CHARCOT-MARIE TOOTH DISEASEGRAND ROUNDS- 06/24/2016
Karthika Veerapaneni,MDClinical Neurophysiology Fellow
Department of Neurology, University of Kansas Medical Center,Kansas City, USA
Charcot-Marie Tooth disease (CMT)
Synonyms
Charcot–Marie–Tooth neuropathy
Peroneal muscular atrophy
Hereditary motor sensory neuropathy (HMSN) type 1
Charcot-Marie Tooth disease (CMT)History
Jean-Martin Charcot
(1825–1893)
Pierre Marie (1853–1940)
Howard Henry Tooth
(1856–1925)
Charcot-Marie Tooth disease (CMT)Introduction
CMT is one of the hereditary motor & sensory neuropathies, a group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body
Charcot-Marie Tooth disease( CMT)Epidemiology
CMT is the most commonly inherited neurological disorder(autosomal dominant or recessive or an X-linked pattern)
Prevalence: 40 per 100,000 ( 1 in 2500)
Males>Females
Age of onset is variable according to subtype, penetrance, familial phenotype, and ascertainment bias
CMT is found world wide in people of all races and ethnic groups
Less common in African Americans
Charcot-Marie Tooth disease (CMT)Clinical Features
Affects both motor and sensory nerves
Symptom onset depends on type of CMT but usually begins in early childhood or early adulthood
Most CMT1 symptoms starts by second decade
Charcot-Marie Tooth disease (CMT)Clinical Features
Foot drop (usually the initial symptom)
High stepped gait
Frequent falls
Hammer toes, high arched feet ( pes cavus) or flat arched feet (pes planus) are classical
Muscle wasting
Weakness in legs later progresses to hands and forearms
Difficulty with fine motor skills
Claw hands
Cramps
Usually no sensory symptoms in early stages
Charcot-Marie Tooth disease (CMT)
Deformities
Hammer Toes
Pes planusPes cavus
Charcot-Marie Tooth disease (CMT)Clinical Features
Charcot-Marie Tooth disease (CMT)Clinical Features
Inverted champagne bottle legs(Stork Legs):
-Hypertrophy of the proximal muscles
-Marked peroneal muscle atrophy with tapering of the distal extremities
-Typical of advanced CMT
Charcot-Marie Tooth disease (CMT)Clinical Features
Sensory changes
Usually no sensory symptoms in early stages
Touch, vibratory and proprioceptive sensations are often damaged
Pain is intact
Neuropathic pain if present, severity varies (mild to severe and can interfere with daily life activities)
Pain due to postural changes, skeletal deformations, muscular fatigue and cramping is fairly common in people with CMT
Charcot-Marie Tooth disease (CMT)Clinical Features
Other features:
Weakness in neck and shoulder muscles
Tremor
Involuntary grinding of teeth, squinting are prevalent and often go unnoticed by the person affected.
Breathing difficulties
Difficulties in hearing and vision
Scoliosis causing hunching and loss of height
Malformed hip sockets
Gastrointestinal problems - difficulty chewing, swallowing
Difficulty speaking-atrophy of vocal cords
Charcot-Marie Tooth disease (CMT)
Exacerbating Factors
Emotional stress
Periods of prolonged immobility
Pregnancy
Drugs:Amiodarone,Bortezomib,Cisplatin, carboplatin, Colchicine (extended use), Dapsone, Didanosine, Dichloroacetate, Disulfiram, Gold salts, Leflunomide, Metronidazole/Misonidazole (extended use),Nitrofurantoin, Nitrous oxide (inhalation abuse or vitamin B12 deficiency), Perhexiline (not used in the United States), Pyridoxine (high dose), Stavudine, Suramin, Tacrolimus, Taxols
(paclitaxel, docetaxel), Thalidomide, Vincristine, Zalcitabine
Charcot-Marie Tooth disease (CMT)
VINCRISTINE IN CMT PATIENTS
Acute worsening or onset of weakness in patients after vincristine administration of 2 to 4 mg for adults or 1.5 mg/m2
per dose in children
Most of the patients had undiagnosed demyelinating forms of CMT (eg, CMT1A)
Definite high risk for patients with CMT, including those who are asymptomatic and/or undiagnosed.
