UPDATED07.23.2021

RELEASED05.07.1999

EXPIRES FOR CME07.23.2024

Charcot-Marie-Tooth disease type 1B

Introduction

Overview

In the general population approximately 1 in 30,000 individuals su�ers from Charcot-Marie-

Tooth disease type 1B (CMT1B). Considering that the prevalence of Charcot-Marie-Tooth

disease in general is 1 in 2500, this subtype is, thus, a relatively rare form. Although several

new gene loci and genes are reported each year for novel subtypes, CMT1B remains among

the best studied forms. In this article, the authors include advances in our understanding of

the clinical phenotype and the relation between particular mutations and the speci�c clinical

and histological changes they cause.

Key points

• Charcot-Marie-Tooth disease type 1B a�ects about 1 out of 30,000 individuals in

the general population.

• It has an autosomal dominant inheritance pattern.

AUTHORS

Florian P Thomas MD MA PhD MS, Francisco de Assis Aquino Gondim MD MSc PhD

EDITOR

Louis H Weimer MD

Historical note and terminology

The Charcot-Marie-Tooth disease entity was recognized independently in Great Britain and

France (20; 115). Several earlier descriptions had been published, including a 6-generation

pedigree by Eichhorst in 1873. A more severe form of inherited neuropathy was described a

few years later (26). A source of confusion was the description of a progressive childhood

neuropathy associated with tremor (97), which has been de�ned genetically (02; 90).

Di�erent forms of inheritance were later recognized (01). Since the late 1960s, the clinical

and pathological spectrum has been de�ned, and a classi�cation system based on 7 types of

hereditary motor and sensory neuropathy has been introduced including HMSN1 and

HMSN2 (30; 42).

HMSN1 is the most common form of hereditary neuropathy, characterized by severely and

uniformly slowed nerve conduction velocities and primary hypertrophic myelin pathology

with prominent onion bulbs and secondary axonal changes. HMSN2, on the other hand,

represents the nondemyelinating neuronal type with relatively normal nerve conduction

velocities and primary axonal pathology. In the neuronal form (HMSN2) characteristically

nerves are not enlarged, weakness is o�en less marked, and onset is generally later, although

the distinction is di�cult to make in individual patients by history and exam alone. Although

the separation of neuronal and nonneuronal forms is an important etiologic and pathogenic

distinction, it is noteworthy that even in HMSN1, the clinical de�cits appear to correlate

better with progressive axonal degeneration than slowed nerve conduction. This fact is not

surprising, given the fact that demyelination disturbs axonal structure and transport. The

distinction between demyelinating and nondemyelinating hereditary motor and sensory

neuropathy has been called into question by a report of relatively normal nerve conduction

velocities suggestive of HMSN2 in younger members of a family with a myelin protein zero

mutation, whereas older relatives had severely slowed conduction consistent with HMSN1

• It is caused by mutations in the myelin protein zero gene.

• It is usually characterized by childhood, slowly progressive peripheral nerve

manifestations with distal dominant weakness, sensory loss, and limb deformities

(pes cavus).

• Demyelinating changes by neurophysiological and histological criteria are

characteristic.

(24). As a dividing value between both forms, nerve conduction velocities of 38 m/s are used

by some, and nerve conduction velocities of 42 m/s are used by others (42; 49). Because

nerve conduction velocities within and between type 1 families range from normal or near

normal to severely abnormal, the diagnostic usefulness of this parameter has its limits.

The hereditary motor and sensory neuropathy and Charcot-Marie-Tooth disease

classi�cation system also covers hereditary motor neuropathies and hereditary sensory

neuropathies and refers to other conditions linked to speci�c chromosomal regions or genes

such as CMT2 and CMT4 with several subtypes.

In the 1980s, linkages to chromosomes 1, 17, and X were recognized for certain Charcot-

Marie-Tooth pedigrees, and Charcot-Marie-Tooth was subcategorized to cover CMT1A,

aka hereditary motor and sensory neuropathy 1A (70% to 80% of CMT1), CMT1B, aka

hereditary motor and sensory neuropathy 1B (4% to 5% of CMT1), and CMTX (39; 116;

60) (15% of Charcot-Marie-Tooth disease). In 1991, 2 groups showed that CMT1A, the

most common form of CMT1 disease, was associated with a 1.5 mB duplication within

chromosome 17p11.2 (94). Some 90% of CMT1A cases result from this duplication (88).

Mutations in the peripheral myelin protein 22 kD (PMP22) gene, contained within the 1.5

kB duplication on chromosome 17, have been demonstrated to cause demyelinating

neuropathies in Trembler and Trembler-J mice as well as in some CMT1A and CMT3

patients (85). Moreover, transgenic mice and rats overexpressing PMP22 develop

neuropathies resembling CMT1 (104). An approximately 1.5 mB long deletion of the

proximal short arm of chromosome 17 is detected in most families with hereditary

neuropathy with predisposition to pressure palsy (18), whereas about 14% to 25% of

patients develop hereditary neuropathy with predisposition to pressure palsies due to other

PMP22 mutations (86). The deletion includes all markers duplicated in CMT1A. Several

nondeletion mutations have been identi�ed, such as nonsense mutations with a stop codon at

G183A (Trp61stop) and G372A (Trp124stop); frameshi� mutations with a premature

termination at 19-20delAG and 434delT or with a longer transcript at 281-282insG; splice

site mutations at 78+1G>T, 179+1G>C; and missense mutations at G208A (Val30Met) in

exon 3 (62). A similar condition, hereditary brachial plexus neuropathy or hereditary

neuralgic amyotrophy with predilection for the brachial plexus, is not linked to the PMP22

locus but was mapped to chromosome 17q25 (89).

The 1990s also saw the identi�cation of other Charcot-Marie-Tooth disease genes, including

myelin protein zero for CMT1B and CMT3 (44; 57; 110) and the gap junction protein

connexin 32 or beta 1 on chromosome Xq13.1 for the more common CMTX1 (05), whereas

the rare CMTX2 was mapped to chromosome Xq24-26 (93), and the zinc-�nger domain

containing transcription factor early growth response 2 gene for congenital hypomyelination

neuropathy and CMT1D (120). Mutations of all of these genes have been associated with

several overlapping clinical phenotypes. For instance, Dejerine-Sottas syndrome is associated

with PMP22 or myelin protein zero mutations or deletions (86; 119; 25).

