General Child Neurology
May. 31, 2021
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This article includes discussion of Charcot-Marie-Tooth disease type 1B, CMT1B, hereditary motor and sensory neuropathy 1B, hereditary motor and sensory neuropathy type 1B, HMSN1B, and myelin protein zero. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In the general population approximately 1 in 30,000 individuals suffers 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 specific clinical and histological changes they cause.
• Charcot-Marie-Tooth disease type 1B affects about 1 out of 30,000 individuals in the general population.
• It has an autosomal dominant inheritance pattern.
• 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.
The Charcot-Marie-Tooth disease entity was recognized independently in Great Britain and France (19; 113). 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 (25). A source of confusion was the description of a progressive childhood neuropathy associated with tremor (95), which has been defined genetically (02; 88). Different forms of inheritance were later recognized (01). Since the late 1960s, the clinical and pathological spectrum has been defined, and a classification system based on 7 types of hereditary motor and sensory neuropathy has been introduced including HMSN1 and HMSN2 (29; 40).
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 often less marked, and onset is generally later, although the distinction is difficult 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 deficits 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 (23). 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 (40; 47). 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 classification system also covers hereditary motor neuropathies and hereditary sensory neuropathies and refers to other conditions linked to specific 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 (37; 114; 58) (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 (92). Some 90% of CMT1A cases result from this duplication (86). 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 (83). Moreover, transgenic mice and rats overexpressing PMP22 develop neuropathies resembling CMT1 (102). 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 (17), whereas about 14% to 25% of patients develop hereditary neuropathy with predisposition to pressure palsies due to other PMP22 mutations (84). The deletion includes all markers duplicated in CMT1A. Several nondeletion mutations have been identified, such as nonsense mutations with a stop codon at G183A (Trp61stop) and G372A (Trp124stop); frameshift 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 (60). 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 (87).
The 1990s also saw the identification of other Charcot-Marie-Tooth disease genes, including myelin protein zero for CMT1B and CMT3 (42; 55; 108) 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 (91), and the zinc-finger domain containing transcription factor early growth response 2 gene for congenital hypomyelination neuropathy and CMT1D (118). 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 (84; 117; 24).
Several new disease linkages and genes have been identified, 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 (48); the gene for the phosphatase myotubularin-related protein-2 (MTMR2) on chromosome 11q22 for autosomal recessive CMT4B (12); a cytoskeletal gene, the neurofilament light subtype gene on chromosome 8p21 for CMT2E (75); 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; 22); and the gene involved in axonal organelle transport on chromosome 1p36-35 for CMT2A (126). 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 (45).
Loci with several candidate genes have been identified 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 (49), the other associated with both large fiber loss and regeneration clusters as well as onion bulbs, and uncompacted enlarged myelin lamellae on chromosome 10q24.1-q25.1 (66; 116). A recessively inherited severe form of Charcot-Marie-Tooth disease with intermediate conduction velocities has been linked to chromosome 10q23 (94). Intermediate conduction velocities also occur with myelin protein zero and neurofilament light subtype gene mutations (23).
Overall, some 100 genes are known at present for the different forms of Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease type 1B.
History. 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. Often 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 (104). 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 affected offspring. Other complaints include thin lower legs, clumsiness, and difficulty running. Onset in the first 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 difficulty finding shoes and suffer from painful calluses. Complaints of cold feet often 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 suffer 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 difficult. Not infrequently, asymptomatic individuals are detected during screening of families after 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 different mutations, eg, periodic paralysis due to SCN4A mutation and CMT1B (43), or CMT1A and McArdle disease (110). 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 (65). 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 (99). Hypertrophic caudal nerve roots can lead to cauda equina syndrome requiring surgical decompression (115). Arm monoplegia mimicking focal chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy have been described in a child with a de novo heterozygous MPZ mutation (125). Nerve biopsy did not reveal inflammation; focally folded myelin sheaths led to the diagnosis of CMT1B.
