Congenital hypomyelinating neuropathy due to a novel MPZ mutation

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.     

Rapid progression of late onset axonal Charcot-Marie-Tooth disease associated with a novel MPZ mutation in the extracellular domain

Myelin protein zero (MPZ) is a major component of compact myelin in peripheral nerves where it plays an essential role in myelin formation and adhesion. MPZ gene mutations are usually responsible for demyelinating neuropathies, namely Charcot-Marie-Tooth (CMT) type 1B, Déjèrine-Sottas neuropathy and congenital hypomyelinating neuropathy. Less frequently, axonal CMT (CMT2) associated with MPZ mutations has been described. We report six patients (one sporadic case and five subjects from two apparently unrelated families) with a late onset, but rapidly progressive, axonal peripheral neuropathy. In all patients, molecular analysis demonstrated a novel heterozygous missense mutation (208C>T) in MPZ exon 2, causing the Pro70Ser substitution in the extracellular domain. The diagnosis of CMT2 associated with MPZ mutations should be considered in both sporadic and familial cases of late onset, progressive polyneuropathy. The mechanism whereby compact myelin protein mutations cause axonal neuropathy remains to be elucidated.     

Phenotypic variation of a novel nonsense mutation in the P0 intracellular domain.

Mutations in the gene for the peripheral myelin protein zero (P0, MPZ) cause type 1B of Charcot-Marie-Tooth sensorimotor neuropathy (CMT1B). Here we report a German family with a novel heterozygous P0 nonsense mutation (G206X) that supposedly removes four-fifths of the amino acid residues constituting the P0 intracellular domain. The 12-year-old propositus had childhood-onset CMT1B associated with bilateral pes cavus, moderate lower limb weakness, and mildly reduced sensory qualities in the distal legs. The electrophysiology was consistent with a demyelinating neuropathy. He inherited the mutation from his mother who had no complaints but slight pes cavus deformity and slow nerve conduction velocities (NCV). Conclusively, truncating mutations within the P0 intracellular domain do not necessarily cause a severe phenotype such as Dejerine-Sottas syndrome (DSS) or congenital hypomyelinating neuropathy (CHN), but can result in mild or moderate CMT1B with intrafamilial clinical variability.     

A novel MPZ gene mutation in exon 2 causing late-onset demyelinating Charcot-Marie-Tooth disease

The myelin protein zero gene (MPZ) encodes the major structural protein component of myelin in the peripheral nervous system. More than 120 mutations in MPZ have been detected so far. Clinical phenotypes include CMT1B, CMT2, Dejerine-Sottas syndrome, and congenital hypomyelination neuropathy. We report a new previously unreported mutation in the MPZ gene causing a demyelinating peripheral neuropathy. The initial apparent absence of a family history resulted in the patient being treated for an inflammatory neuropathy with some subjective improvement. We subsequently identified another affected member of the same family with the same genotype leading to the correct diagnosis. Both the affected individuals had an 8-base pair deletion, c.160_167delTCCCGGGT in MPZ exon 2.     

A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths

We found the association of a heterozygous novel MPZ gene point mutation, Ile62Phe in exon 2, with autosomal dominant motor and sensory neuropathy with focally folded myelin sheaths. Family study revealed that de novo Ile62Phe mutation on the MPZ gene occurred in the proband and was inherited by her children with early onset slowly progressive neuropathy. Our study suggests that the characteristic pathologic findings of the sural nerve in these patients are closely related to the site and nature of amino acid substitutions of the MPZ gene.     

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77‐year‐old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine‐36 with glycine in the extracellular domain. Our observation suggests that MPZ‐related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.     

Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation

OBJECTIVE: To report a novel hereditary motor and sensory neuropathy (HMSN) phenotype, with partial steroid responsiveness, caused by a novel dominant mutation in the myelin protein zero (MPZ) gene. Most MPZ mutations lead to the HMSN type I phenotype, with recent reports of Déjérine-Sottas, congenital hypomyelination, and HMSN II also ascribed to MPZ mutations. Differing phenotypes may reflect the effect of particular mutations on MPZ structure and adhesivity. METHODS: Clinical, neurophysiological, neuropathological, and molecular genetic analysis of a family presenting with an unusual hereditary neuropathy. RESULTS: Progressive disabling weakness, with positive sensory phenomena and areflexia, occurred in the proband with raised CSF protein and initial steroid responsiveness. Nerve biopsy in a less severely affected sibling disclosed a demyelinating process with disruption of compacted myelin. The younger generation were so far less severely affected, becoming symptomatic only after 30 years. All affected family members were heterozygous for a novel MPZ mutation (Ile99Thr), in a conserved residue. CONCLUSIONS: This broadens the range of familial neuropathy associated with MPZ mutations to include steroid responsive neuropathy, initially diagnosed as chronic inflammatory demyelinating polyneuropathy.     

