Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy. It is a pathologically heteroge- neous group of hereditary motor and sensory neuropathies, characterized by slowly progressive weakness and atrophy, pri- marily in the distal leg muscles. The incidence is estimated to be approximately 1 in 2500.
GENETICS/BASIC DEFECTS
1. Charcot-Marie-Tooth disease type 1 (CMT1)
a. Also called hereditary motor and sensory neuropathy type I (HMSN I)
b. The most common subtype (accounting for about 50% of CMT)
c. A demyelinating neuropathy d. Autosomal dominant form
i. CMT1A: caused by a 1.5-Mb tandem duplica- tion of the chromosomal region 17p11.2, which contains the peripheral myelin protein 22 (PMP 22) gene (90% of CMT1 patients)
ii. CMT1B: caused by mutations of the myelin pro- tein zero (MPZ) gene (1q22) (5–10%)
iii. CMT1C: caused by mutations of LITAF gene (16p13.1-p12.3)
iv. CMT1D: caused by mutations of early growth response gene 2 (EGR2) gene (10q21.1-q22.1) 2. Charcot-Marie-Tooth disease type 2 (CMT2)
a. Also called hereditary motor and sensory neuropathy type II (HMSN II)
b. An axonal neuropathy
c. Autosomal dominant inheritance d. Accounting for 20–40% of CMT e. Disease gene loci for CMT2
i. CMT2A: 1p36.2 (KIF1Bβ) ii. ΧΜΤ2Β: 3q21 (RAB7) iii ΧΜΤ2Χ: 12q23-q24 iv. ΧΜΤ2D: 7p15
v. ΧΜΤ2Ε: 8p21 (NEFL)
vi. ΧΜΤ2F: 7q11-21ΧΜΤ2Γ: 3q13.1
3. Intermediate form of autosomal dominant CMT (rare) a. Autosomal dominant inheritance
b. Combination of myelinopathy and axonopathy in individual patients
c. At least two chromosome loci (10q24.1-25 and 19p12-13.2) identified by linkage analysis
4. Autosomal recessive form of CMT (CMT4) (rare) a. CMT4A: The first locus identified: 8q13-q21.1 (cor-
responding gene, GDAP1) b. CMT4B1: 11q22 (MTMR2) c. CMT4B2: 11p15 (CMT4B2) d. CMT4C: 5q32
e. CMT4D: 8q24.3 (NDRG1) f. CMT4E: 10q21.1-q22.1 (EGR2) g. CMT4F: 19q13.1-q13.2 (PRX)
5. X-linked dominant form of CMT (CMT1X)
a. Accounting for 10–20% of CMT (the second most common form of inherited demyelinating neuropathy, next to CMT1A)
b. Caused by mutations in the gene for the gap junction protein 1 (GJB1) or connexin 32 (Cx32) on Xq13.1 c. An identical clinical phenotype caused by mutations
within all regions of the Cx32 gene coding sequence 6. Dejerine-Sottas syndrome (DSS)
a. Also called hereditary motor and sensory neuropathy type III (HMSN III)
b. A severe demyelinating neuropathy
c. Autosomal dominant new mutations (PMP22 muta- tions)
d. Clinical symptoms overlapping with CMT1: these two disorders may represent a spectrum of related clinical phenotypes that can arise from allelic mis- sense point mutations in the PMP22 gene
e. Allelic mutations in the MPZ gene similarly identi- fied in sporadic patients with DSS, also implying that CMT type 1 and DSS constitute a spectrum of periph- eral neuropathy phenotypes with common genetic bases
7. Hereditary neuropathy with liability to pressure palsies (HNPP)
a. Characterized by recurrent episodes of nerve palsies b. Associated with apparent reciprocal deletion of 1.5-Mb
at 17p11.2–p12, which implicates decreased dosage and expression of the PMP22 gene as a possible cause of HNPP
8. Problems in classification of inherited neuropathies a. PMP22 deletion causes HNPP
b. PMP22 duplication causes CMT1A
c. Deletion and duplication of PMP22 causes HNPP and CMT1A, respectively, establishing a singular genetic mechanism as the cause of the two most common inherited neuropathies
d. PMP22 mutations cause DSS, CMT1A, and HNPP e. MPZ mutations cause DSS, CMT1B, and a CMT2-
like phenotype
f. GJB1 mutations cause CMT1X g. EGR2 mutations cause CMT1 and DSS
CLINICAL FEATURES
1. Clinical phenotype of all forms of CMT a. Generally similar
b. Clinical presentation with distal leg weakness and atrophy
c. Followed by hand involvement
2. Presence of a wide range of variation and severity of symptoms in the affected areas and in the rate of progres- sion of symptoms
3. CMT1A 142
a. Accounting for 90% of CMT1 patients