Several new disease linkages and genes have been identi�ed, which include 2 signal

transduction genes: the N-MYC downstream-regulated gene-1 (NDRG1) on chromosome

8q24.3 for the Lom form of autosomal recessive motor and sensory neuropathy (50); the

gene for the phosphatase myotubularin-related protein-2 (MTMR2) on chromosome 11q22

for autosomal recessive CMT4B (12); a cytoskeletal gene, the neuro�lament light subtype

gene on chromosome 8p21 for CMT2E (77); the periaxin gene on chromosome 19q13.1-2,

which is regulated by EGR2, for recessive Dejerine-Sottas syndrome (11); the gene for a

serine palmitoyltransferase subunit on chromosome 9q22 for hereditary sensory neuropathy

type 1 (04; 23); and the gene involved in axonal organelle transport on chromosome 1p36-35

for CMT2A (128). A demyelinating neuropathy also results in some Pelizaeus-Merzbacher

patients from absent proteolipid protein expression. Mutations in the cytoskeletal protein

gigaxonin have been linked to giant axonal neuropathy (13). A locus for autosomal dominant

CMT2F was found on chromosome 7q11-q21 (47).

Loci with several candidate genes have been identi�ed in 2 families with autosomal

dominant Charcot-Marie-Tooth disease and conduction velocities between 24 and 54 m/s.

These include 1 on chromosome 19p12-p13.2 (51), the other associated with both large

�ber loss and regeneration clusters as well as onion bulbs, and uncompacted enlarged myelin

lamellae on chromosome 10q24.1-q25.1 (68; 118). A recessively inherited severe form of

Charcot-Marie-Tooth disease with intermediate conduction velocities is linked to

chromosome 10q23 (96). Intermediate conduction velocities also occur with myelin protein

zero and neuro�lament light subtype gene mutations (24).

Overall, some 100 genes are known at present for the di�erent forms of Charcot-Marie-

Tooth disease.

Clinical manifestations

Presentation and course

Charcot-Marie-Tooth disease type 1B. Due to its insidious onset, some patients are

unaware of their disease or seek medical attention only late in life. Motor symptoms

predominate over sensory symptoms. O�en patients complain of loss of balance, muscle

weakness, and foot deformities. Some children are referred by teachers for clumsiness or toe

walking. Rather than presenting with a classical Charcot-Marie-Tooth phenotype, patients

seem to manifest signs and symptoms either prior to walking or around age 40 (106).

Insertion of a charged amino acid, altering a cysteine residue in the extracellular domain,

truncation of the cytoplasmic domain, or alteration of an evolutionarily conserved amino

acid causes a severe early-onset neuropathy, possibly due to disruption of the tertiary

structure of myelin protein zero and of the myelin-protein-zero-mediated adhesion and

myelin compaction. Late-onset neuropathy is usually caused by mutations that more subtly

alter myelin structure, disrupting Schwann cell-axonal interactions.

Onset. The subjective age of onset within CMT1B families may relate both to the particular

mutation and the awareness of early manifestations. Some families notice delayed walking in

a�ected o�spring. Other complaints include thin lower legs, clumsiness, and di�culty

running. Onset in the �rst decade is typical, but some patients date disease onset into young-

or mid-adulthood.

Symptoms. Patients complain of tripping over objects because of foot-drop. Ankle sprains

and fractures are frequent. Because of hammer toes and high arches, patients have di�culty

�nding shoes and su�er from painful calluses. Complaints of cold feet o�en associated with

hair loss or leg edema are common. Pain results from pressure or strain of various structures

associated with bones, joints, and tendons. Abnormal gait and scoliosis lead to back pain.

Patients su�er from leg and hand cramps. Dysesthetic pain is less common than with

acquired neuropathies. Manipulating small objects such as zippers, forks, or pencils may be

di�cult. Not infrequently, asymptomatic individuals are detected during screening of

families a�er a relative has been diagnosed. Chronic cough occurred with a myelin protein

zero Thr124Met mutation (03). In general, one should be attentive to unusual phenotypes,

which could result from co-occurrence of 2 di�erent mutations, eg, periodic paralysis due to

SCN4A mutation and CMT1B (45), or CMT1A and McArdle disease (112). Mild

phenotypes with recurrent symptoms due to acute nerve compression in patients with

demyelinating neuropathy have been associated with heterozygous nonsense mutation

(Tyr145Stop), which leads to formation of an extracellularly truncated protein (67). A

combination of distal sensorimotor symptoms, cramps, restless legs syndrome,

neuropathic pain, and carpal tunnel syndrome has been reported in a family with a

missense mutation (c.700G> T p.Asp234Tyr). The index patient responded to

immunoglobulin and immunosuppression, suggesting a role for an autoimmune process

(101). Hypertrophic caudal nerve roots can lead to cauda equina syndrome requiring

surgical decompression (117). Arm monoplegia mimicking focal chronic in�ammatory

demyelinating polyneuropathy or multifocal motor neuropathy have been described in a

child with a de novo heterozygous MPZ mutation (127). Nerve biopsy did not reveal

in�ammation; focally folded myelin sheaths led to the diagnosis of CMT1B.

Physical �ndings. Cranial neuropathies are rare, but several instances of pupillary

abnormalities including light near dissociation have been reported (06). Distally dominant

weakness and muscle atrophy a�ect the legs more and earlier than the arms. In young

children, the exam may be entirely normal with the exception of impaired heel gait.

Sensation may be normal until adulthood, but distal, mild, pansensory loss is common.

Re�exes are absent or depressed. Foot deformities include high arches or �at feet, hammer

toes, and tight Achilles’ tendons. Foot deformities become more prevalent with age but are

variable even among relatives of the same age (30). Gait is compromised by distal weakness,

position sense, or foot deformities. Enlarged and excessively �rm nerves are found in over

25% of patients, o�en visible in the super�cial cervical nerves and palpable in the arms.

