Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis

Alexander Conant; Julian Curiel; Amy Pizzino; Parisa Sabetrasekh; Jennifer Murphy; Miriam Bloom; Sarah H Evans; Guy Helman; Ryan J Taft; Cas Simons; Matthew T Whitehead; Steven A Moore; Adeline Vanderver

doi:10.1177/0883073818776157

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Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis

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Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis

Alexander Conant, Julian Curiel, Amy Pizzino, Parisa Sabetrasekh, Jennifer Murphy, Miriam Bloom, Sarah H Evans, Guy Helman, Ryan J Taft, Cas Simons, …

Journal of child neurology, Vol.33(10), pp.642-650

09/2018

DOI: 10.1177/0883073818776157

PMCID: PMC6800098

PMID: 29882456

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https://www.ncbi.nlm.nih.gov/pmc/articles/6800098View

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Abstract

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.

Magnetic Resonance Imaging

Demyelinating Diseases - diagnostic imaging

Neuroglia - ultrastructure

Demyelinating Diseases - genetics

Neuroglia - pathology

Humans

Arthrogryposis - complications

Demyelinating Diseases - complications

Male

Arthrogryposis - genetics

Mutation - genetics

Arthrogryposis - diagnostic imaging

Cell Adhesion Molecules, Neuronal - genetics

Ranvier's Nodes - ultrastructure

Axons - pathology

Axons - ultrastructure

Female

Ranvier's Nodes - pathology

Child

Details

Title: Subtitle: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis
Creators: Alexander Conant - 1 Department of Neurology, Children's National Health System, Washington, DC, USA
Julian Curiel - 2 Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Amy Pizzino - 1 Department of Neurology, Children's National Health System, Washington, DC, USA
Parisa Sabetrasekh - 1 Department of Neurology, Children's National Health System, Washington, DC, USA
Jennifer Murphy - 3 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Miriam Bloom - 4 Department of Pediatric Hospitalist Medicine, Children's National Health System, Washington, DC, USA
Sarah H Evans - 5 Department of Physical Medicine and Rehabilitation, Children's National Health System, Washington, DC, USA
Guy Helman - 7 Murdoch Children's Research Institute, Parkville, Melbourne, Australia
Ryan J Taft - 9 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
Cas Simons - 9 Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
Matthew T Whitehead - 11 George Washington University School of Medicine, Washington, DC, USA
Steven A Moore - 12 Department of Pathology, University of Iowa Carver College of Medicine and Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, Iowa City, IA, USA
Adeline Vanderver - 11 George Washington University School of Medicine, Washington, DC, USA
Resource Type: Journal article
Publication Details: Journal of child neurology, Vol.33(10), pp.642-650
DOI: 10.1177/0883073818776157
PMID: 29882456
PMCID: PMC6800098
NLM abbreviation: J Child Neurol
ISSN: 0883-0738
eISSN: 1708-8283
Publisher: United States
Grant note: U54 NS053672 / NINDS NIH HHS
Language: English
Date published: 09/2018
Academic Unit: Pathology
Record Identifier: 9984046811402771

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