Abstract #3

Presenter

I obtained my medical degree from Queen’s University in 2006. Following completion of a 5-year residency in Anatomic Pathology in 2011, I completed a 2-year residency in Neuropathology at the University of Calgary and have board certification in Anatomic Pathology and Neuropathology from the Royal College of Physicians and Surgeons of Canada and the American Board of Pathology. In 2014, I completed a 1-year fellowship in Forensic Pathology at the University of New Mexico (New Mexico Office of the Medical Investigator) and have board certification in Forensic Pathology from the American Board of Pathology.
Since 2018 I have worked as a Forensic Pathologist at the Eastern Ontario Regional Forensic Pathology Unit in Ottawa. I am a registered Forensic Pathologist with the Ontario Forensic Pathology Services. I also work as a Neuropathologist at The Ottawa Hospital and CHEO (Children’s Hospital of Eastern Ontario). I hold the appointment of Assistant Professor in the Department of Pathology and Laboratory Medicine at the University of Ottawa. I also perform medicolegal consultations as a consultant pathologist with the National Autopsy Assay Group. I am the Chair of the Continuing Professional Development committee with the Canadian Association of Neuropathologists.

Authors

Leslie E. Hamilton¹, Priya T. Bhola², Radha Mishra³, Jennifer E. Posey³, Gail E. Graham², Care4Rare Canada Consortium⁴, Kym M. Boycott^2,4, Damien D’Amours³, Kristin D. Kernohan^4,9

¹Department of Pathology and Laboratory Medicine, Children’s Hospital of Eastern Ontario and University of Ottawa, Ottawa, Canada

²Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Canada

³Department of Cellular and Molecular Medicine, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada

⁴Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada

⁹Newborn Screening Ontario (NSO), Ottawa, Canada

CanMEDS:
Medical Expert (the integrating role), Collaborator, Health Advocate, Scholar

A Novel Association: Distal Arthrogryposis, Kif21a And Fetal Neuroaxonal Dystrophy

Although fetal neuroaxonal dystrophy is an established etiology for fetal akinesia, the underlying genetics were not known. KIF21A is a kinesin motor protein that plays an important role in microtubule dynamics, including regulation of axonal growth. Recently, Falk et al. (2023) linked bi-allelic loss-of-function variants in KIF21A to severe fetal akinesia with arthrogryposis.

 We present the case of an young infant diagnosed in utero with distal arthrogryposis, who died at 3 weeks of age, that represents an independent discovery of this autosomal recessive KIF21A-related condition. Her course was complicated by respiratory issues, hypotonia, seizures and neurological deterioration. Brain MRI was significant for polymicrogyria, diffuse brain volume loss and mild thinning of optic nerves. Autopsy findings confirmed the bilateral extensive polymicrogyria and reduced brain volume, with probable thinning of the corpus callosum and descending corticospinal tracts. Histologically, axonal spheroids were seen throughout multiple regions of the central and peripheral nervous system. Other findings included cerebellar heterotopia, simplification of the inferior olives and a congenital neurogenic myopathy. Clinical exome sequencing revealed biallelic compound heterozygous variants in KIF21A. Functional yeast studies supported the causality of the described variants.

 Our case represents an independent discovery and second report of the autosomal recessive condition related to KIF21A and reveals fetal neuroaxonal dystrophy as the underlying neuropathology, which has not previously described in the literature. Our findings expand the spectrum of KIF21A-related disorders, and highlight the importance of a multidisciplinary approach, exome sequencing, and multi-site collaboration in the investigation of rare genetic conditions.