<i>CNTNAP1</i> mutations in an adult with Charcot Marie Tooth disease

Freed, Amanda S.; Weiss, Michael D.; Malouf, Emily A.; Hisama, Fuki M.

doi:10.1002/mus.26658

Cited by 4 publications

(2 citation statements)

References 10 publications

(26 reference statements)

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“…The affected contactin-associated protein 1 (CNTNAP1) gene has been previously implicated in human autosomal recessive neurological diseases with a broad spectrum of clinical phenotypes and neonatal and childhood onsets: congenital hypomyelinating neuropathy type 3 (OMIM 618186), lethal congenital contracture syndrome 7 (OMIM 616286), and childhood-onset Charcot-Marie-Tooth disease [32]. CNTNAP1 is essential in the formation of paranodal axoglial junctions in myelinated axons and is also involved in regulating neural progenitor cells and the development of the cerebral cortex [33].…”

Section: Discussionmentioning

confidence: 99%

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy

Letko

Minor

Friedenberg

et al. 2020

Genes

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Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative disease seen in two closely related giant dog breeds, the Leonberger and Saint Bernard. Neuropathology of an affected dog from each breed showed variable nerve fiber loss and scattered inappropriately thin myelinated fibers. Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. CNTNAP1 encodes a contactin-associated protein important for organization of myelinated axons. The herein described likely pathogenic CNTNAP1 variant occurs in unrelated breeds at variable frequencies. Individual homozygous mutant LPPN-affected Labrador retrievers that were on average four years younger than dogs affected by geriatric onset laryngeal paralysis polyneuropathy could be explained by this variant. Pathologic changes in a Labrador retriever nerve biopsy from a homozygous mutant dog were similar to those of the Leonberger and Saint Bernard. The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear. Pathogenic variants in CNTNAP1 have previously been reported in human patients with lethal congenital contracture syndrome and hypomyelinating neuropathy, including vocal cord palsy and severe respiratory distress. This is the first report of contactin-associated LPPN in dogs characterized by a deleterious variant that most likely predates modern breed establishment.

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Section: Discussionmentioning

confidence: 99%

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy

Letko

Minor

Friedenberg

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…The broad phenotypic spectrum that resulted from the CNTNAP1 mutations included prenatal onset (fatal akinesia and polyhydramnios) and lethal neonatal symptoms (severe respiratory distress leading to tracheotomy,ventilator dependency, and hypotonia). Most of the patients who survived to infancy (one-fourth died within 1 month) were found to have seizures and brain atrophy (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). However, the common clinical phenotypes, such as prenatal onset…”

Section: Introductionmentioning

confidence: 99%