Four novel mutations of the myelin protein zero gene presenting as a mild and late-onset polyneuropathy

Inherited neuropathies caused by mutations of the major structural protein of peripheral myelin, myelin protein zero (MPZ), contribute to 5% of all cases of Charcot-Marie-Tooth disease (CMT). They can be divided into an early-onset neuropathy with symptoms prior to the stage of walking, and a late-onset neuropathy with symptoms at the age of 40 and older. In this study, five patients with four novel MPZ mutations were identified by molecular genetic testing which presented as mild and late-onset neuropathies. We recommend testing for MPZ mutations in patients with a late-onset neuropathy, as late-onset inherited neuropathies might be more frequent than previously thought.     

Charcot-Marie-Tooth Neuropathy Type 2 And P0 Point Mutations: Two Novel Amino Acid Substitutions (ASP61GLY, TYR119CYS) and a Possible "Hotspot" on THR124MET

Mutations in the gene for the major protein component of peripheral nerve myelin, myelin protein zero (MPZ, PO), cause hereditary disorders of Schwann cell myelin such as Charcot-Marie-Tooth neuropathy type 1B (CMT1B), Dejerine-Sottas syndrome (DSS), and congenital hypomyelinating neuropathy (CHN). More recently, PO mutations were identified in the axonal type of CMT neuropathy, CMT2, which is different from the demyelinating variants with respect to electroneurography and nerve pathology. We screened 49 patients with a clinical and histopathological diagnosis of CMT2 for mutations in the PO gene. Three heterozygous single nucleotide changes were detected: two novel missense mutations, Asp61Gly and Tyr119Cys, and the known Thr124Met substitution, that has already been reported in several CMT patients from different European countries. Haplotype analysis for the PO locus proved that our patients with the 124Met allele were not related to a cohort of patients with the same mutation, all of Belgian descent and all found to share a common ancestor (7). Our data suggest that PO mutations account for a detectable proportion of CMT2 cases with virtually every patient harbouring a different mutation but recurrence of the Thr124Met amino acid substitution. The high frequency of this peculiar genotype in the European CMT population is presumably not only due to a founder effect but Thr124Met might constitute a mutation hotspot in the PO gene as well.     

Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration

Mutations in the major peripheral nervous system (PNS) myelin protein, myelin protein zero (MPZ), cause Charcot-Marie-Tooth Disease type 1B (CMT1B), typically thought of as a demyelinating peripheral neuropathy. Certain MPZ mutations, however, cause adult onset neuropathy with minimal demyelination but pronounced axonal degeneration. Mechanism(s) for this phenotype are unknown. We performed an autopsy of a 73-year-old woman with a late-onset neuropathy caused by an H10P MPZ mutation whose nerve conduction studies suggested severe axonal loss but no demyelination. The autopsy demonstrated axonal loss and reorganization of the molecular architecture of the axolemma. Segmental demyelination was negligible. In addition, we identified focal nerve enlargements containing MPZ and ubiquitin either in the inner myelin intralaminar and/or periaxonal space that separates axons from myelinating Schwann cells. Taken together, these data confirmed that a mutation in MPZ can cause axonal neuropathy, in the absence of segmental demyelination, thus uncoupling the two pathological processes. More important, it also provided potential molecular mechanisms as to how the axonal degeneration occurred: either by disruption of glial-axon interaction by protein aggregates or by alterations in the molecular architecture of internodes and paranodes. This report represents the first study in which the molecular basis of axonal degeneration in the late-onset CMT1B has been explored in human tissue.     

Congenital hypomyelinating neuropathy, a long term follow-up study in an affected family

Congenital hypomyelinating neuropathy is a rare condition characterized by prenatal, neonatal or early infantile onset of hypotonia, paresis and areflexia. Most of the few patients described in literature die within the first years of life. Histopathologically there are no or thin myelin sheaths. Mutations have been described in the following genes, MPZ, EGR2, PMP22, and MTMR2. Here we describe a family with a heterozygous mutation in MPZ, confirmed in two generations.     

Phenotypic presentation of the Ser63Del MPZ mutation

Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63del mice suggest that Ser63del MPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy. Clinical information about patients with this mutation is limited. We present clinical and electrophysiological data on a large multigenerational family with CMT1B caused by Ser63del MPZ. The patients have a classical CMT1 phenotype that is much less severe than that of patients with Arg98Cys MPZ that also activates the UPR. These results suggest that clinical presentation along cannot predict which MPZ mutations will be retained in the ER and activate the UPR.     

Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene

MPZ gene mutations cause demyelinating and axonal Charcot-Marie-Tooth (CMT) disease. Two novel MPZ mutations are reported in very late onset and progressive CMT syndrome. The N60H caused axonal CMT in a large family, whereas the I62M occurred in a single patient presenting with a primary axonal neuropathy. Previously, chronic polyradiculoneuritis was assumed in two patients. Molecular genetic testing and particularly screening for MPZ mutations in late onset neuropathies are important to differentiate acquired and inherited neuropathies.     

