Congenital Hypomyelinating Neuropathy Research Articles

A Young Man With Hereditary Motor And Sensory Neuropathy: A Rare Genetic Association

Hereditary motor and sensory neuropathies with early onset are uncommon conditions that include Dejerine-Sottas neuropathy, which begins in infancy, and congenital hypomyelinating neuropathy, which manifests in the early postnatal period. However, these two historically defined disease entities are only small parts of the clinical spectrum. It is well recognized that very early onset hereditary neuropathies are frequently caused by de novo dominant mutations in PMP22, MPZ, and EGR2. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. A 20-year-old boy had complaints of weakness of both lower limbs for 1 year, followed by wasting and foot drop, which subsequently involved the upper limbs. Nerve conduction velocity and electromyography of both lower limbs revealed demyelinating sensory motor polyneuropathy. Histological examination of the sural nerve revealed a nerve trunk with perineural soft tissue, with the nerve bundles being irregular and separated by fibrous tissue bands. The later reveals small perivascular infiltration of chronic inflammatory cells, and no granuloma or AFB is seen. The genetic test of whole exome screening for heriditatory neuropathy showed pathogenic (PM2, PVS, PP5) with a gene impact of (NF2: c.363+1G>T), which is a rare entity in our case study to consider the diagnosis despite negative family history. We highlight this rare disease in young man with a high index of clinical suspicion for its diagnosis. Bangladesh J Medicine 2024; 35: 101-105

Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits

The Contactin-associated protein 1 (Cntnap1) mouse mutants fail to establish proper axonal domains in myelinated axons. Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which causes severe neurological deficits. To understand the human neuropathology and to model human CNTNAP1C323R and CNTNAP1R764C mutations, we generated Cntnap1C324R and Cntnap1R765C mouse mutants, respectively. Both Cntnap1 mutants show weight loss, reduced nerve conduction, and progressive motor dysfunction. The paranodal ultrastructure shows everted myelin loops and the absence of axo-glial junctions. Biochemical analysis reveals that these Cntnap1 mutant proteins are nearly undetectable in the paranodes, have reduced surface expression and stability, and are retained in the neuronal soma. Postnatal transgenic expression of Cntnap1 in the mutant backgrounds rescues the phenotypes and restores the organization of axonal domains with improved motor function. This study uncovers the mechanistic impact of two human CNTNAP1 mutations in a mouse model and provides proof of concept for gene therapy for CNTNAP1 patients.

Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

A de novo EGR2 variant, c.1232A\u2009>\u2009G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.

Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.

In a Mouse Model, Researchers Restore Myelination in Congenital Hypomyelinating Neuropathy

In a Mouse Model, Researchers Restore Myelination in Congenital Hypomyelinating Neuropathy

Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

Corrigendum: Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy

BackgroundCongenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. MethodsWhole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. ResultsA novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. ConclusionsThese findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.

A nonsense mutation in myelin protein zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function.

Protein zero (P0) is the major structural protein in peripheral myelin, and mutations in the Myelin Protein Zero (Mpz) gene produce wide-ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead in part aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells. We show that the loss of the C-terminal Tyr-Ala-Met-Leu motif is responsible for P0 mislocalization, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wild-type P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.

Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy

CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype–phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families.

P.171 - CNTNAP1: Extending the phenotype of congenital hypomyelinating neuropathy in 6 further patients

CNTNAP1 (OMIM # 602346) encodes rat contactin-associated protein (CASPR) and was first implicated in human disease in 2014.1 CASPR2, forms part of a high molecular mass complex in the paranodal junction and interacts with contactin. Normal paranodal junctions do not form if CASPR is absent and this occurs in conjunction with disruption of the paranodal loops. Using a whole exome sequencing (WES) approach in 31 non-syndromic arthrogryposis multiplex congenital families, Laquerriere et al identified four unrelated familes with homozygous frameshift mutations in CNTNAP1. Death occurred within the first 40 days of life in all four cases. CNTNAP1 has since been described in association with a severe congenital hypomyelinating neuropathy (CHN) in a further 5 patients in the literature. We describe the clinical findings in 6 further patients extending the phenotype beyond that of neonatal lethality. We report neuropathological findings on muscle and nerve biopsy of 3 of the patients. Further molecular genetic analysis is ongoing and the results will be reported. Our findings demonstrate that CNTNAP1 causes a reproducible specific phenotype of polyhydramnios with associated premature birth, severe central hypotonia from birth with severe demyelinating peripheral neuropathy, cranial nerve involvement including orobulbar dysfunction, vocal cord palsy, severe respiratory distress from birth with associated requirement for tracheostomy and profound intellectual disability. Onion bulb fibres were noted on neuropathological specimens concurring with previous reports, although not specific to CNTNAP1. Brain MRI demonstrated a varying combination of central hypomyelination, delayed myelination and loss of white matter bulk. This specific clinical pattern has not been previously reported in association with any of the other genes associated with CHN and should guide clinical management and genetic counselling.

Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region.

Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in CNTNAP1 have been described in a few patients. CNTNAP1 encodes contactin-associated protein 1 (caspr-1), which is an essential component of the paranodal junctions of the peripheral and central nervous systems, and is necessary for the establishment of transverse bands that stabilize paranodal axo-glial junctions. We present the results of nerve biopsy studies of three patients from two unrelated, non-consanguineous families with compound heterozygous CNTNAP1 mutations. The lesions were identical, characterized by a hypomyelinating process; on electron microscopy, we detected, in all nodes of Ranvier, subtle lesions that have never been previously described in human nerves. Transverse bands of the myelin loops were absent, with a loss of attachment between myelin and the axolemma; elongated Schwann cell processes sometimes dissociated the Schwann cell and axon membranes that bound the space between them. These lesions were observed in the area where caspr-1 is located and are reminiscent of the lesions reported in sciatic nerves of caspr-1 null mice. CNTNAP1 mutations appear to induce characteristic ultrastructural lesions of the paranodal region.

Gastric Perforation Because of Non-Invasive Positive-Pressure Ventilation: Review of Complications

Abstract Background: Non-invasive positive-pressure ventilation (NIPPV) is a useful tool, especially for patients with respiratory failure. Although NIPPV is accepted now as harmless and comfortable treatment tools for patients, the associated equipment can induce a critical illness if expiratory pressure is not adjusted adequately. Case: A 23-year-old male was admitted to our hospital complaining of severe abdominal pain. He had a history of congenital hypomyelination neuropathy. Because of respiratory insufficiency due to neuropathy, his doctor had prescribed NIPPV and increased end expiratory pressure three months earlier. Because abdominal computed tomography (CT) revealed ascites and pneumoperitoneum indicating gastrointestinal perforation, emergent laparotomy was performed. Intra-operative findings showed a gastric perforation and hematoma at the gastric anterior walls. The patient recovered from post-operative bowel obstruction and was transferred to pediatrics on post-admission day 26. Conclusion:...

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

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.

A Novel Asp121Asn Mutation of Myelin Protein Zero Is Associated with Late-Onset Axonal Charcot-Marie-Tooth Disease, Hearing Loss and Pupil Abnormalities.

Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves. Mutations in MPZ have been associated with different Charcot–Marie–Tooth disease (CMT) phenotypes (CMT1B, CMT2I/J, CMTDI), Dejerine–Sottas syndrome, and congenital hypomyelination neuropathy. Here, we report phenotypic variability in a four-generation Chinese family with the MPZ mutation Asp121Asn. Genetic testing was performed on nine family members and 200 controls. Clinical, electrophysiological and skeletal muscle MRI assessments were available for review in six family members. A novel heterozygous missense mutation, Asp121Asn, was observed in five affected members of the family. Unaffected relatives and 200 normal controls were without the mutation. Four of the affected members of the family displayed late-onset, predominantly axonal sensory and motor neuropathy, pupil abnormalities, and progressive sensorineural hearing loss. One young affected member presented with Argyll–Robertson pupils and diminished deep tendon reflexes in the lower limbs. The MPZ mutation Asp121Asn may be associated with late-onset axonal neuropathy, early onset hearing loss and pupil abnormalities. Our report expands the number and phenotypic spectrum of MPZ mutations.

P.180 - Severe autosomal recessive congenital hypomyelinating neuropathy causing death in the first four months of life

P.180 - Severe autosomal recessive congenital hypomyelinating neuropathy causing death in the first four months of life

Structural and Functional Abnormalities of the Neuromuscular Junction in the Trembler-J Homozygote Mouse Model of Congenital Hypomyelinating Neuropathy.