b. A wide range of variation in clinical presentation and severity among affected members of large families with CMT1A
c. CMT1A PMP22 duplication i. Asymptomatic patients
a) Observed in some family members in large pedigrees
b) No symptoms
c) Normal neurologic examination including ability to walk on their heels and normal stretch reflexes
d) Slow MNCV
e) Duplication of PMP22 confirming the diag- nosis of CMT1A
ii. Symptomatic patients
a) Onset: first decade or early in the second decade
b) Presenting symptoms in infants and chil- dren: walking on their toes and have severe tightness of the heel cord
c) Occasional patients born with foot deformi- ties including clubfeet
d) Other symptoms: abnormal gait, foot defor- mities, or loss of balance
e) Muscle weakness starting in the feet and legs f) Frequently trip over objects on the floor and sprain ankles as a result of weakness of the dorsiflexor muscles of the feet, innervated by the peroneal nerves
g) Difficulty or inability to walk on heels h) Tight heel cords
i) Foot drops with each step, forcing the patient to flex the hip, giving the steppage or equine gait
j) Pes cavus deformity developing with age k) Atrophy of the legs, due to wasting of the
peroneal muscles giving the stork legs or
‘inverted champagne bottle’ appearance l) Weakness of the intrinsic hand muscles
usually occurring late in the course of the disease
m) Claw hands
n) Mild sensory loss to pricking pain in the legs in some patients
o) Frequently decreased vibratory sense iii. Associated symptoms
a) Enlarged (auricular, ulnar, and peroneal) nerves in 20–25% of the patients, not related to the age of the patient or the severity of the disease
b) Tremor in 40% of the patients
c) Hip dysplasia with hip pain and a limp d) Restrictive lung disease usually not a major
problem in patients with CMT1
e) Other associated features: spastic parapare- sis, deafness, optic atrophy, Marfan-like appearance, and absence of eyebrows f) Exacerbation of the weakness in 50% of the
patients with early onset disease during pregnancy and delivery
g) Certain medication and neurotoxic sub- stances may aggravate the neuropathy in patients with CMT.
d. CMT1A point mutations in PMP22 i. Show severe disease in childhood
ii. Found in patients that have been diagnosed with the Dejerine-Sottas syndrome
4. CMT1B
a. Accounting for less than 10% of CMT1 patients b. MPZ mutations identified in CMT1B, DDS, or con-
genital hypomyelination phenotype c. Differentiating from CMT1A
i. An earlier onset of the symptoms manifested by delayed ability to walk
ii. Proximal leg weakness without decreasing ambulation
iii. Slower motor NCVs 5. CMT2
a. Neuronal type (a progressive peripheral motor and sensory neuropathy)
b. Clinical phenotype similar to the type 1 CMT i. Symptoms
a) Tingling b) Numb feeling c) Pain
d) Muscle cramp
e) Loss of muscle strength: distal weakness with feet involvement first
f) Walking instability g) Increased loss of strength h) Increased sensory loss ii. Signs
a) Atrophied hands b) Atrophied legs c) Postural tremors d) Fasciculations e) Pes cavus f) Claw toes g) Steppage gait h) Leg atrophy
i) Short calf muscles j) Abnormal Romberg sign
k) Absent biceps, triceps, knee, and ankle jerks c. Other characteristics
i. Generally a later onset of the symptoms than seen in the type 1
ii. Pes cavus and short calf muscles: predominantly present in patients with early-onset disease iii. Less involvement of the hand muscles
iv. No clinical evidence of palpable enlarged nerves v. No sensory deterioration
vi. Normal or slightly diminished motor nerve con- duction velocities
6. Autosomal recessive CMT (CMT4)
a. Progressive motor and sensory neuropathy
b. Rare heterogeneous forms with a broad spectrum of clinical severity
c. Presentation of symptoms in infancy by delay in walking
d. Early and rapidly progressive deformities of the feet and spine
e. A high incidence of associated features such as sen- sorineural hearing loss