Physical findings. Cranial neuropathies are rare, but several instances of pupillary abnormalities including light near dissociation have been reported (06). Distally dominant weakness and muscle atrophy affect 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. Reflexes are absent or depressed. Foot deformities include high arches or flat feet, hammer toes, and tight Achilles’ tendons. Foot deformities become more prevalent with age but are variable even among relatives of the same age (29). Gait is compromised by distal weakness, position sense, or foot deformities. Enlarged and excessively firm nerves are found in over 25% of patients, often visible in the superficial 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 (95; 88). Steroid responsive forms of Charcot-Marie-Tooth disease have been recognized (30); this finding has also been reported for CMT1B (27). A phenotype with tonic pupils and conduction block was described in a patient with a p.Ile112Thr mutation in myelin protein zero (79).
Disability. Disability may vary greatly between family members, ranging from asymptomatic individuals with minimal findings 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 fingers. Significant phenotypic differences may exist among monozygotic twins, suggesting phenotypic modulation of myelin protein zero mutations by external, nongenetic influences (67). Whether disability is greater in CMT1B or CMT1A remains controversial, possibly due in part to the smaller number of CMT1B patients available for comparison (29; 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 (110).
Genetic studies suggest that a phenotypic classification system cannot be strictly applied because mutations in the same gene can cause different 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 difficult 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, areflexia, 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 offspring 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 (68; 18; 23; 100; 77; 39; 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 (23; 39). Incidentally, a slight decrease in conduction velocities with age was also in CMT2F (45). Mersiyanova and colleagues found a Gln333Pro mutation in the neurofilament light subtype gene on chromosome 8p21 in typical autosomal dominant CMT2 (75).
Life expectancy is normal. Disability is highly variable and difficult 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 (110). Often, males are affected 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 difference (64; 73). Rare complications include radiculopathies due to enlarged nerve roots.
Two patients, father and son, from a CMT1B pedigree presented with slowly progressive weakness since childhood, affecting the arms more than the legs, and numbness in the hands and feet (111). They denied recurrent focal weakness, liability to pressure palsies, or pain. Multiple living male and female relatives from 4 generations were affected. They carried a codon 96 mutation that substituted a positively charged lysine for a negatively charged glutamate in the extracellular region (42; 108).
Findings were similar in father and son, but more pronounced in the former. Both had pes cavus. The father had enlarged, firm, peripheral nerves. Muscle strength was reduced to 4/5, worse distally. Deep tendon reflexes were absent. Plantar responses were flexor. 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 left 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 findings were similar in father and son. Semithin cross-sections of nerve showed a reduction of myelinated fiber density. Many remaining fibers had thin myelin sheaths. Frequent small onion bulbs and scattered tomacula were found.
The myelinated fiber density was 250/mm2 in the father and 3147/mm2 in the son. Histometric measurements showed a unimodal distribution of myelinated fibers with a shift 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 fibers larger than 5 µm in diameter had tomacula.
Teased fibers and longitudinal semithin sections revealed sausage-shaped expansions of myelin located in both the paranodal and internodal regions in virtually all fibers.
Segmental remyelination was found in all teased myelinated nerve fibers.
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 fiber.
Incorporation of the altered myelin protein zero into the myelin sheath was demonstrated immunohistochemically.
Multiple differing mutations in the myelin protein zero gene, located in the q21.3-q22 region on chromosome 1, have been identified 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 different exons have been identified. These clusters are in exons 2 and 3, with some in exons 4 and 6 (82).
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 (18; 71; 97). 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 modifications 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 disulfide bond in the immunoglobulin domain.
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 (28). 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 (82). More than half are missense, the rest nonsense, frameshift, 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.
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 (44; 63). Some are single amino-acid deletions or mutations resulting in a truncated myelin protein zero (Gly74 frame shift, stop codon at codons 53, 125, and 152). A Ser34 deletion resulted in absent myelin protein zero protein, as did a Gly24 frameshift 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 (76) and c.160_167delTCCCGGGT mutations (20). Roussy-Levy syndrome is associated with a heterozygous Asn131Lys substitution in the extracellular domain of myelin protein zero (88). Steroid-responsive CMT1B was reported with a Ile99Thr substitution in exon 3 of the extracellular domain (27). 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 (57). 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 (89). 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 (Sorour et al 1997; 103). 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; 41). 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-shifted cytoplasmic domain, which is expected to abolish homotypic adhesion (96). 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 (61).