A novel mutation of myelin protein zero associated with an axonal form of Charcot-Marie-Tooth disease

OBJECTIVE: To report a new mutation in the MPZ gene which encodes myelin protein zero (P0), associated with an axonal form of Charcot-Marie-Tooth disease (CMT). METHODS: Three patients from an Italian family with a mild, late onset axonal peripheral neuropathy are described clinically and electrophysiologically. To detect point mutation in MPZ gene the whole coding sequence was examined. The structure of the mutated protein was investigated using the three dimensional model of P0. RESULTS: All patients showed a relatively mild CMT phenotype characterised by late onset and heterogeneity of the clinical and electrophysiological features. Molecular analysis demonstrated a novel heterozygous T/A transversion in the exon 3 of MPZ gene that predicts an Asp109Glu amino acid substitution in the extracellular domain of the P0. Asp109 is found at the protein surface, on beta strand E, in the interior of the P0 tetramer. CONCLUSIONS: The identification of Asp109Glu mutation confirms the pivotal role of P0 in axonal neuropathies and stresses the phenotypic heterogeneity associated with MPZ mutations. This study suggests the value of screening for MPZ mutations in CMT family members with minor clinical and electrophysiological signs of peripheral neuropathy.     

Clinical and genetic analysis of CMT1B in a Nigerian family.

We report a Nigerian family with a late-onset autosomal dominant neuropathy consistent with Charcot-Marie-Tooth disease. Electrophysiological examination of the index patient confirmed a severe demyelinating neuropathy with secondary axonal features. Sequence analysis of the myelin protein zero (MPZ) gene identified a C-to-G transversion at nucleotide position 234, resulting in a serine-to-tryptophan mutation in codon 78 (S78W) of the translated protein. The presence of this novel missense mutation suggests a diagnosis of Charcot-Marie-Tooth disease type 1B. Our study confirms the worldwide distribution of this disorder and extends the genetic spectrum of mutations in the MPZ gene.     

Mutation analysis in Charcot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity

Charcot-Marie-Tooth disease type 1 (CMT1) is a demyelinating peripheral neuropathy most commonly caused by a DNA duplication on chromosome 17p11.2 including the peripheral myelin protein 22 (PMP22). Point mutations in the myelin protein zero gene (MPZ) and gap junction protein, beta-1 gene (GJB1) are also found in association with CMT1 or the subclass of CMT type X (CMTX), respectively. Recently point mutations in these genes have been found in patients showing the axonal variant of CMT, CMT type 2 (CMT2). We here describe the clinical and electro-physiological findings caused by two novel and two recently described MPZ mutations and six GJB1 mutations. Different MPZ and GJB1 mutations were associated with different grades of severity in CMT1 and CMTX. The novel MPZ Glu141st op mutation was associated with the axonal CMT2. We conclude that the clinical and electrophysiological heterogeneity among CMT patients carrying point mutations in MPZ and GJB1 is similar. Thus for clinical purposes CMT1 and CMT2 patients should be screened for mutations in these two genes after duplication on chromosome 17p11.2 has been excluded as the disease causing mutation.     

Normal expression of myelin protein zero with frame-shift mutation correlates with mild phenotype

Mutations in the gene encoding for myelin protein zero (MPZ) cause inherited demyelinating peripheral neuropathies of different severity. The molecular and cellular mechanisms by which the MPZ mutations cause neuropathy are incompletely understood. We investigated MPZ, myelin basic protein, and peripheral myelin protein 22 (PMP22) protein expression levels in a nerve biopsy of a Charcot-Marie-Tooth type 1B patient heterozygous for the Val 102 frame-shift mutation. We demonstrate by quantitative immunohistochemical as well as by Western blot analyses that MPZ expression levels were not reduced in myelin membranes, a finding that is in accordance with the mild phenotype of this patient. Our data show that heterozygous 'loss-of-function' of MPZ may not necessarily lead to reduced protein levels. In conclusion, we demonstrate that careful analysis of protein expression levels in peripheral nerve tissues provides important information with respect to the understanding of the molecular basis of these neuropathies.     

A new MPZ mutation associated with a mild CMT1 phenotype presenting with recurrent nerve compression

P0 is a transmembrane protein of the immunoglobulin superfamily that plays a role in myelin structure and function. Myelin protein zero gene (MPZ) mutations usually cause a demyelinating variant of Charcot-Marie-Tooth disease type 1B (CMT1B), but there is a wide spectrum of phenotypic manifestation of these mutations. We describe three patients from one family and one separate patient who presented with a demyelinating neuropathy. Some had recurrent lesions at compression sites mimicking hereditary neuropathy with liability to pressure palsies (HNPP). A heterozygous nonsense mutation (Tyr145Stop) corresponding to a T-to-A transition at nucleotide position 435 in exon 3 of the MPZ gene was identified in all patients. This mutation leads to an extracellular truncated protein, which may explain the mild phenotype. Therefore, such MPZ gene mutations should be searched for in cases of demyelinating neuropathy with acute nerve compression as well as in cases of the HNPP phenotype associated with normal the PMP22 gene.