Tremor occurs in up to 25% of patients. Whether it is incidental or part of the syndrome

remains controversial (97; 90). Steroid responsive forms of Charcot-Marie-Tooth disease

have been recognized (31); this �nding has also been reported for CMT1B (28). A

phenotype with tonic pupils and conduction block was described in a patient with a

p.Ile112Thr mutation in myelin protein zero (81).

Disability. Disability may vary greatly between family members, ranging from asymptomatic

individuals with minimal �ndings to others with severe neuropathy. Some adults require

ankle foot orthoses only in the 6th decade, whereas some children may already have foot

drop, proximal leg weakness, and clawing of the �ngers. Signi�cant phenotypic di�erences

may exist among monozygotic twins, suggesting phenotypic modulation of myelin protein

zero mutations by external, nongenetic in�uences (69). Whether disability is greater in

CMT1B or CMT1A remains controversial, possibly due in part to the smaller number of

CMT1B patients available for comparison (30; 08).

Course. Clinical progression is slow in the 2nd to 4th decades. Therefore, any change in pace

requires consideration of superimposed acquired or possibly independently inherited forms

of neuromuscular diseases (112; 15).

Genetic studies suggest that a phenotypic classi�cation system cannot be strictly applied

because mutations in the same gene can cause di�erent clinical syndromes. Three conditions

other than CMT1B are associated with myelin protein zero mutations and are also linked to

mutations of other genes.

Dejerine-Sottas syndrome or hereditary motor and sensory neuropathy type 3.

Dejerine-Sottas syndrome is a heterogeneous disorder caused by heterozygous or

homozygous myelin protein zero or peripheral myelin protein 22 or periaxin mutations.

There may also be linkage to the chromosome 8q23-q24 region. Dominantly and recessively

inherited and sporadic cases exist. Although the more severe phenotype with earlier onset of

typical Dejerine-Sottas syndrome is easily distinguished from CMT1B, overlap cases are

di�cult to classify. As expected, there are instances of heterozygous parents with CMT1B

and children with Dejerine-Sottas syndrome due to a homozygous or compound

heterozygous myelin protein zero mutation.

Congenital hypomyelination neuropathy. Congenital hypomyelination neuropathy

presents with neonatal hypotonia, are�exia, distal weakness, slow nerve conduction

velocities, and at times with contractures or arthrogryposis. It may be due to myelin protein

zero mutations that are heterozygous or homozygous in o�spring of 2 parents with CMT1B.

Milder cases overlap with Dejerine-Sottas syndrome. Other cases are caused by mutations of

the early growth response 2 gene (EGR2 or Krox-20).

Charcot-Marie-Tooth disease type 2. Myelin protein zero mutation was found in several

families with a clinical diagnosis of CMT2 (70; 19; 24; 102; 79; 41; 10). It has been

suggested that in some of these cases, nerve conduction velocities may be normal in young

patients, consistent with a CMT2 diagnosis, but they become abnormally slow with

advancing age, thus, producing a CMT1 phenotype (24; 41). Incidentally, a slight decrease

in conduction velocities with age was also in CMT2F (47). Mersiyanova and colleagues

found a Gln333Pro mutation in the neuro�lament light subtype gene on chromosome 8p21

in typical autosomal dominant CMT2 (77).

Prognosis and complications

Life expectancy is normal. Disability is highly variable and di�cult to predict in young

individuals, even among siblings. In general, Charcot-Marie-Tooth disease is a slowly

progressive condition. If progression accelerates, other causes such as acquired neuropathies

or other inherited neuromuscular conditions should be sought (112). O�en, males are

a�ected more than females, possibly due to a greater likelihood of nerve trauma. However, a

study of myelin protein zero regulation by androgens and progesterone derivatives suggests a

possible genetic course of this gender di�erence (66; 75). Rare complications include

radiculopathies due to enlarged nerve roots.

Clinical vigne�e

Two patients, father and son, from a CMT1B pedigree presented with slowly progressive

weakness since childhood, a�ecting the arms more than the legs, and numbness in the hands

and feet (113). They denied recurrent focal weakness, liability to pressure palsies, or pain.

Multiple living male and female relatives from 4 generations were a�ected. They carried a

codon 96 mutation that substituted a positively charged lysine for a negatively charged

glutamate in the extracellular region (44; 110).

Findings were similar in father and son, but more pronounced in the former. Both had pes

cavus. The father had enlarged, �rm, peripheral nerves. Muscle strength was reduced to 4/5,

worse distally. Deep tendon re�exes were absent. Plantar responses were �exor. All sensory

modalities were impaired.

Laboratory and electrophysiological studies in the father revealed normal B12, folate, and

lead levels, negative myelin-associated glycoprotein and GM1 antibody titers, and serum

protein electrophoresis.

No sensory or motor responses were obtained with surface recordings. Needle examination

of the le� median nerve revealed motor nerve conduction velocities of 11 m/s (lower normal

value is 49 m/s), and a compound motor action potential amplitude of 0.3 mV (lower normal

value is 5 mV). Sensory responses and F waves were absent. Electromyography revealed

minimal spontaneous activity with high amplitude motor unit potentials.

Sural nerve biopsy �ndings were similar in father and son. Semithin cross-sections of nerve

showed a reduction of myelinated �ber density. Many remaining �bers had thin myelin

sheaths. Frequent small onion bulbs and scattered tomacula were found.

The myelinated �ber density was 250/mm2 in the father and 3147/mm2 in the son.

Histometric measurements showed a unimodal distribution of myelinated �bers with a shi�

of the peak to diameters between 1 and 4 µm in the father and a bimodal distribution with 1

peak between 1 and 4 µm and a second peak at 6 µm in the son. Most of the �bers larger

than 5 µm in diameter had tomacula.

Teased �bers and longitudinal semithin sections revealed sausage-shaped expansions of

myelin located in both the paranodal and internodal regions in virtually all �bers. Segmental

remyelination was found in all teased myelinated nerve �bers.

Tomacula in Charcot-Marie-Tooth disease type 1B (light microscopical appearance)(A) Semithin cross-section shows a marked depletion of myelinated nerve �bers.

Sca�ered onion bulbs consist of concentrically arranged Schwann cell processes (arrowheads), some without a central myelinated �ber. Several myelin...

