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

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.

CNTNAP1 Mutations and Their Clinical Presentations: New Case Report and Systematic Review

“…To this day, most of the 31 identified patients (11 LCCS7 and 20 CHN3), issued from 20 families, were males and answered to diverse ethnicities (Palestinian, Irish, English, American, Qatari, Lebanese, and French), which brings the number of affected families to twenty [1,2,[6][7][8][9][10][11]. Only seven girls were reported to be affected, three of which were diagnosed with LCCS7 and four with CHN3 [8][9][10]. First degree consanguinity was noted in most families [6][7][8]10].…”

“…large myelinated fibers [1,10,11] and thin myelin sheaths [1,6,[9][10][11], all consistent with hypomyelinating neuropathies [1,7,10]. Muscle biopsy can reveal early muscle innervation disorder [11] with generalized small muscle fibers [8,9] and neurogenic muscular atrophy [8,9].…”

“…Nerve biopsy is now less often performed, as genetic testing in patients with hereditary neuropathies is becoming increasingly used [7,12]. However, sural nerve biopsy is nonspecific and consists mainly of paranodal abnormalities [7,9], along with significant homogeneous axonal loss [1, 6, 9, 11], significant decrease of…”

“…large myelinated fibers [1,10,11] and thin myelin sheaths [1,6,[9][10][11], all consistent with hypomyelinating neuropathies [1,7,10]. Muscle biopsy can reveal early muscle innervation disorder [11] with generalized small muscle fibers [8,9] and neurogenic muscular atrophy [8,9]. On electron microscopic examination, a marked widening of the nodes of Ranvier is often noticed [1,2,6,11], leading to a loss of attachment sites of the myelin loops in the paranodal regions [1,2,11] and an absence of the typical transverse bands that cross the paranodal junctional gap [1,13].…”

“…It was first implicated in human disease in 2014, leading to disorders characterized by polyhydramnios, severe neonatal hypotonia, arthrogryposis, facial diplegia, and severe motor paralysis, leading to death in early infancy [6]. ese mutations have been reported in 31 patients, with a wide phenotypic spectrum and promising survival up to early childhood [7][8][9].…”