Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients. HYPOTHESIS/OBJECTIVES: Define the clinical manifestations and genetic cause of a suspected form of EDS in a cat. ANIMALS: A 14-week-old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. METHODS: Blood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases. RESULTS: Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501-2A>C). CONCLUSIONS AND CLINICAL IMPORTANCE: Our report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.

The Surgical Histopathology of the Filum Terminale: Findings from a Large Series of Patients with Tethered Cord Syndrome.

This study investigated the prevalence of embryonic and connective tissue elements in the filum terminale (FT) of patients with tethered cord syndrome (TCS), examining both typical and pathological histology. The FT specimens from 288 patients who underwent spinal cord detethering from 2013 to 2021 were analyzed. The histopathological examination involved routine hematoxylin and eosin staining and specific immunohistochemistry when needed. The patient details were extracted from electronic medical records. The study found that 97.6% of the FT specimens had peripheral nerves, and 70.8% had regular ependymal cell linings. Other findings included ependymal cysts and canals, ganglion cells, neuropil, and prominent vascular features. Notably, 41% showed fatty infiltration, and 7.6% had dystrophic calcification. Inflammatory infiltrates, an underreported finding, were observed in 3.8% of the specimens. The research highlights peripheral nerves and ganglion cells as natural components of the FT, with ependymal cell overgrowth and other tissues potentially linked to TCS. Enlarged vessels may suggest venous congestion due to altered FT mechanics. The presence of lymphocytic infiltrations and calcifications provides new insights into structural changes and mechanical stress in the FT, contributing to our understanding of TCS pathology.

Redosing Adeno-Associated Virus Gene Therapy to the Central Nervous System.

Adeno-associated virus (AAV)-mediated gene therapies have provided promising treatments for numerous neurological disorders. Redosing of AAV to the central nervous system (CNS) is an attractive research area due to both the somewhat immunologically privileged status of the CNS as well as the possibility of reduced glial transgene expression over time following a single injection. Continued study of the immune responses to both intraparenchymal and intra-CSF delivery of AAV mediated gene therapies, as well as the continued study of immunosuppressive regimens, could allow for eventual redosing in patients.

Diseased Filum Terminale as a Cause of Tethered Cord Syndrome in Ehlers-Danlos Syndrome: Histopathology, Biomechanics, Clinical Presentation, and Outcome of Filum Excision.

BACKGROUND: Patients with hypermobile Ehlers-Danlos syndrome (hEDS), a heritable connective tissue disorder, present frequently with symptoms of tethered cord syndrome (TCS) but without a low-lying conus. Currently, surgical treatment of such cases is controversial. Because connective tissue disorder affects fibrous structures, we hypothesized that a diseased filum terminale (FT) might cause TCS in hEDS, justifying surgical transection for treatment. METHODS: We investigated FT pathology, FT biomechanics, clinical presentation, and outcome following FT excision in 78 radiologically occult hEDS-TCS cases and for comparison in 38 typical TCS cases with low-lying conus and/or fatty FT infiltration but without hEDS. RESULTS: In hEDS-TCS, electron microscopy revealed inherited collagen fibril abnormalities and acquired fibril damage. Biomechanical tension tests revealed elastic properties of the FT in both study groups, but they were impaired in the hEDS TCS. Follow-up examinations at 3 and 12 months after FT excision showed statistically significant improvement of urinary, bowel, and neurologic symptoms in both study groups; intergroup comparison revealed no differences in outcome except more pronounced neurologic improvement in the hEDS-TCS group. CONCLUSIONS: Both morphologic findings and biomechanical tests indicate limited elastic properties of the FT in hEDS, which is no more able to dampen but still transmitting spine movement-related stretch forces. That mechanism exposes the conus medullaris to unphysiologic stretch forces, causing TCS, especially when considering the hypermobile spine in hEDS. This notion is supported by the observed clinical improvement following FT resection in hEDS-TCS cases without a low-lying conus.