealed generalized brain atrophy, reduced cortical demarcation, hypoplastic corpus callosum, and cerebellar folia thinning, highly suggestive of a neurodegenerative disorder. We sequenced the genomes of the two affected dogs and their unaffected parents. Filtering for protein-changing variants that had homozygous alternate genotypes in the affected dogs, heterozygous genotypes in the parents, and homozygous reference genotypes in 1576 control genomes yielded a single missense variant in the RAB24 gene, XM_038534663.1:c.239G>T or XP_038390591.1:p.(Gly80Val). Genotypes at this variant showed the expected co-segregation with the ataxia phenotype in the investigated family. The predicted amino acid affects the conserved RabF4 motif. Glycine-80 resides at the protein surface and the introduction of a hydrophobic isopropyl side chain of the mutant valine might impede solvent accessibility. Another missense variant in RAB24, p.Glu38Pro, was previously reported to cause a clinically similar form of cerebellar ataxia in Gordon Setters and Old English Sheepdogs. Taken together, the available data suggest that RAB24:p.Gly80Val represents the causal variant in the studied dogs. To the best of our knowledge, this is only the second report of a potentially pathogenic RAB24 variant in any species and further supports that RAB24 should be considered a candidate gene in human ataxia patients with unclear molecular etiology.

Background: Congenital mirror movement disorders (CMMs) are clinically and genetically heterogeneous in human patients. CMMs have not been documented to occur spontaneously in animals.Objective: The objective of this work was to document the first case of CMMs spontaneously occurring in Weimaraner dogs and to identify the underlying genetic cause.Methods: Clinical and pathological investigations were performed. Genetic investigations used linkage and autozygosity mapping followed by whole‐genome sequencing of 3 affected dogs and 1489 control dogs to identify disease‐associated variants.Results: Three of 11 puppies in a litter of Weimaraner dogs exhibited an abnormal gait characterized by synchronized saltatorial locomotion. Their phenotype was tentatively termed congenital mirror movement disorder 1 (CMM1). The underlying genetic cause was identified as a 2‐bp duplication in EFNB3 encoding ephrin‐B3, a transmembrane protein important for axon guidance and spinal midline barrier formation during neurodevelopment. The identified variant, XM_038536724.1:c.643_644dup, is predicted to lead to a frameshift and introduction of a premature stop codon XP_038392652.1:p.(Ala216Valfs*79). CMM1 is inherited as an autosomal recessive trait in these dogs.Conclusions: Similar to humans, CMMs may occur in dogs as an inherited disease as a result of a spontaneously arisen genetic variant. The CMM1 phenotype in dogs resembles the phenotype of experimentally induced Efnb3^−/− knockout mice. So far, no human patients with EFNB3‐related CMMs have been reported. Our study provides the first naturally occurring large‐animal model for CMMs. EFNB3 should be considered a candidate gene in human CMM patients with unclear disease etiology. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Muscular dystrophies represent a group of disorders characterized by progressive muscle degeneration and weakness. An important subgroup are the dystrophin‐related muscular dystrophies caused by variants in the DMD gene. They can be divided into the more severe Duchenne muscular dystrophy and the milder Becker muscular dystrophy. Here, we characterize the clinical, histopathological and molecular genetic aspects of two male Entlebucher Mountain Dogs with clinical signs of muscular dystrophy. The two dogs presented with marked dysphagia starting at the age of several weeks and in the later course recognizable exercise intolerance with highly increased serum creatine kinase levels. Histopathological signs of a dystrophic myopathy represented by degeneration of muscle fibers and signs of regeneration were present. Whole genome sequencing of one affected dog identified an intragenic 8.6 kb duplication in the X‐chromosomal DMD gene, c.7528‐4048_7645 + 4450dup. No other protein‐changing variants in candidate genes for muscular dystrophy were identified. The duplication includes exon 52 of DMD and is predicted to lead to a frameshift and truncation of 30% of the wild‐type open reading frame. Genotyping of the whole family confirmed the presence of the mutant allele in both affected dogs and the unaffected dam. The correct co‐segregation of the mutant allele in the affected family as well as knowledge from humans and other species suggest the identified DMD variant as the most likely candidate variant for the muscular dystrophy phenotype in the two investigated dogs.

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.