Mutations in peripheral myelin protein 22 (PMP22) result in the most common form of Charcot-Marie-Tooth (CMT) disease, CMT1A. This hereditary peripheral neuropathy is characterized by dysmyelination of peripheral nerves, reduced nerve conduction velocity, and muscle weakness. APMP22 point mutation in L16P (leucine 16 to proline) underlies a form of human CMT1A as well as the Trembler-J mouse model of CMT1A. Homozygote Trembler-J mice (Tr(J)) die early postnatally, fail to make peripheral myelin, and, therefore, are more similar to patients with congenital hypomyelinating neuropathy than those with CMT1A. Because recent studies of inherited neuropathies in humans and mice have demonstrated that dysfunction and degeneration of neuromuscular synapses or junctions (NMJs) often precede impairments in axonal conduction, we examined the structure and function of NMJs in Tr(J)mice. Although synapses appeared to be normally innervated even in end-stage Tr(J)mice, the growth and maturation of the NMJs were altered. In addition, the amplitudes of nerve-evoked muscle endplate potentials were reduced and there was transmission failure during sustained nerve stimulation. These results suggest that the severe congenital hypomyelinating neuropathy that characterizes Tr(J)mice results in structural and functional deficits of the developing NMJ.

G.P.296: Severe, early onset Charcot-Marie-Tooth disease with rare presentations

Charcot–Marie–Tooth disease (CMT) has diverse clinical presentations and molecular genetic heterogeneity. Herein we describe the clinical features, neurophysiological and morphological studies of 2 fatal cases of CMT. Case 1 was a healthy newborn who developed foot drop, daily frequent vomiting and severe constipation at 7 months of age. His arm and leg weakness rapidly progressed within a few months. He subsequently developed diaphragmatic paralysis and died at 2.5 years of age due to respiratory failure. NCS/EMG showed a severe, axonal sensory and motor neuropathy. He had a novel and de novo mutation (c.296–297dupAAG) of the MFN2 gene. Case 2 had congenital hypomyelinating neuropathy confirmed by NCS and nerve biopsy, associated with a novel and de novo missense mutation (p.His384Arg) of the EGR2 gene. The patient presented a few weeks after birth with failure to thrive and hypotonia. She had facial, severe proximal > distal arm and leg weakness, pain insensitivity, areflexia and symptoms of autonomic dysfunction. She progressed to respiratory failure requiring mechanical ventilation. Her CSF protein was elevated (136 mg/dl). She had a fluctuating clinical course that let to the initial consideration of chronic inflammatory demyelinting polyneuropathy. She did not respond to prednisone, but she responded to IVIG therapy initially with some improvement of muscle strength and decrease autonomic dysfunction. She subsequently experienced deterioration of weakness not responding to either IVIG or plasmapheresis, and died at 16.5 months of age. Our report expanded the genotype and phenotype of MFN2 and EGR2 mutations. Although early onset CMT has been well described, autonomic features and fatality due to respiratory failure are rarely described. MFN2 mutations frequently cause severe phenotype, but diaphragmatic paralysis and autonomic dysfunction have not been described. Similarly, severe autonomic dysfunction has not been reported to be associated with EGR2 mutations.

Fenótipos Raros de Neuropatia Hereditária: Charcot-Marie-Tooth Tipo 4

Introduction. The Charcot-Marie-Tooth Disease (CMT) comprises a genetic heterogeneous group of motor and sensory inherited neu­ropathies, with autosomal dominant, recessive and X-linked forms. Objective. The aim of this study is to review the available medical literature about the main types of CMT4 (autosomal recessive de­myelinating CMT forms). Method. We conducted an extensive literature review searching for articles written in English (or at least with abstracts in English), with description about the clinical charac­teristics, ethnic and geographic distribution of CMT4 using NCBI’s OMIM and pubmed database. Results. We identified and described the genes, clinical characteristics, ethnic and geographic distribution of 12 variants of CMT4: A, B1, B2, B3, C, D, E, F, G, H, J and “L” (SURF gene mutation, with undefined nomenclature and here named as “CMT4L”). Conclusion. We conclude that CMT4, due to its autosomal recessive inheritance, is more commonly localized in restricted ethnic and geographic regions, contrasting with other forms of CMT. Despite extreme varaibility, there is a tendency towards more severe phenotypes in CMT, and overlap with diseases such as Déjèrine-Sottas syndrome (CMT3) and congenital hypomyelinating neuropathy (CHN).