Charcot-Marie Tooth disease (CMT)Pathophysiology/Etiology
Pathophysiology is either a demyelinating process or an axonal process
Etiology is intragenic mutation and/or DNA duplications or deletions
More than 50 genes causing CMT have been identified
Mutations usually affect one of the several myelin genes, but some affect the axon
Charcot-Marie Tooth disease (CMT)Pathophysiology/Etiology
Mutation results in defects of myelin structure, maintenance, and formation
Demyelinating Schwann cells causes abnormal axon structure and function
Some mutations affect the gene MFN2 which codes for mitochondrial protein
Usually mitochondria travels down the long axons. Mutated MFN2 causes mitochondria to form large clusters or clots and prevents synapse from functioning
Charcot-Marie Tooth disease (CMT)
Defective Myelin
Defective Axon
http://chronicpainreliefoptions.com/charcot-marie-tooth-a-very-painful-disorder
Charcot-Marie Tooth disease (CMT)
Mode of inheritance
Autosomal Dominant( most common)
Autosomal Recessive
X-linked
Charcot-Marie Tooth disease (CMT)Classification
Genetically heterogeneous with more than 50 genes identified to date
Classified as types 1 through 7
Each type additionally has many subtypes
The major division comprises types 1 and 2, which together are the most common hereditary peripheral neuropathies
Charcot-Marie Tooth disease (CMT)TYPES
CMT1 (Hypertrophic demyelinating)
CMT2 (Axonal)
CMT3 (Dejerine-sotta’s disease)
CMT4 (Refsum’s disease-AR)
CMT5 (Spastic Paraplegia)
CMT6 (Optic Atrophy)
CMT7 (Retinitis Pigmentosa)
Charcot-Marie Tooth disease (CMT)Classification-Subtypes
Vocal cord paralysis-CMT 2C
Charcot-Marie Tooth disease (CMT)Classification-Subtypes
CMT1 Demyelinating disorder of peripheral nerves
Subtypes: 1A,1B,1C, 1D,1E,1F
Type 1A: 70 to 80 percent of CMT1 cases and 40-50% of all CMT patients
Clinical features:
-Symptoms typically start in the early second decade, but can manifest in infancy as well
-Foot drop
-Clumsy walking/difficulty running
-Sensory loss is gradual and mainly involves proprioception and vibration
-Deformities
CMT1Physical findings:
Early changes:
Loss of reflexes, pes cavus foot deformity, and hammer toes
Distal calf muscle atrophy often occurs, causing the classic "stork leg deformity."
Later changes:
atrophy of the intrinsic hand and foot muscles
Palpable enlargement of the peripheral nerves secondary to nerve hypertrophy
kyphosis or scoliosis often develops.
CMT1
Life expectancy: normal
Disease exacerbation can occur in pregnancy, an effect that may be mediated by increased plasma progesterone
sleep apnea can associate (in one study, 11 of 14 patients found to have sleep apnea)
CMT1
SUB TYPES
CMT1A:
Associated with a 1.5 Mb duplication or, less commonly, a point mutation of the peripheral myelin protein 22 (PMP22) gene on chromosome 17p11.2-p1
Duplication leads to overexpression of PMP22 and it gets inserted in the myelin sheath
Point mutations alter distribution of the protein and therefore PMP22 partially accumulates in the Schwann cells
Interestingly, patients with a 1.5 Mb deletion at this site develop hereditary neuropathy with pressure palsy( HNPP)
CMT1
CMT1B:
Originally known as peroneal muscular atrophy
Point mutations in the myelin protein zero (MPZ) gene on chromosome 1q22, which cause overexpression of the major myelin structural protein resulting in malfunctioning of myelin
**Myelin protein-zero is normally expressed on the cell membrane of
Schwann cells, and plays a major role in myelin membrane adhesion
CMT1E:
deafness is common
Gene is either PMP22 or PO
CMT1
Roussy-Levy syndrome:
CMT type 1 phenotype
First described in 1926
Manifestations include postural tremor, gait ataxia, distal muscle atrophy, pes cavus, areflexia, and mild distal sensory loss
One family: Mutation in the extracellular domain of the MPZ gene, indicating type 1B disease
Another family: Partial duplication at chromosome 17p11.2, indicating type 1A disease
CMT2 Hereditary motor sensory neuropathy (HMSN) type 2
Synonym: Axonal CMT
More heterogeneous disorder than CMT1
Classic features:
distal weakness, atrophy, sensory loss, decreased deep tendon reflexes, and variable foot deformity
The onset of symptoms usually is in the second decade of life
The clinical course is similar to that of CMT1, but sensory symptoms, with loss of vibration and proprioception, typically predominate over motor symptoms, and peripheral nerves are not palpably enlarged. Distal trophic ulcerations in the feet may occur.