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 (18; 23; 77). Indirect support for a pathogenic role of such mutations comes from a myelin protein immunization study that resulted in deafness in experimental mice (71). 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 (103). A His39Pro myelin protein zero mutation in the extracellular domain was linked to premature hearing loss and restless leg symptoms (50). Reyes-Marin and colleagues reported a homozygous mutation leading to late-onset demyelinating phenotype with brain white matter lesions (93).
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 (31). 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 disulfide 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 shift 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 (105). 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 (90).
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-shifts, or stop codons: Gly167Arg, Leu145frame shift, Ala192frame shift, Gln186stop, Val203frame shift. 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 (123). 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 fifths of the protein constituting the intracellular domain. Despite this truncation, no affected 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 (101). 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 effect. 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 disulfide bridge was detected in several reports. De Jonghe and colleagues reported families with a dominantly inherited neuropathy initially classified as CMT2 with late-onset weakness, marked sensory abnormalities, occasional deafness, and pupillary abnormalities (23). 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 (121; 68; 100; 77; 81).
A Ser44Phe mutation in the extracellular domain was detected in a CMT2 family with nerve conduction velocities greater than 42 m/s (68). A family with nerve conduction velocities greater than 38 m/s and frameshift mutation due to 1 bp deletion at codon 102 leading to myelin protein zero truncation was reported. Heterozygous offspring had a CMT2-like phenotype, whereas homozygous offspring had Dejerine-Sottas syndrome (109; 117; 85). Axonal features in these cases might result from mutations that affect axon-myelin interactions more than myelin compaction (119; 109). An intracytoplasmic domain Lys236del mutation associated with variable penetrance was reported ranging from asymptomatic to foot deformities and nonuniform intermediate range conduction velocities (107). Velocities were normal in a 15-year-old clinically affected girl, suggesting age-dependent progressive slowing.
Dominant negative effects. In part, the effect of a heterozygous myelin protein zero mutation is explained by a 50% reduction in functional gene dosage. However, the clinical, electrophysiologic, and histological differences between patients harboring different 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 effect, thus, reducing the amount of functional myelin protein zero to under 50% and causing a more severe phenotype. Without this dominant negative effect, a milder form of CMT1B would result.
Experimental systems. Both in vitro and in vivo models confirm and expand the phenotype-genotype correlations from human studies. Cell culture studies show that mutated myelin protein zero differs from wild-type protein in adhesiveness and complex formation. Coexpression of wild-type and mutated myelin protein zero confirms that the biological consequences of specific 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 benefit of steroids in some cases of CMT1 in particular, and in immune mediated neurologic conditions in general (26). 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 (123). Overexpressed myelin protein zero also leads to its mistargeting and myelination arrest (124). An in vitro study of an exon 2 Ile62Phe mutation, which in humans causes irregular myelin folding (80), 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 (72).
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 (69; 74; 127). 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 effect (122).
In addition, Cx32 and myelin protein zero deficient mice exhibit similar immunopathogenic mechanisms with immune mediated demyelination (15; 52). In myelin protein zero deficient mice, T-lymphocytes and macrophages are increased in demyelinating nerves (15), 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 (120; 99).
Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. An exhaustive study from Norway indicated a prevalence of 1 in 2500 (106), whereas a worldwide metaanalysis estimated a prevalence of 1 in 10,000 (32). 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 identified genotype, and its prevalence is estimated at 1 in 30,000 (84). De novo mutations have been described. CMT1B has been reported in an African family (46).
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 deficiencies, neurotoxic drugs, carpal tunnel syndrome, and prolonged immobilization of limbs during surgery.
The differential diagnosis for CMT1B includes CMT1A, CMTX, CMT2, Dejerine-Sottas syndrome, congenital hypomyelination neuropathy, and associated acquired neuropathies.
The purpose of studies in patients with a possible inherited neuropathy is to confirm 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 deficiencies, and nerve compression.
Spinal fluid analysis. 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 (41).