Ultrathin sections demonstrated that the tomacula consisted of closely apposed, redundant

loops of myelin sheath wound around or layered on 1 side of a thinly myelinated �ber.

Tomacula in Charcot-Marie-Tooth disease type 1B (electron microscopy)Ultrastructure of a representative tomaculum. A redundant fold of myelin is wrappednearly twice around the axon. The membranes of this fold are compacted about the

original myelin sheath (19 lamellae) to form a hypermyelinated st...

Incorporation of the altered myelin protein zero into the myelin sheath was demonstrated

immunohistochemically.

Tomacula in Charcot-Marie-Tooth disease type 1B (immunohistochemical appearance)Sural nerve, indirect immuno�uorescence. Cryosections were incubated with a rabbit

polyclonal antiserum to myelin protein zero, followed by a Texas red-conjugated antibodyto rabbit IgG. The antigen is expressed on myelin sheaths...

Biological basis

Etiology and pathogenesis

Multiple di�ering mutations in the myelin protein zero gene, located in the q21.3-q22 region

on chromosome 1, have been identi�ed in families with inherited motor sensory

neuropathies. Clinical phenotypes include CMT1B, Dejerine-Sottas syndrome, congenital

hypomyelination, and surprisingly also CMT2. Some 55 point mutations in di�erent exons

have been identi�ed. These clusters are in exons 2 and 3, with some in exons 4 and 6 (84).

Protein structure. Myelin protein zero is an integral type I membrane protein of compact

peripheral nerve myelin, where it constitutes more than 50% of total protein and links

adjacent lamellae and stabilizes the myelin assembly. Expression in the CNS of mutated

protein might be responsible for features such as dysphagia and deafness (19; 73; 99). Its

gene spans about 7 kb of DNA, is composed of 6 exons, and encodes a protein of 219 amino

acids (248 with exon 1, the signal peptide) with an apparent molecular weight of 28 kd. It

contains a highly basic intracellular domain (exons 5 and 6, amino acid residues 151 to 219),

a single membrane-spanning domain (exon 4, residues 125 to 150), and an extracellular

domain (exons 2 and 3, residues 1 to 124) that resembles the immunoglobulin VH domain in

length and predicted secondary structure and carries the L2/HNK-1 carbohydrate epitope, a

mediator of membrane adhesion. Myelin protein zero is, thus, a member of the

immunoglobulin supergene family and a cell adhesion molecule, but also has homology to

the human sodium channel beta-1 subunit. Posttranslational modi�cations include acylation

at Cys153, serine/threonine and developmentally regulated tyrosine phosphorylation,

sulfation, N-glycosylation at Asp122 in exon 3, which is required for myelin adhesion, and a

Cys21-Cys127 disul�de bond in the immunoglobulin domain.

Structure of myelin protein zeroMyelin protein zero relative to the myelin membrane. Characteristic mutations are

indicated. (Contributed by Dr. Florian Thomas.)

As a homophilic tetrameric adhesion molecule, its extracellular domain adheres to the

corresponding domains of myelin protein zero molecules on apposing membranes through

hydrogen bonds and polar interactions and, thus, contributes to myelin compaction and

formation of the interperiod (minor dense) line seen by electron microscopy. However,

colocalization of myelin protein zero and peripheral myelin protein 22 in compact myelin

and the presence of the L2/HNK-1 carbohydrate epitope on peripheral myelin protein 22

suggest that these 2 molecules may also interact in a heterophilic interaction. In vitro,

complex formation in the myelin membrane of myelin protein zero and peripheral myelin

protein 22 was demonstrated (29). The basic cytoplasmic domain interacts through its

positive charge with negatively charged head groups of membrane phospholipids, thereby

linking apposed membrane surfaces and contributing to the formation of the major dense line

of myelin. It undergoes phosphorylation and dephosphorylation on serine/threonine and

tyrosine residues and, thus, participates in signal transduction.

Human mutations. Over 100 mutations in myelin protein zero have been detected and

correlated with clinical phenotypes that include CMT1B, CMT2, Dejerine-Sottas

syndrome, and congenital hypomyelination neuropathy (84). More than half are missense,

the rest nonsense, frameshi�, deletion, or insertion mutations. The vast majority are in exons

2 and 3 of the extracellular domain, where they can disturb myelin compaction. Others are

in the transmembrane (exon 4) or cytoplasmic (exons 5 and 6) domains or its margins. Some

mutations are associated with particular clinical, electrophysiological, and histological

phenotypes. Two conservative polymorphisms exist at Gly200 and Ser228 in exons 5 and 6

in the intracellular domain.

Structure of myelin protein zeroMyelin protein zero relative to the myelin membrane. Characteristic mutations are

indicated. (Contributed by Dr. Florian Thomas.)

Most mutations are associated with typical CMT1B phenotypes. Most are single amino-acid

substitutions in exons 2 and 3 of the extracellular domain. Copy number mutations can also

cause CMT1B demyelinating phenotype (46; 65). Some are single amino-acid deletions or

mutations resulting in a truncated myelin protein zero (Gly74 frame shi�, stop codon at

codons 53, 125, and 152). A Ser34 deletion resulted in absent myelin protein zero protein, as

did a Gly24 frameshi� mutation, which caused CMT1B in heterozygous parents and

Dejerine-Sottas syndrome in their children. A mild late-onset phenotype with nerve

conduction velocities of 32 m/s resulted from an Asp122Glu substitution, which eliminates

the crucial N-glycosylation site (09). Mild phenotypes were associated with Ser63del (78)

and c.160_167delTCCCGGGT mutations (21). Roussy-Levy syndrome is associated with

a heterozygous Asn131Lys substitution in the extracellular domain of myelin protein zero