CMT2Early-onset form: before 5 years old
Rapidly progressive with loss of strength below the knees by the second decade
Sensory symptoms are present but overshadowed by the motor weakness
Ambulation often is lost by mid-teens
Late-onset form: between 35 to 85 years of age (median age 57)
6 families identified so far
Genetically heterogeneous
Autosomal dominant inheritance was demonstrated in two of the families, while inheritance patterns were unclear in the remaining four families
CMT2
Genetics of CMT2
Heterogeneous
majority are autosomal dominant
Mitochondrial fusion protein mitofusin 2 (MFN2) gene mutations, most common cause of the CMT2 phenotype, accounting for approximately one-third of autosomal dominantly inherited CMT2 cases
some MFN2 mutations cause early onset CMT2, autosomal recessive inheritance
CMT2Genetics of CMT2
Other Genes:
MPZ gene mutations
GARS-autosomal dominant mutations-CMT2D
(**same gene for HMN too)
NEFL gene mutations, both autosomal dominant and recessive
Dynamin 2 (DNM2) gene mutations
MME gene mutations, autosomal recessive CMT2
X-linked and autosomal recessive inheritance
CMT2
SUB TYPES
CMT2A:most common CMT2 phenotype and maps to chromosome 1p35-36. Gene is mitochondrial fusion protein mitofusin 2 (MFN2)
Other subtypes:
CMT2B
CMT2C Vocal Cord Paralysis
CMT2DArms>legs
CMT2E ,CMT2F ,CMT2G ,CMT2I ,CMT2K, CMT2L ,CMT2S
CMT3
HMSN/CMT3
Genetically heterogeneous.
Severe, early-onset peripheral neuropathies
Inability of the Schwann cells to produce normal myelin, resulting in thin, poorly formed myelin
Two diseases:
1. Dejerine-Sottas syndrome
2. Congenital hypomyelinating neuropathy
CMT3Dejerine-Sottas syndrome
Severe demyelinating neuropathy clinically evident in early infancy because of hypotonia
Delayed motor development, prominent sensory loss, distal followed by proximal weakness, absent reflexes, ataxia, and profound slowing of nerve conduction velocities to ≤10 m/sec Scoliosis appears early and progresses with time, and contractures develop
Progression is slow, often with ambulation maintained through adult life
CMT3Dejerine-Sottas syndrome
Genetics:
Mutations in the PMP22 gene (as in CMT1A), the MPZ gene (as in CMT1B) and the EGR2 gene (as perhaps occurs in CMT1C)
Autosomal recessive and several dominant heterozygous forms have been described
Histology:
Thin myelin sheaths and large onion bulb formation
EMG/NCS:
Profound slowing of nerve conduction velocities to ≤10 m/sec
CMT3
Congenital hypomyelinating neuropathy
Presents at birth with profound hypotonia and contractures
Feeding difficulties and respiratory distress often lead to death in infancy
spontaneous improvement in motor function with increasing age have been reported in several cases
one patient completely recovered by four months
CMT3Congenital hypomyelinating neuropathy
Genetics:
genetically heterogeneous
mutations in PMP22 gene, MPZ gene mutations , early growth response 2 gene (EGR2) and the myotubularin related 2 gene (MTMR2)
most cases-autosomal dominant, but rare autosomal recessive cases have been reported
Histology:
absent myelin without evidence of inflammation, myelin breakdown, or onion bulbs.
