Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation

An in frame, lys236 deletion in the intracytoplasmic domain of myelin protein zero (MPZ) has recently been designated as a mutation possibly associated with Charcot-Marie-Tooth disease (CMT) but requiring further documentation. In this report we present a detailed clinical, electrophysiological, and genotype correlation in three generations of a family with the MPZ lys236del mutation and provide further evidence that this mutation is associated with CMT. The MPZ lys236del mutation is associated with an autosomal dominant, adult onset CMT phenotype, with variable penetrance ranging from an asymptomatic state to foot deformities, pedal numbness, and muscle cramps. Nerve conduction studies disclose intermediate range, somewhat non-uniform slowing of motor nerve conduction, which is accentuated in forelimb rather than distal nerve segments. Based on the contrasting finding of entirely normal conduction velocities (CV) in a genetically affected 15 year old in this family, it remains to be established whether CV slowing with this mutation is progressive in life, a pattern that would contrast with CMT1a (PMP22 gene duplication).     

Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B

We previously reported familial cases characterized by Charcot-Marie-Tooth disease (CMT) phenotype with abnormal myelin foldings and MPZ Ile62Phe mutation. To further clarify the molecular mechanisms in this family, we produced wild-type MPZ, Ile62Phe mutant and other mutations in the neighboring regions producing thin myelin sheaths (Ser63del, Ser63Cys and Ser63Phe) by site-specific mutagenesis and transfected these into rat pheochromocytoma cells (PC12). We investigated the expression and aggregation properties of the MPZ protein through immunoblotting, immunohistochemical staining and adhesion assay. MPZ protein with Ile62Phe mutation was immunohistochemically detectable mainly in the plasma membrane of the cells, and it induced a cell aggregation behavior different from the other mutations or the wild-type MPZ. These studies suggested that MPZ Ile62Phe mutation in CMT1B with abnormal myelin folding induced dysregulation of adhesion function of the MPZ protein in a manner unlike those seen in cells with other mutations. The present study provides evidence that the site and nature of amino acid substitutions in the MPZ protein are closely related to the abnormal myelination in CMT1B.     

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.     

An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val)

OBJECTIVES AND METHODS: Seven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene-Thr124Met or Asp75Val. RESULTS: Patients with these mutations commonly showed relatively late onset sensorimotor neuropathy predominantly involving the lower limbs. Sensory impairment typically was marked, and distal muscle atrophy and weakness were also present in the legs. Adie's pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present. Relatively well preserved motor and sensory nerve conduction velocities contrasted with reduced or absent compound muscle action potentials and sensory nerve action potentials. Axonal change with marked axonal sprouting was seen in sural nerve specimens. CONCLUSION: The similar associated clinical findings suggest that patients with axonal CMT with an MPZ gene mutation share distinctive clinical features.     

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.     

Clinical and electrophysiological features in Charcot-Marie-Tooth disease with mutations in the NEFL gene

BACKGROUND: To date, 13 different neurofilament light-chain polypeptide gene (NEFL) mutations have been identified in 55 patients with Charcot-Marie-Tooth disease (CMT) from 16 families. NEFL mutations were found to be associated with axonal and demyelinating variants of CMT. OBJECTIVES: To describe the clinical features of 11 patients with CMT and NEFL mutations and to explore possible genotype-phenotype correlations. DESIGN: Standardized neuromuscular and nerve conduction studies were performed, and the coding regions of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), gap junction beta-1 protein (GJB1), and NEFL genes were analyzed by direct DNA sequencing. SETTING: Two university hospitals in Austria (referral centers for neuromuscular disorders). Patients Eleven patients with CMT and NEFL mutations. Main Outcome Measure We genotyped NEFL in all of the patients and healthy relatives and correlated the genotype with the phenotype. RESULTS: A novel NEFL mutation (p.L93P) was detected in 1 family with 4 affected individuals exhibiting a severe CMT phenotype. Nerve conduction velocities were intermediately slowed to a range of 35 to 39 m/s. In a second family and in a sporadic patient, a p.P8R mutation was identified with intermediate and severe nerve conduction slowing. CONCLUSION: The results argue against an obvious genotype-phenotype correlation regarding disease onset, degree of muscle weakness, and nerve conduction slowing caused by NEFL mutations.     