f. Weakness beginning in the feet but affecting both dis- tal and proximal muscles
g. No enlargement of superficial nerves h. Presence of three pathologic forms 7. X-linked CMT (CMTX)
a. Inheritance
i. Dominant form in 90% of cases ii. Recessive form in 10% of cases
b. A disease-causing mutation and a family pedigree consistent with X-linked dominant inheritance
i. Presence of a disease-causing mutation in the GJB1 (Cx32) gene
ii. Lack male to male transmission
c. Males and females with peripheral motor and sensory neuropathy
i. Affected males
a) More severe phenotype than the affected females
b) More severe progressive peripheral motor and sensory neuropathy than that seen in CMT1A
c) Moderately slow median nerve MNCV:
34.5 ± 6.2 m/sec
d) Reduced motor and sensory nerve ampli- tudes (median nerve CMAP): 3.7 ± 3.7 mV ii. Affected females
a) Normal, or mild to moderate signs and symptoms
b) Moderately slow MNCV: 45.8 ± 7.3 m/sec c) Reduced motor and sensory nerve ampli-
tudes (median nerve CMAP): 7.8 ± 3.4 mV d. Signs and symptoms
i. Typical presenting symptom: weakness of the feet and ankles
ii. Initial physical findings: depressed or absent ten- don reflexes with weakness of foot dorsiflexion at the ankle
iii. Typical adult patients a) Bilateral foot drop
b) Symmetrical atrophy of muscles below the knee with stork leg appearance
c) Pes cavus
d) Atrophy of intrinsic hand muscles especially the thenar muscles of the thumb
e) Absent tendon reflexes in both upper and lower extremities
f) Proximal muscles usually remain strong.
g) Mild to moderate sensory loss (deficits of position, vibration, and pain/temperature) commonly occurring in the feet
e. Other characteristics
i. Symptoms typically develop between ages 5 and 25 years
ii. Onset commonly within the first decade in males iii. Earlier onset with delayed walking in infancy as well as later onset beyond the 4th decades possible
iv. Mild symptoms may be overlooked by patient and physician
v. Severe motor slowing in most families, consis- tent with a demyelinating form of the disease vi. A predominant axonal type also been described 8. Dejerine-Sottas syndrome (DSS)
a. The syndrome still used to define the rare cases of severe hypo-demyelinating neuropathy of early onset b. Criteria for diagnosis
i. Early onset of the disease by age 2 years with delayed motor milestones
ii. Severe motor, sensory, and skeletal muscle deficits, frequently extending to proximal mus- cles. Sensory ataxia and scoliosis also present.
iii. Very low conduction velocities, usually <12 m/s iv. Nerve biopsy reveals severe hypomyelination and basal lamina reduplication, with multiple onion bulb formation
v. Presence of the enlarged nerves
c. De novo point mutations in either MPZ or PMP22 found in most DSS cases
d. May be a variant of CMT1A or CMT1B 9. Congenital hypomyelination (CH)
a. An ill-defined and extremely rare disease merging into Dejerine-Sottas disease
b. A clinical syndrome characterized by infantile hypoto- nia due to distal muscle weakness, areflexia and very slow NCVs. Severe weakness may lead to early death c. Severe contractures of joints or arthrogryposis multi-
plex congenita in severe cases
d. Mutation analysis showing MPZ mutations, suggest- ing some of the DSS and CH are part of a spectrum of the demyelinating form of CMT1B
10. Hereditary neuropathy with liability to pressure palsies (HNPP)
a. Also called familial recurrent polyneuropathy or tomaculous neuropathy
b. Clinical manifestations
i. Periodic/transient//recurrent episodes of numb- ness, muscular weakness, and atrophy
ii. Palsies after relatively minor compression or trauma of the peripheral nerves (the axillary, median, radial, ulnar, and peroneal nerves) c. Nerve conduction abnormalities mainly localized at
common entrapment sites
d. Nerve biopsy: occurrence of focal myelin thickenings (tomacula) in several fibers
e. Commonly associated with deletion of PMP22 gene
DIAGNOSTIC INVESTIGATIONS
