CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis

Abstract

Objective:To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in the CNTNAP1 gene.Methods:In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in the CNTNAP1 gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for further CNTNAP1 mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.Results:We identified 3 novel CNTNAP1 mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.Conclusions:CNTNAP1 mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature. CNTNAP1-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.

International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita

“…It is known that different types of congenital neuropathies may contribute to the genesis of joint contractures (Bamshad et al, ; Evangelista et al, ; Ravenscroft et al, ; Scoto et al, ). Most are motor neuropathies, but some do affect proprioception, at least in animal studies (Haliloglu et al, ; Hengel et al, ; Masingue, Fauré, Solé, Stojkovic, & Léonard‐Louis, ). Auditory sensory abnormalities have been identified in some children with DA.…”

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].…”

“…Mutations the CNTNAP1 gene (contactin associated protein 1) (OMIM 602346) have been associated with two rare autosomal recessive congenital diseases, lethal congenital contracture syndrome type 7 (LCCS7) (OMIM 616286), and congenital hypomyelinating neuropathy type 3 (CHN3) (OMIM 618186). CNTNAP1 is located on chromosome 17q21 and encodes a contactin-associated transmembrane receptor (CASPR), highly essential in the formation of paranodal axoglial junctions in myelinated axons [1][2][3][4][5][6].…”

“…CNTNAP1 is also involved in regulating neural progenitor cells and the development of cerebral cortex [1]. 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].…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…This entity was designated lethal congenital contracture syndrome 7 (MIM 616286). Later, Hengel et al 26 described five patients from two families with biallelic truncating CNTNAP1 mutations causing severe hypomyelinating leucodystrophy with peripheral neuropathy.…”