Mild recurrent neuropathy in CMT1B with a novel nonsense mutation in the extracellular domain of the MPZ gene

Clinical, electrophysiological, and neuropathological features are reported associated with a novel heterozygote point mutation in the extracellular domain of the MPZ gene, where a transversion at codon 71 in exon 3 leads to a codon stop: Glu71stop (ie GAA-->TAA). A 36 year old woman developed a mild recurrent neuropathy after intensive manual work. The motor nerve conduction velocities were slow without conduction blocks and the nerve biopsy showed signs of demyelination-remyelination, axonal loss, and regular uncompacted myelin lamellae. She inherited the mutation from her father who displayed the same mutation with a normal phenotype. This nonsense mutation may cause a dosage difference of normal P0, and is probably underrepresented in the current mutation data bases. This report further extends the phenotype of MPZ mutations and also emphasises that mild phenotype of CMT1B may be more frequent than has been appreciated.     

A novel MPZ mutation in Charcot-Marie-Tooth disease type 1B with focally folded myelin and multiple entrapment neuropathies

Charcot-Marie-Tooth type 1B (CMT1B) is a demyelinating neuropathy caused by mutations in the myelin protein zero (MPZ) gene. Here, we describe a patient with CMT1B with focally folded myelin, a rarely reported phenotype of CMT1B, who initially presented with multiple entrapment neuropathies. She complained of palmar dysesthesia on both sides and on both soles of her feet in her 30's. She underwent bilateral carpal and tarsal tunnel release at age 44, which provided transient relief from the symptoms. A sural nerve biopsy performed at age 49 revealed focally folded myelin. Molecular genetic analysis revealed a novel Asn131Ser mutation in MPZ.     

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.     

Charcot-Marie-Tooth disease: a novel Tyr145Ser mutation in the myelin protein zero (MPZ,P0) gene causes different phenotypes in homozygous and heterozygous carriers within one family

Charcot-Marie-Tooth disease type 1B (CMT 1B) is caused by mutations in the gene coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this mutation. On neurological examination the heterozygous parents and their homozygous children both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner myelin layers were found. This Costa Rican family shows phenotypic variability depending on the homozygous or heterozygous state of the Tyr145Ser mutation carriers.A. Leal and C. Berghoff contributed equally to this work.     

Morphological And Electrophysiological Signs Of Dysmyelination In Transgenic Mice Expressing CMT1B (MPZ DELSer34) or DSS (MPZ Ser34Cys) Mutations

Charcot-Marie-Tooth 1B neuropathy (CMT1B), Déjèrine-Sottas syndrome (DSS) and Congenital Hypomyelination are each associated with mutations in MPZ , encoding P0 glycoprotein, the major structural protein of peripheral nerve myelin. To explore whether new abnormal functions of mutant MPZ can explain this phenotypic diversity, we expressed either of two MPZ mutations: DELSer34 (causing CMT1B) or Ser34Cys (causing DSS) in addition to the two normal endogeneous copies of Mpz in transgenic mice. We have shown previously that overexpression of wild type Mpz causes dose-dependent dysmyelination. However, multiple lines of mice containing the MPZ mutants showed not only hypomyelination, but also abnormalities in myelin sheaths and onion bulbs that were never observed in Mpz overexpressor mice. To create a mouse model of CMT1B with no Mpz overexpression, one line of DELSer34 that expresses mutant Mpz at levels similar to one wildtype Mpz allele was crossed with heterozygous Mpz knock-out mice, to obtain the genotype Mpz ^wt/−/ Mpz ^DELSer34. These mice manifest progressive peripheral neuropathy with hypomyelination, and onion bulbs that appear around 6 months of age. As a first step towards longitudinal studies of phenotype, we performed detailed neurophysiological analyses at 12 months of age. We found signs of demyelination, with statistically significant increases of both motor latency after proximal stimulation and F-wave latencies, and decreases in both motor and mixed afferent nerve conduction velocities of sciatic nerve. The motor response was polyphasic and there was a trend towards reduced CMAP amplitudes. Thus, the clinical onset and progression, pathological features and neurophysiological findings provide a reasonable model of CMT1B. Longitudinal studies to correlate the onset and progression of morphological and electrophysiological abnormalities in these mice are ongoing.     