1. Two types of CMT, currently distinguishable by the value of motor nerve conduction velocity (MNCV) of median nerve on electrophysiologic examination and nerve biopsy findings
a. Demyelinating form (CMT1)
i. Slowing of MNCV (15–30 m/sec)
ii. Hypertrophy of peripheral nerves with onion bulb formation and segmental demyelination b. Axonal form (CMT2)
i. Normal or mildly slow MNCV (>40 m/sec) ii. Normal size nerves
iii. No evidence of segmental demyelinations
2. Motor nerve conduction velocity of the median nerve (MNCV)
a. Uniform conduction slowing i. CMT1A
ii. CMT1B iii. CMT4
iv. Dejerine-Sottas syndrome b. Multifocal conduction slowing
i. CMTX
ii. Hereditary neuropathy with liability to pressure palsies (HNPP)
c. Incompletely characterized electrophysiology i. PMP22 point mutations
ii. MPZ point mutations iii. EGR2 mutations d. Usually normal in CMT2
3. EMG testing: evidence of an axonal neuropathy in CMT2
a. Positive waves b. Polyphasic potentials c. Fibrillations
d. Reduced amplitudes of evoked motor and sensory responses
4. Compound motor action potentials (CMAP): greatly reduced in CMT2
5. Nerve biopsy a. CMT1A
i. Regression of onion bulb
ii. Significantly increased ratio of axon diameter/total fiber diameter, indicating arrestedremyelination b. CMT1B
i. Demyelinating process with onion bulb forma- tion (sural nerve biopsy)
ii. Ultrastructural finding of uncompacted myelin is consistent with the accepted function Po as a homophilic adhesion molecule
c. CMT2
i. No histological evidence of well-formed onion bulbs on the nerve biopsies
ii. Loss of myelinated fibers with signs of regener- ation, axonal sprouting, and atrophic axons with neurofilaments
d. Autosomal recessive demyelinating CMT with three pathologic forms:
i. Classical onion bulbs ii. Basal laminar onion bulbs iii. Focally folded myelin sheaths e. CMTX
i. Nerve hypertrophy or onion bulb formation: rare ii. A primary axonal neuropathy with axonal
sprouting in most affected individuals
iii. Prominent demyelination consistent with a CMT1 phenotype in some cases
f. Congenital hypomyelination: hypomyelination (few thin myelin lamella) without active myelin break- down products and early onion bulb formations g. Hereditary neuropathy with liability to pressure
palsies (HNPP): demyelination and remyelination with tomacula or sausage-like thickening on the myelin sheath
6. Molecular genetic testing a. CMT1
i. CMT1A
a) Sequence analysis for point mutations in the PMP22 gene
b) Mutation scanning for point mutations in the PMP22 gene
ii. CMT1B
a) Sequence analysis for point mutations in the MPZ gene
b) Mutation scanning for point mutations in the MPZ gene
iii. CMT1C: direct DNA/linkage analysis for point mutation in LITAF
iv. CMT1D
a) Sequence analysis for point mutations in the EGR2 gene
b) Mutation scanning for point mutations in the EGR2 gene
b. CMT2E: sequence analysis for mutations in NEFL c. CMT4
i. CMT4E: molecular genetic testing for EGR2 ii. CMT4F: molecular genetic testing for PRX d. CMTX: sequence analysis to detect mutations in the
GJB1 coding region (accounting for about 90% of mutations in patients with CMTX)
e. Molecular genetic testing approach i. In cases of HNPP
a) Test for the PMP22 deletion (since this is by far the major cause)
b) If negative, then sequence PMP22
ii. In CMT patients with uniform slowing of motor NCVs between 10–35 ms
a) Test for the PMP22 duplication (since this is the major cause of CMT1)
b) If negative, sequence PMP22, MPZ, GJB1, and EGR2
iii. In DSS with appropriately slowed NCVs a) Test for the duplication: usually negative b) Sequence PMP22, MPZ, GJB1, EGR2, and
PRX genes
iv. In cases where CMT1X is the most likely diag- nosis (based on intermediate slowing of NCVs, no male-to-male transmission)
a) Sequence GJB1 alone: the appropriate initial test
b) If negative, sequence MPZ and NEFL v. In cases of suspected CMT2
a) Probably premature to test for MPZ and NFEL mutations alone (the only commer- cially available tests)
b) Await a comprehensive battery in the future
