The NFASC disease is caused by mutations in the NFASC gene and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). The gene provides instructions for making a protein which belongs to the L1 family of immunoglobulin cell adhesion molecules, which play a critical role in the assembly of the node of Ranvier. Nfasc155 is a glial isoform abundantly expressed in myelinating Schwann cells and predominantly enriched at the paranodal sites, acting as a ligand for the axonal contactin-1 (CNTN1)/contactin-associated protein-1 (CASPR1) complex. Nfasc186 represents the axonal isoform expressed at the node of Ranvier membranes where it is involved in the long-term maintenance and stability of Nav channels.
Autoantibodies against Nfasc186 and Nfasc155 are associated with severe forms of chronic inflammatory demyelinating polyneuropathy (CIDP) and cause an immune-mediated nodo-paranodopathy (Querol et al. 2017; Vallat et al. 2018) further demonstrating that these proteins play a crucial role in conduction.
The genetic disorder, a neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) is an autosomal recessive neurologic disorder with a highly variable phenotype. At the severe end of the spectrum, patients may have hypotonia apparent from birth, necessitating mechanical respiration and tube-feeding, and global developmental delay with absence of reaction to touch and no eye contact. At the mild end of the spectrum, patients may present with infantile-onset progressive ataxia and demyelinating peripheral neuropathy. The variable clinical phenotype may be caused by several factors, including the severity of the mutation, the selective involvement of distinct isoforms by pathogenic variants, and the presence of genetic modifiers.
NFASC