Genetic testing. Patients in whom the clinical phenotype, family history, and electrodiagnostic studies suggest that they might have an inherited neuropathy should be genotyped. This is important because clinical exam and electrodiagnostic studies often cannot definitively establish a precise diagnosis due to the overlap between clinical syndromes and the significant variability between family members with an identical genotype. Genotyping permits sound genetic and prognostic counseling and advances the scientific understanding of phenotypes. The importance of genetic testing has been convincingly illustrated by the report of 2 sisters with severe CMT1 and healthy parents, for whom autosomal recessive inheritance had been presumed, until genetic testing identified low-level somatic and germline mosaicism of a myelin protein zero extracellular domain Gly74Glu mutation in the healthy mother, which she transmitted to her affected daughters (35).
Electrodiagnostic studies. Compared with acquired neuropathies, CMT1 is typically characterized by diffuse and uniform conduction slowing. Because nerve conduction is stable and secure in contradistinction to acute or chronic inflammatory demyelinating polyradiculoneuropathies, conduction block and dispersion are rare. Conduction values are symmetric, and there are few differences between proximal and distal nerve segments. Nerves often 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 significantly slower than in CMT1A patients (07), whereas in a comparison of 119 CMT1A patients with 10 CMT1B patients, no differences were found (08). Because of the rarity of CMT1B relative to CMT1A, such studies are difficult to assess and may reflect 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 (33). 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 (121; 68; 98; 18; 70). A study of 205 Charcot-Marie-Tooth disease patients with PMP22, myelin protein zero, and Cx32 mutations demonstrated that depending on the specific 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 (41).
After 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 specific mutations and patterns of conduction slowing (59). 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. Ultrasound is a new tool in the evaluation of neuromuscular conditions. Patients with CMT1B have larger median and vagus nerves than controls (16). Cranial nerve size did not differ between patients with and without cranial neuropathies. Lower limb MRI assesses the fat fraction in different muscles and is a marker of disease progression (78). Whole-body neurography can demonstrate plexus and nerve thickening (21).
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 fibers, preferentially those of large diameter (29; 40). Two autopsies have been reported. One study revealed hypertrophy and endoneurial fibrosis 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 (62).
As stated above, a link between specific myelin protein zero mutations and axonal versus demyelinating pathology was established in 11 sural nerve biopsies (41), further confirming the particular properties and potential for disruption of normal nerve metabolism of myelin protein zero domains. Thomas and colleagues first described prominent tomacula in 2 CMT1B patients from a family with a Lys96Glu mutation (111). The association of tomacula or focally folded myelin with myelin protein zero mutations has since been confirmed 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 fibers with mutations that include Thr4Ile, Arg69Cys, Arg69His, Asn131Lys, and Ser34 deletion (38; 56; 80; 36; 72; 53). 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 (51). 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 (54); the same mutation was detected in a severely affected infant who died at 22 months (38). Mutational introduction of cysteine residues is likely to compromise the correct disulfide 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 first extracellular loop of the PMP22 protein, which may contribute to a heterophilic interaction with P0 (34); we had suggested that myelin protein zero and peripheral myelin protein 22 act in parallel or have different roles along 1 functional pathway (111). This is supported by the demonstration that myelin protein zero and peripheral myelin protein 22 form complexes in the myelin membrane in vitro (28).
Dejerine-Sottas syndrome and congenital hypomyelination neuropathy are characterized by more severe hypo- and demyelination and axonal loss.
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 affect the peripheral nervous system. Drugs with various degrees of nerve toxicity include the following:
Definite high risk
Moderate to significant risk
Uncertain or minor risk
Negligible or doubtful risk
Nutritional and vitamin deficiencies. 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 often 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 antiinflammatory 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 benefit from Achilles tendon lengthening, tendon transfers, hammertoe correction, and release of the plantar fascia.
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 (112).
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 offspring with Dejerine-Sottas syndrome or congenital hypomyelination neuropathy.
As stated above, prolonged body and limb positions can result in nerve compression. More specifically, any regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.
Florian P Thomas MD MA PhD MS
Dr. 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 PhD
Dr. Gondim of Universidade Federal Ceará & Unichristus, Fortaleza, Brazil, received consulting fees from Alnylan.See Profile
Louis H Weimer MD
Dr. Weimer of Columbia University has received consulting fees from Roche.See Profile
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