Classification of myasthenia gravis and congenital myasthenic syndromes in dogs and cats.

Myasthenia, a syndrome of impaired neuromuscular transmission, occurs as either an acquired or congenital condition. Myasthenia gravis (MG) is an acquired autoimmune disorder with autoantibodies against the neuromuscular junction (NMJ) of skeletal muscle whereas congenital myasthenic syndromes (CMSs) are a clinically heterogeneous group of genetic disorders affecting the NMJ with a young age of onset. Both conditions are diseases for which recognition is important with regard to treatment and outcome. We review the published literature on MG and CMSs in dogs and cats, and by comparison with published classification used in humans, propose a classification system for MG and CMSs in dogs and cats. Myasthenia gravis is first classified based on focal, generalized, or acute fulminating presentation. It then is subclassified according to the autoimmune disease mechanism or seronegativity. Autoimmune disease mechanism relates to the presence or absence of a thymoma, or administration of thiourylene medication in cats. Congenital myasthenic syndromes are classified according to the affected NMJ component, the mechanism of the defect of neuromuscular transmission, the affected protein, and ultimately the mutated gene responsible. In proposing this categorization of MG and CMSs, we hope to aid recognition of the disease groups for both conditions, as well as guide treatment, refine prognosis, and provide a framework for additional studies of these conditions.

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BACKGROUND: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog. HYPOTHESIS/OBJECTIVE: Clinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies. ANIMALS: Four GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs. METHODS: Complete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database. RESULTS: Clinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: We confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness.

Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review.

Myasthenia gravis (MG) is a disorder of neuromuscular transmission in which muscle weakness results from an autoantibody mediated depletion of acetylcholine receptors (AChRs) at the neuromuscular junction. Myasthenia gravis occurs spontaneously in dogs and cats, and as in human MG, an autoimmune response against nicotinic AChRs has been demonstrated and autoantibodies against AChRs implicated in the pathogenesis. While both species are affected with MG, there are distinct differences in clinical presentations and frequency of spontaneous remission. Congenital myasthenic syndromes (CMSs) are hereditary disorders of neuromuscular transmission resulting in structural or functional defects of the neuromuscular junction. The clinical presentation and pathogenesis of a CMS in Jack Russell terriers was first described in the 1970's and 1980s and has since been reported in a few other breeds. Mutations have been reported in CHRNE, COLQ and CHAT in canine CMS. A form of COLQ deficient CMS has recently been reported in cats.

A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome.

Congenital myasthenic syndromes (CMSs) are heterogeneous neuromuscular disorders characterized by skeletal muscle weakness caused by disruption of signal transmission across the neuromuscular junction (NMJ). CMSs are rarely encountered in veterinary medicine, and causative mutations have only been identified in Old Danish Pointing Dogs and Brahman cattle to date. Herein, we characterize a novel CMS in 2 Labrador Retriever littermates with an early onset of marked generalized muscle weakness. Because the sire and dam share 2 recent common ancestors, CMS is likely the result of recessive alleles inherited identical by descent (IBD). Genome-wide SNP profiles generated from the Illumina HD array for 9 nuclear family members were used to determine genomic inheritance patterns in chromosomal regions encompassing 18 functional candidate genes. SNP haplotypes spanning 3 genes were consistent with autosomal recessive transmission, and microsatellite data showed that only the segment encompassing COLQ was inherited IBD. COLQ encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of signal transduction in the NMJ. Sequences from COLQ revealed a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type. A recent study in which 2 human CMS patients were found to be homozygous for an identical COLQ mutation (c.1010T>C; I337T) provides further evidence that this mutation is pathogenic. This report describes the first COLQ mutation in canine CMS and demonstrates the utility of SNP profiles from nuclear family members for the identification of private mutations.

The CHRNE 470del20 mutation causing congenital myasthenic syndrome in South African Brahman cattle: prevalence, origin, and association with performance traits.

Genotyping of the South African, registered, Brahman cattle population for the 470del20 mutation in the CHRNE gene causing congenital myasthenic syndrome (CMS) was carried out in 1,453 animals. Overall prevalence of carriers was 0.97% (0.50 to 1.68%, 95% confidence interval). Carrier prevalence among breeding bulls in 2004 was 1.22% (0.65 to 2.15%, 95% confidence interval), and had not changed significantly since 2000. Using segregation analysis, CMS genotype probabilities were calculated for all 612,219 animals in the pedigree, leading to the identification of 2 founder animals as the most likely original carriers. Pedigree analysis revealed no ancestors common to all known carriers, but rather that the mutation had been introduced at least twice into the South African Brahman population, probably via animals imported from the United States. The effects of CMS genotype probability on adjusted birth, 200-d, 400-d, and 600-d BW, as well as on EBV for birth, 200-d, 400-d, and 600-d BW, and milk, were estimated, accounting for effects of sire. Heterozygosity for the CHRNE 470del20 mutation was associated with a 13.3-kg increase in adjusted 600-d BW (P = 0.03). Positive effects of CMS carrier status on all BW EBV were found, but no effect was found on milk EBV. We conclude that CMS carriers have a BW advantage at 600 d and possibly also at birth, 200 d, and 400 d. This may confer a selective advantage and tend to increase the frequency of the mutation.

Congenital myasthenia gravis in Smooth-Haired Miniature Dachshund dogs.

Three 8-week-old Miniature Smooth Haired Dachshund littermates were diagnosed with myasthenia gravis based on clinical signs, results of electrophysiological testing, and response to the short-acting anticholinesterase drug, edrophonium chloride. Congenital myasthenia gravis was confirmed by the demonstration of decreased acetylcholine-receptor density in external intercostal muscle in the absence of demonstrable serum antiacetylcholine receptor antibody or antibodies complexed to acetylcholine receptors in muscle biopsy samples. Unlike most previously reported cases of congenital myasthenia gravis that are relentlessly progressive, clinical signs resolved spontaneously by 6 months of age.

Congenital myasthenic syndrome of Brahman cattle in South Africa.

A congenital myasthenic syndrome in Brahman cattle is caused by a homozygous 20 base pair deletion (470del20) in the gene coding for the epsilon subunit of the acetylcholine receptor at the neuromuscular junction. It causes a progressive muscle weakness starting either at birth or within the first month. A PCR-based DNA test, using blood or semen stored on FTA paper, was developed and validated; the test makes it possible to differentiate rapidly and accurately between homozygous wild-type, heterozygous and homozygous affected animals. Preliminary testing of Brahman cattle in South Africa has revealed several carrier animals, some of them influential animals in the breeding population.