Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

Abstract

Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.

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

“…CNTNAP1 involvement in human diseases was first described by Laquérriere in 2014 [6]. 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].…”

“…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].…”

“…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].…”

“…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]. [7], while electromyography (EMG) and nerve conduction studies converge to a neurogenic rather than a myopathic pattern [7,9].…”

“…[7], while electromyography (EMG) and nerve conduction studies converge to a neurogenic rather than a myopathic pattern [7,9]. Auditory and visual evoked potentials could be nonspecifically altered [11].…”