(90). Steroid-responsive CMT1B was reported with a Ile99Thr substitution in exon 3 of the

extracellular domain (28). There is additional evidence that patients with CMT1B as well as

other CMT forms may be also more prone to immune-mediated neuropathies. A patient

with subclinical neuropathy and a de novo heterozygous null mutation (p.Tyr68Ter) became

symptomatic due to superimposed chronic in�ammatory demyelinating polyneuropathy and

improved with immunoglobulin therapy (15). CIDP-like characteristics were also described

with a p.Ser63del mutation (35). Mild recurrent CMT1B with an exon 3 Glu71stop

mutation that may reduce the amount of myelin protein zero was associated with sensitivity

to intense manual work, demyelination and remyelination, axonal loss, and myelin

uncompaction (59). A double mutation with a de novo extracellular Val42 deletion and an

intracellular Ala221Thr substitution were both found in a 25-year-old woman with a

progressive neuropathy since the age of 2 years. Her father had 2 normal alleles, whereas her

mother had the Ala221Thr substitution (91). A CMT2 phenotype was associated with 3

myelin protein zero mutations: (1) Ile89Asn, (2) Val92Met, and (3) Ile162Met (10). A

mixed demyelinating and axonal neuropathy, pes cavus, and pupillary light-near dissociation

were associated with myelin protein zero mutations His81Arg and Val113Phe on the same

allele (06); the phenotype was less severe than in 2 instances of isolated His81Arg mutations

(105). Although these 2 amino acids are not close together in 3-dimensional models, an

interaction between them cannot be excluded. Pupillary abnormalities have also been

reported with Thr124Met and Asp75Val mutations (06).

The mechanism underlying expression of a predominantly axonal versus a predominantly

demyelinating mutation for a given myelin protein zero mutation is unclear, but defective

myelin or myelin-axon interactions are the likely causes for both (10; 43). Skin biopsy

analysis in a family with minimally slowed nerve conduction velocities and a mutation that

abolishes a 5' donor site recognition in intron 4 revealed normal myelin protein zero levels

but loss of the myelin protein zero transmembranous exon 4 and a frame-shi�ed cytoplasmic

domain, which is expected to abolish homotypic adhesion (98). An autopsy study of a case

of late-onset neuropathy with a His10Pro myelin protein zero mutation revealed axonal loss,

axolemmal reorganization, and focal nerve enlargements with myelin protein zero and

ubiquitin deposits in the inner myelin and periaxonal spaces with minimal demyelination

(63).

Rare mutations are associated with central nervous system or cranial nerve

manifestations. Thr124Met and Asp75Val mutations were found in families with variable

combinations of a CMT2 phenotype, dysphagia, deafness, or pupillary abnormalities (19;

24; 79). Indirect support for a pathogenic role of such mutations comes from a myelin protein

immunization study that resulted in deafness in experimental mice (73). An exon 3

Arg81His mutation in the extracellular domain was found in a girl with severe CMT1B or

Dejerine-Sottas syndrome, thickened trigeminal nerves, and prolonged conduction times

from the eighth cranial nerve to the pontomedullary portions of the auditory pathway (105).

A His39Pro myelin protein zero mutation in the extracellular domain was linked to

premature hearing loss and restless leg symptoms (52). Reyes-Marin and colleagues reported

a homozygous mutation leading to late-onset demyelinating phenotype with brain white

matter lesions (95).

Some mutations are associated with severe phenotypes. In general, myelin protein zero

mutations in the transmembrane domain are associated with more severe phenotypes.

However, a G1064C/Gly163Arg mutation was linked to a mild phenotype (32).

Substitutions such as Cys63Ser, Ser34Cys, Arg69Cys, and Trp72Cys in exons 2 and 3 of

the extracellular domain are associated with particularly severe manifestations. Dejerine-

Sottas syndrome has been linked to a Ser34Cys substitution, which can lead to free thiol

group and disul�de aggregates and may act as dominant negative, thus, inactivating normal

myelin protein zero expressed from the other allele. Not surprisingly, Dejerine-Sottas

syndrome is also seen in the homozygous children of parents with CMT1B and heterozygous

Gly74 frame shi� or Phe35 deletion mutations. A Gln,Pro,Tyr,Ile86-89His,Leu,Phe

substitution in exon 3 that could greatly alter protein structure was detected in another

patient with Dejerine-Sottas syndrome (107). A severe demyelinating phenotype was

associated with a missense mutation, D32N, that resulted in a new glycosylation sequence

and a hyperglycosylated protein with partial retention in the Golgi apparatus and disrupted

intercellular adhesion (92).

Dejerine-Sottas syndrome or congenital hypomyelination neuropathy also occurs with

mutations in exon 4 of the cytoplasmic domain and exons 5 or 6 of the transmembrane

domain or its margins, resulting in substitutions, frame-shi�s, or stop codons: Gly167Arg,

Leu145frame shi�, Ala192frame shi�, Gln186stop, Val203frame shi�. An Ala221 insertion

that causes Dejerine-Sottas syndrome disrupts a tyrosine phosphatase recruitment site at the

C terminus; this is evidence of the importance of signal transduction properties of myelin

protein zero (125). However, intracellular truncation mutations are not inevitably associated

with a severe phenotype, as evidenced by a family with a heterozygous Gly206stop mutation

leading to removal of four ��hs of the protein constituting the intracellular domain. Despite

this truncation, no a�ected relatives had Dejerine-Sottas syndrome or other severe

phenotypes; intrafamilial variability was marked with 1 family member displaying only pes

cavus and conduction slowing and another displaying only hammertoes (103). The authors

suggested that the ability of the mutated protein to form intracellular tetramers with other

myelin protein zero would determine the severity of the phenotype. This interaction might

be impossible with large truncations, thus, allowing the unmutated protein expressed from

the other allele to establish normal protein complexes, whereas smaller truncations would

connect to other proteins and have a dominant negative e�ect. Alternatively, mRNA from

the mutated allele could be unstable and decay.

Mutations associated with Charcot-Marie-Tooth disease type 1-Charcot-Marie-Tooth

disease type 2 overlap syndromes. Reports indicate that myelin protein zero mutations are

associated not only with predominantly demyelinating CMT1-like neuropathies, but also

with axonal CMT2-like neuropathies. A Thr124Met mutation in the extracellular domain

and close to the Asp122 glycosylation site and the Cys127 involved in a disul�de bridge was

detected in several reports. De Jonghe and colleagues reported families with a dominantly

inherited neuropathy initially classi�ed as CMT2 with late-onset weakness, marked sensory

abnormalities, occasional deafness, and pupillary abnormalities (24). Most patients have at

least 1 nerve conduction velocity greater than 38 m/s. Although demyelinating features were

found in biopsies, axonal degeneration was also prominent, as were tomacula. Several

CMT2-like families carry this or mutations such as Asp75Val, Ala76Val, Val113IIe,

Tyr119Cys, or Asp61Gly (123; 70; 102; 79; 83).