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal dominant CMT
a) Majority of CMT1 patients carry the PMP22 duplication and represent de novo mutation
cases: recurrence risk to sib not increased unless a parent is affected, in which case the recurrence risk is 50%
b) Patients with de novo MPZ mutation: recur- rence risk to sibs not increased unless a par- ent is affected, in which case the recurrence risk is 50%
ii. Autosomal recessive CMT: 25%
iii. X-linked dominant CMT (patients with Cx32 mutation)
a) A carrier mother has a 50% risk of transmit- ting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected. Daughters who inherit the mutation will be carriers and may or may not be affected
b) A noncarrier mother: recurrence risk to sibs low but not zero since the risk of germline mosaicism in mothers is not known
b. Patient’s offspring
i. Autosomal dominant CMT: Patients with PMP22 duplication, PMP22 deletion, or MPZ mutation will have a 50% risk of transmitting the disease to the offspring
ii. Autosomal recessive CMT: not increased unless the spouse is a carrier or affected
iii. X-linked dominant CMT (patients with Cx32 mutation)
a) All the daughters of an affected male inherit the mutation but may or may not have symp- toms
b) None of his sons will be affected
2. Prenatal diagnosis available to pregnancies at risk for CMT1A, CMT1B, CMT2E, CMT4E, CMT4F, and CMTX a. Identify the disease-causing allele of an affected fam-
ily member before prenatal diagnosis
b. Mutation analysis of fetal DNA obtained from amnio- centesis or CVS
c. CMT1
i. Prenatal diagnosis of CMT1A by FISH
a) Parental blood samples studied to confirmed to be duplicated for PMP22 by FISH b) Interphase FISH assay performed on amni-
otic fluid specimens and chorionic villus samples to detect a submicroscopic 17p12 duplication in the fetus with CMT1A ii. Preimplantation diagnosis for CMT1A: selection
of healthy embryos is made based on the pres- ence of the nonduplicated haplotype and het- erozygosity of a marker
d. CMT2E: molecular genetic testing of DNA extracted from fetal cells obtained from amniocentesis or CVS for testing of NEFL mutation when both disease- causing alleles of an affected family member are identified
e. CMT4E and CMT4F: molecular genetic testing of DNA extracted from fetal cells obtained by amnio- centesis or CVS for testing of EGR2 and PRX muta- tions respectively when both disease-causing alleles of an affected family member are identified
f. CMTX
i. Prenatal diagnosis available to pregnancies of women who are heterozygotes for a disease- causing GJB1 mutation that has been identified in an affected family member
ii. Amniocentesis or CVS
a) Determination of the fetal sex
b) DNA extracted from cells from male fetuses tested to determine if a disease-causing mutation is present
3. Management
a. No specific treatment to reverse or slow the natural disease process
b. Supportive care
i. Daily heel cord stretching exercises ii. Special shoes to support ankle
iii. Ankle/foot orthoses to correct foot drop and aid walking
iv. Orthopedic surgery to correct severe pes cavus deformity
v. Forearm crutches or canes for gait stability vi. Wheelchairs required for less than 5% of patients c. Avoid medications known to cause nerve damage
i. Vincristine ii. Taxol iii. Cisplatin
iv. Isoniazid v. Nitrofurantoin
d. Acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain
e. Tricyclic antidepressants, carbamazepine, or gabapentin for neuropathic pain
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Fig. 1. Two patients with Charcot-Marie-Tooth disease showing stork- like legs and pes cavus deformities.
Fig. 2. A 23-year-old female with Charcot-Marie-Tooth disease show- ing stork legs with muscle wasting, pes cavus deformities and foot drop. She has absent deep tendon reflexes. Her onset of disease began in the third grade with a history of tripping, falling, and clumsiness.
Family history revealed affected individuals in three generation.
