Congenital hypomyelinating neuropathy due to a novel MPZ mutation

Abstract

Congenital hypomyelinating neuropathy (CHN) is a severe inherited neuropathy with neonatal or early infancy onset, reduced nerve conduction velocity, and pathological evidence of hypomyelination. We describe a case of CHN that presented with neonatal hypotonia and a progressive downhill clinical course, developing cranial nerve dysfunction, and respiratory failure. The nerve conduction velocities were severely slowed and sural nerve biopsy revealed non-myelinated and poorly myelinated axons, with no typical onion bulbs. The mutational screening showed that our proband harbored a novel missense mutation, p.S121F, in the MPZ gene. In silico analyses and molecular modeling predicted that the replacement of a serine by a phenylalanine is a non-tolerated change and may affect the folding and the stability of the protein. Subcellular location studies were performed and revealed that the mutant protein loses its correct location on the cell membrane surface and is mainly expressed in the cytosol, reducing its adhesive properties. This case illustrates the clinical heterogeneity that exists in neuropathies associated with MPZ mutations and highlights that in patients with mild hypotonia in the first months that develop a very severe demyelinating neuropathy, the MPZ gene must be taken into account.

Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy

“…In the first group, the disease manifests in the neonatal period, and patients often die at an early age from associated complications, including pneumonia. In the second group, patients come to medical attention later in infancy and, despite severe disability, have a better prognosis, often becoming capable of ambulation without significant support within the first decade of life …”

“…In the second group, patients come to medical attention later in infancy and, despite severe disability, have a better prognosis, often becoming capable of ambulation without significant support within the first decade of life. 1,5 Detailed electrophysiological testing is required to confirm the clinical diagnosis, but given the variable clinical course during the first few years of life, counseling about the prognosis should be guarded. Nerve biopsy is now less often performed, as genetic testing in patients with hereditary neuropathies is becoming increasingly used.…”

“…2 Previous reports of genetic analyses of patients with this spectrum of signs have described specific mutations in genes known to be important in myelination, including de novo mutations in the myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), and early growth response 2 (EGR2) genes. [3][4][5][6] Recessive mutations in other genes may result in a less severe phenotype, but because many of these patients are not evaluated with molecular studies, these lists are incomplete. 2 Contactin-associated protein 1 (CNTNAP1) is a cell-adhesion molecule, commonly referred to as CASPR in the literature, that was the first identified constituent of paranodal junctions in the peripheral nervous system (PNS).…”

“…The clinical presentation varies, but most patients come to medical attention in infancy, with respiratory difficulties and profound hypotonia . Previous reports of genetic analyses of patients with this spectrum of signs have described specific mutations in genes known to be important in myelination, including de novo mutations in the myelin protein zero ( MPZ ), peripheral myelin protein 22 ( PMP22 ), and early growth response 2 ( EGR2 ) genes . Recessive mutations in other genes may result in a less severe phenotype, but because many of these patients are not evaluated with molecular studies, these lists are incomplete …”

Congenital Amyelinating Neuropathy: A Neuropathology Case Report and Review of Prior Cases

“…CHN is believed to affect only peripheral myelination, though no autopsies with central nervous system examination have been reported in the literature. Several mutated genes (MPZ, PMP22, EGR2, MTMR2 and SOX10, and MPZ) encoding peripheral nerve myelin proteins have been identified in congenital hypomyelinating neuropathy, Dejerine-Sottas syndrome and Charcot Marie Tooth including late onset axonal CMT2 [8]. Among those genes, myelin basic protein zero (MPZ) is the most frequent cause of CHD.…”