A Ser44Phe mutation in the extracellular domain was detected in a CMT2 family with

nerve conduction velocities greater than 42 m/s (70). A family with nerve conduction

velocities greater than 38 m/s and frameshi� mutation due to 1 bp deletion at codon 102

leading to myelin protein zero truncation was reported. Heterozygous o�spring had a

CMT2-like phenotype, whereas homozygous o�spring had Dejerine-Sottas syndrome (111;

119; 87). Axonal features in these cases might result from mutations that a�ect axon-myelin

interactions more than myelin compaction (121; 111). An intracytoplasmic domain

Lys236del mutation associated with variable penetrance was reported ranging from

asymptomatic to foot deformities and nonuniform intermediate range conduction velocities

(109). Velocities were normal in a 15-year-old clinically a�ected girl, suggesting age-

dependent progressive slowing.

Dominant negative e�ects. In part, the e�ect of a heterozygous myelin protein zero

mutation is explained by a 50% reduction in functional gene dosage. However, the clinical,

electrophysiologic, and histological di�erences between patients harboring di�erent

mutations may additionally be due to various consequences of particular mutations on the

interaction of abnormal with normal myelin protein zero units in the tetramer and with other

cellular proteins. Abnormal protein would, therefore, exert a dominant negative e�ect, thus,

reducing the amount of functional myelin protein zero to under 50% and causing a more

severe phenotype. Without this dominant negative e�ect, a milder form of CMT1B would

result.

Experimental systems. Both in vitro and in vivo models con�rm and expand the

phenotype-genotype correlations from human studies. Cell culture studies show that

mutated myelin protein zero di�ers from wild-type protein in adhesiveness and complex

formation. Coexpression of wild-type and mutated myelin protein zero con�rms that the

biological consequences of speci�c mutations vary: some mutations inactivate wild-type

protein, whereas others do not. This fact may provide an explanation of variation between

families. In Schwann cell cultures, glucocorticoids stimulate (directly or indirectly) the

activity of both the myelin protein zero and PMP22 gene promoters; this may explain the

bene�t of steroids in some cases of CMT1 in particular, and in immune mediated neurologic

conditions in general (27). Schwann cells from myelin protein zero knockout mice

downregulate PMP22 and upregulate myelin associate glycoprotein and proteolipid protein;

mistargeting of these and other proteins to inappropriate cellular compartments and

dysregulation of other adhesion molecules also occur, indicating that myelin protein zero is

involved in the regulation of myelin gene expression (125). Overexpressed myelin protein

zero also leads to its mistargeting and myelination arrest (126). An in vitro study of an exon 2

Ile62Phe mutation, which in humans causes irregular myelin folding (82), revealed abnormal

cell aggregation relative to other mutations and wild-type myelin protein zero, suggesting

that this protein domain is crucial for normal myelin adhesion and compaction (74).

Mice homozygous for a myelin protein zero deletion develop severe hypomyelination with

prolonged distal motor latencies, clinical and electrical neuromyotonia, and reduced nerve

conduction velocities (71; 76; 129). Reduced axon diameter, distal axon loss, and myelin

uncompaction are found. Many other myelin proteins are reduced or show altered

intracellular distribution. This phenotype resembles that of congenital hypomyelination

neuropathy or Dejerine-Sottas syndrome. Mice heterozygous for a myelin protein zero

deletion are normal at birth but, similar to CMT1B, later develop impaired nerve

conduction, neuromyotonia, demyelination, and onion bulbs. They also display a severe age-

dependent disturbance in the expression and localization of other myelin proteins. Mice

engineered to carry myelin protein zero mutations resulting in congenital hypomyelination

neuropathy (S63C and S63del) developed a syndrome mimicking the human disease.

Genetic analysis indicated that pathologic changes arose from a gain-of-function e�ect

(124).

In addition, Cx32 and myelin protein zero de�cient mice exhibit similar immunopathogenic

mechanisms with immune mediated demyelination (16; 54). In myelin protein zero de�cient

mice, T-lymphocytes and macrophages are increased in demyelinating nerves (16),

suggesting that immune-mediated demyelination may play an important role in hereditary

neuropathies. A role for autoimmunity in CMT1B is also suggested by cases that respond to

steroids, immunoglobulin, and immunosuppression (122; 101).

Epidemiology

Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. An exhaustive

study from Norway indicated a prevalence of 1 in 2500 (108), whereas a worldwide

metaanalysis estimated a prevalence of 1 in 10,000 (33). CMT1 accounts for about two

thirds of cases and CMT2 for about one third, whereas other forms are rare. CMT1B

patients contribute 5% to 10% of the cases with an identi�ed genotype, and its prevalence is

estimated at 1 in 30,000 (86). De novo mutations have been described. CMT1B has been

reported in an African family (48).

Prevention

Preventive measures focus on awareness and avoidance of intercurrent medical problems or

interventions that can lead to systemic or focal neuropathies, such as diabetes mellitus,

hypothyroidism, vitamin de�ciencies, neurotoxic drugs, carpal tunnel syndrome, and

prolonged immobilization of limbs during surgery.

Di�erential diagnosis

The di�erential diagnosis for CMT1B includes CMT1A, CMTX, CMT2, Dejerine-Sottas

syndrome, congenital hypomyelination neuropathy, and associated acquired neuropathies.

Diagnostic workup

The purpose of studies in patients with a possible inherited neuropathy is to con�rm or refute

this working diagnosis and to ascertain the presence of a treatable neuropathy, which might

be the sole condition or a superimposed condition. This workup should include tests that

address causes of neuropathies such as endocrine, infectious, and immunological

abnormalities, vitamin and nutritional de�ciencies, and nerve compression.