Focally folded myelin in Charcot–Marie–Tooth type 1B disease is associated with Asn131Lys mutation in myelin protein zero gene: short report

Charcot-Marie-Tooth disease type 1B (CMT1B) is a demyelinating neuropathy inherited as an autosomal dominant trait. The majority of CMT1B cases are caused by mutations in the myelin protein zero (P0) gene (MPZ). Only a few mutations in MPZ gene have been reported to be associated with focally folded myelin sheaths. We have studied five patients from one family with five generations, affected by CMT1B disease. The morphological studies of sural nerve biopsy performed in the proband revealed fibers with focally folded myelin. DNA sequencing analysis showed the Asn131Lys mutation in the MPZ gene in three members of the affected family.     

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.     

Peripheral myelin modification in CMT1B correlates with MPZ gene mutations.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.     

Clinical and genetic description of a family with Charcot-Marie-Tooth disease type 1B from a transmembrane MPZ mutation

Mutations in the myelin protein zero gene (MPZ) are associated with certain demyelinating neuropathies, and in particular with Charcot-Marie-Tooth disease type 1B (CMT1B), Dejerine-Sottas syndrome, and congenital hypomyelination. MPZ mutations affecting the protein's transmembrane domain are generally associated with more severe phenotypes. We describe a family with mild CMT1B associated with a transmembrane MPZ mutation. Sequence analysis identified a G-to-C transversion at nucleotide 1064, predicting a glycine-to-arginine substitution in codon 163 (G163R) of MPZ. This report furthers the understanding of the clinical and electrophysiological manifestations of MPZ mutations.     

Mutations disrupting extracellular structure of MPZ cause early onset severe forms of CMT1B

Missense mutations in myelin protein zero (MPZ), an important molecule for myelin compaction, cause inherited neuropathies collectively referred to as CMT1B. Depending on the mutation, phenotypes can be severe, or mild. To determine genotype‐phenotype correlations in CMT1B we evaluated patients from 11 different families seen in our clinic and 80 reported cases from the literature with respect to (1) how the mutation affected amino acids known to be critical for homotypic MPZ interactions; (2) whether the mutation affected the charge or hydrophobicity of an amino acid; (3) whether the mutation was likely to affect the secondary or tertiary structure of the MPZ, or (4) whether it affected evolutionarily conserved amino acids. We found that mutations that added a charged residue to the extracellular domain, introduced a cysteine or altered a conserved amino acid, caused a severe neuropathy. Mutation of an amino acid critical for cis or trans homotypic adhesion, however, had no obvious consequences on disease severity. We conclude that mutations which significantly disrupt the secondary or tertiary structure of MPZ are likely to cause severe, early onset neuropathies, whereas mutations which do not cause milder disease. Studies on how mutations disrupt protein trafficking and adhesion are underway.     

Peripheral neuropathies caused by mutations in the myelin protein zero

Charcot-Marie-Tooth disease type 1B (CMT1B) is caused by mutations in the major PNS myelin protein myelin protein zero (MPZ). MPZ is a member of the immunoglobulin supergene family and functions as an adhesion molecule helping to mediate compaction of PNS myelin. Mutations in MPZ appear to either disrupt myelination during development, leading to severe early onset neuropathies, or to disrupt axo-glial interactions leading to late onset neuropathies in adulthood. Identifying molecular pathways involved in early and late onset CMT1B will be crucial to understand how MPZ mutations cause CMT1B so that rational therapies for both early and late onset neuropathies can be developed.     

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.