Spinal �uid analysis. Although lumbar puncture is rarely indicated, protein levels are

usually normal in patients with CMT1B but may be elevated above 100 mg/dL. By contrast,

it is elevated in most but not all cases of Dejerine-Sottas syndrome. In a comparison of

CMT1A, CMT1B, and CMTX CSF protein (and CK), elevations were more common with

myelin protein zero mutations (43).

Genetic testing. Patients in whom the clinical phenotype, family history, or

electrodiagnostic studies suggest that they might have an inherited neuropathy should be

genotyped. This is important because clinical exam and electrodiagnostic studies o�en

cannot de�nitively establish a precise diagnosis due to the overlap between clinical

syndromes and the signi�cant variability between family members with an identical

genotype. Genotyping permits sound genetic and prognostic counseling and advances the

scienti�c understanding of phenotypes. The importance of genetic testing was illustrated by

the report of 2 sisters with severe CMT1 and healthy parents, for whom autosomal recessive

inheritance had been presumed, until genetic testing identi�ed low-level somatic and

germline mosaicism of a myelin protein zero extracellular domain Gly74Glu mutation in the

healthy mother, which she transmitted to her a�ected daughters (37).

Electrodiagnostic studies. Compared with acquired neuropathies, CMT1 is typically

characterized by di�use and uniform conduction slowing. Because nerve conduction is stable

and secure in contradistinction to acute or chronic in�ammatory demyelinating

polyradiculoneuropathies, conduction block and dispersion are rare. Conduction values are

symmetric, and there are few di�erences between proximal and distal nerve segments.

Nerves o�en are refractory to stimulation or require higher amplitude and prolonged

stimulation.

Nerve conduction velocities have limited diagnostic value among patients with inherited

neuropathies because of the extreme range. In a study of a single CMT1B pedigree, nerve

conduction velocities were signi�cantly slower than in CMT1A patients (07), whereas in a

comparison of 119 CMT1A patients with 10 CMT1B patients, no di�erences were found

(08). Because of the rarity of CMT1B relative to CMT1A, such studies are di�cult to assess

and may re�ect particular characteristics of single myelin protein zero mutations. Among

CMT1A patients, median nerve conduction velocities varied by 30 m/s (with a range from

10 to 42 m/s) within families by 20 m/s and by 10 m/s among siblings (34). The variability

among CMT1B patients may be more limited, but patients with myelin protein zero

mutations, a CMT2-like phenotype, and nerve conduction velocities in the normal or

intermediate range have been reported (123; 70; 100; 19; 72). A study of 205 Charcot-

Marie-Tooth disease patients with PMP22, myelin protein zero, and Cx32 mutations

demonstrated that depending on the speci�c myelin protein zero mutation, CMT1B can

present with phenotypes that do not overlap within families: (1) pure axonal features with

preserved conduction velocities, and (2) exclusively demyelinating changes; sensorineural

deafness, Adie pupil, and CK elevations were more prevalent in the axonal group (43).

A�er the peripheral nerves reach their mature state in early childhood, nerve conduction

velocities in Charcot-Marie-Tooth disease patients change little during life, even as disease

manifestations progress. Thus, they do not correlate with severity. However, patients with

extremely slow nerve conduction speeds are likely to have a more severe phenotype. There is

some debate about the relationship between speci�c mutations and patterns of conduction

slowing (61). Late onset axonal neuropathy due to myelin protein zero mutation has been

reported in a patient who was initially thought to have amyloid neuropathy (14). Despite

the presence of mild macroglossia and positive changes on abdominal fat biopsy, the lack of

autonomic changes and other systemic features led to the correct genetic diagnosis.

Imaging studies. Patients with CMT1B have larger median and vagus nerves than controls

(17). Cranial nerve size did not di�er between patients with and without cranial

neuropathies. Lower limb MRI assesses the fat fraction in di�erent muscles and is a marker

of disease progression (80). Whole-body neurography can demonstrate plexus and nerve

thickening (22).

Neuropathologic studies. Most nerve biopsies from CMT1B patients show evidence of a

hypertrophic demyelinating neuropathy with onion bulbs as evidence of chronic

remyelination and loss of myelinated �bers, preferentially those of large diameter (30; 42).

Two autopsies have been reported. One study revealed hypertrophy and endoneurial �brosis

in peripheral and spinal nerves (07). The other, of a patient with His10Pro mutation, showed

prominent axonal pathology including focal axonal enlargements and thin myelin but not

segmental demyelination; there was also disorganization of paranodal expression of

molecules involved in axon-glia interaction and of potassium channels (64).

As stated above, a link between speci�c myelin protein zero mutations and axonal versus

demyelinating pathology was established in 11 sural nerve biopsies (43), further con�rming

the particular properties and potential for disruption of normal nerve metabolism of myelin

protein zero domains. Thomas and colleagues �rst described prominent tomacula in 2

CMT1B patients from a family with a Lys96Glu mutation (113). The association of

tomacula or focally folded myelin with myelin protein zero mutations has since been

con�rmed for extracellular domain (exons 2 or 3) substitutions such as Ser49Leu, Lys96Glu,

Lys101Arg, Lys130Arg, lle135Leu, Ile106Leu, and Asp109Asn, whereas uncompacted

myelin shape was found in 23% to 68% of �bers with mutations that include Thr4Ile,

Arg69Cys, Arg69His, Asn131Lys, and Ser34 deletion (40; 58; 82; 38; 74; 55). Patients with

mutations in the intracellular domain (exons 5 and 6) and in the exon 4 transmembrane

domain (Gln186stop) or its margins showed severe hypomyelination and myelin

uncompaction. A link was demonstrated between particular extracellular domain mutations

and ultrastructural phenotypes. One study reported widening or irregularity of the

extracellular apposition alone with a Ser34 deletion and a Arg69Cys mutation, widening at

the extracellular and cytoplasmic appositions with a Arg69His mutation, the presence of

focal bridges in the widened extracellular space with a Arg69His mutation, and diminished

(Arg69Cys) or absent (Arg69His) staining of the double intraperiod line (53). Surprisingly,

not only typical demyelination and remyelination, but also intracellular myelin

uncompaction at the major dense line, was associated with an exon 3 Arg98Cys mutation in

the extracellular domain in a patient with delayed motor development, typical Charcot-

Marie-Tooth disease as an adult, and nerve conduction velocities less than 10 m/s (56); the

same mutation was detected in a severely a�ected infant who died at 22 months (40).

Mutational introduction of cysteine residues is likely to compromise the correct disul�de

bond and, thus, protein structure.

It should be noted that tomaculous neuropathy is also a hallmark of hereditary neuropathy,

with liability to pressure palsy resulting from a 1.5 MB deletion at chromosome 17p11.2 and

rare peripheral myelin protein 22 nonsense mutations. Furthermore, Bolino and colleagues

linked autosomal recessive CMT4B with focally folded myelin sheaths to several mutations

in a signal transduction gene, MTMR2, resulting in lack of functional protein and possibly in

constitutive phosphorylation of an unknown substrate and myelin overgrowth (12).

Tomaculum formation and myelin uncompaction were also reported in CMT1A with a

peripheral myelin protein 22 Asp37Val substitution in the �rst extracellular loop of the

PMP22 protein, which may contribute to a heterophilic interaction with P0 (36); we had

suggested that myelin protein zero and peripheral myelin protein 22 act in parallel or have

di�erent roles along 1 functional pathway (113). This is supported by the demonstration that

myelin protein zero and peripheral myelin protein 22 form complexes in the myelin

membrane in vitro (29).

Dejerine-Sottas syndrome and congenital hypomyelination neuropathy are characterized by

more severe hypo- and demyelination and axonal loss.

Management

It is particularly important to prevent, look for, and treat acquired neuropathies as well as to

avoid compression neuropathies. This may require adjustments in lifestyle and avoidance of

job-related nerve injury.

Neurotoxic drugs. Patients, family members, and physicians need to be aware of drugs that

can a�ect the peripheral nervous system. Drugs with various degrees of nerve toxicity

include the following:

De�nite high risk

• Vincristine

Moderate to signi�cant risk

• Amiodarone

• Bortezomib

• Cisplatin, Oxaliplatin

• Colchicine

• Dapsone

• Dichloroacetate

• Didanosine (ddI)

• Disul�ram

• Gold salts

• Metronidazole (extended use)

• Misonidazole (extended use)

• Nitrofurantoin

• Nitrous oxide

• Perhexiline (not used in the United States)

• Pyridoxine (Vitamin B6) (high doses)

• Stavudine (d4T)

• Suramin

• Taxols (Paclitaxel)

• Thalidomide

• Zalcitabine (ddC)

Uncertain or minor risk

• 5-Fluorouracil

• Adriamycin

• Almitrine (not in the United States)

• Chloroquine

• Cytarabine

• Ethambutol

• Etoposide (VP-16)

• Fluoroquinolone

• Gemcitabine

• Griseofulvine

• Hexamethylmelamine

• Hydralazine

• Ifosfamide

• Isoniazid

• Me�oquine

• Penicillamine

• Phenytoin

• Podophyllin

• Sertraline

• Statins

• Tacrolimus

• Zimeldine (not in the United States)

• Interferon

Nutritional and vitamin de�ciencies. Patients should maintain a well-balanced diet and

avoid obesity, which can contribute to spinal root disease and certain entrapment

neuropathies (meralgia paresthetica).

Physical therapy and prosthetics. Physical therapy is o�en required to prevent and treat

joint deformities.

Prosthetic devices such as ankle-foot orthoses can prevent Achilles tendon shortening and

extend near normal ambulation. At times, boots can delay the need for such ankle braces.

Thick-handle tools and cutlery can render certain activities of daily living easier.

Pain. Pain may result from joint deformities or compensatory overuse of certain muscle

groups. Some types of pain may respond to nonsteroidal antiin�ammatory drugs. Dysesthetic

pain may occur but is not typical; it responds to antidepressants such as amitriptyline,

desipramine, or paroxetine and to anticonvulsants such as gabapentin or carbamazepine.

Surgery. Depending on the degree of foot deformities, patients may bene�t from Achilles

tendon lengthening, tendon transfers, hammertoe correction, and release of the plantar

fascia.

Negligible or doubtful risk

• Allopurinol

• Amitriptyline

• Chloramphenicol

• Chlorprothixene

• Cimetidine

• Clioquinol

• Clo�bratel

• Cyclosporin A

• Enalapril

• Glutethimide

• Lithium

• Phenelzine

• Propafenone

• Sulfonamides

• Sulfasalazine

Experimental therapy. Introduction of recombinant DNA encoding normal myelin protein

zero into the nerves of myelin protein zero knock-out mice is being investigated as a

therapeutic strategy. Another approach explores neurotrophin gene transfer into the spinal

cord to prevent secondary axonal changes in models of Charcot-Marie-Tooth disease.

ACE-083, a locally acting muscle therapeutic in the TGF β family that upregulates

contractile muscle protein synthesis, increased muscle mass in a phase 2 trial of patients with

CMT1 and CMTX (114).

Special considerations

Pregnancy

Although no particular complications are associated with pregnant CMT1B patients, many

report faster deterioration during pregnancy, usually but not always with recovery. As with

surgical procedures, prolonged positioning of the body and limbs in particular positions can

result in nerve compression, which could make any underlying neuropathy worse.

Furthermore, due to the variability of clinical manifestations, couples who both have

symptomatic or asymptomatic CMT1B might have homozygous o�spring with Dejerine-

Sottas syndrome or congenital hypomyelination neuropathy.

Anesthesia

As stated above, prolonged body and limb positions can result in nerve compression. More

speci�cally, any regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.

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Authors

Florian P Thomas MD MA PhD MSDr. Thomas of Hackensack University Medical Center, Hackensack Meridian School of Medicine,has received honorariums from Acceleron and Pharnext for consulting work.SEE PROFILE

Francisco de Assis Aquino Gondim MD MSc PhDDr. Gondim of Universidade Federal Ceará, Fortaleza, Brazil, received consulting fees from PTCTherapeutics.SEE PROFILE

Editor

Contributors

Louis H Weimer MDDr. Weimer of Columbia University has received consulting fees from Roche.SEE PROFILE

Former Authors

Gisele Oliveira MD

Patient Pro�le