EMG/NCS:
Conduction velocities are either absent or extremely slow
Charcot-Marie Tooth disease (CMT)
Hereditary neuropathy with liability to pressure palsies (HNPP)
Focal episodes of weakness or sensory loss and focal slowing of motor never conduction velocities.
Test for PMP22 deletion and point mutations
Charcot-Marie Tooth disease (CMT) Diagnosis
Clinical History( *including family history):
-Weakness in muscles of legs/arms, foot drop, deformities( pes cavus, pes planus and hammer toes)
-Family history of high arched feet(lack of family history does not rule out CMT)
-usually no sensory symptoms reported
Physical Examination:
-distal weakness, proximal hypertrophy
-foot deformities, Inverted champagne bottle legs(Stork Legs)
-DTRs reduced or absent in CMT patients
-decreased vibratory and proprioception on exam
Charcot-Marie Tooth disease (CMT) Diagnosis
Symptoms and signs alone do not lead to diagnosis
EMG/NCS and genetic testing are needed to confirm the diagnosis
Nerve biopsy is not indicated
Charcot-Marie Tooth disease (CMT) DiagnosisEMG/NCS:
CMT1:
-diffusely and equally decreased conduction velocities in demyelinating form
-In every nerve tested, both sensory and motor, roughly the same degree of
marked slowing is found
-CMT1 median motor NCV is around 15-25 m/s
-consider testing of family members as needed
Charcot-Marie Tooth disease (CMT) Diagnosis
EMG/NCS:
CMT2:Normal or mildly reduced nerve conduction velocity
(>38 m/sec) with decreased amplitude
CMTX: 25-40 m/sec
Distal intermediate CMT: 15-50 m/sec
Dejerine-Sottas syndrome: <10 m/sec
Charcot-Marie Tooth disease (CMT) Diagnosis
Nerve Biopsy: Not necessary for diagnosis
-Fiber type grouping, a similarly non-specific finding which is
evidence of a cycle of denervation/reinnervation
-Type 1 reveals demyelination and multiple layers of
remyelination, called “onion bulb”
-Type 2 reveals axon loss with wallerian degeneration
-Type 3 reveals demyelination with thinning of the myelin sheath
**There should be no inflammatory infiltrate indicating an
autoimmune demyelinating process.
Charcot-Marie Tooth disease (CMT) Diagnosis
“Onion bulbs”
Charcot-Marie Tooth disease (CMT) Diagnosis
Genetic testing: DNA testing can give a definitive diagnosis, but not all the genetic markers for CMT are known
Advantages:
-Can simplify the diagnosis of CMT by avoiding uncomfortable and invasive procedures such as electromyography and nerve biopsy respectively
-Early diagnosis can facilitate early interventions such as physical therapy
Disadvantages:
-Often will not affect the management for individual patients with CMT
-Cost
Charcot-Marie Tooth disease( CMT)Genes
CMT1:
PMP22 (CMT1A and CMT1E)
MPZ (CMT1B)
LITAF (CMT1C)
EGR2 (CMT1D)
NEFL (CMT1F)
Charcot-Marie Tooth disease( CMT)Genes
CMT2:
MFN2 and KIF1B (CMT2A)
RAB7A (CMT2B)
LMNA (CMT2B1)
TRPV4 (CMT2C)
BSCL2 and GARS (CMT2D)
NEFL (CMT2E)
HSPB1 (CMT2F)
MPZ (CMT2I and CMT2J)
GDAP1 (CMT2K); and HSPB8 (CMT2L)
DNM2 gene mutations
Algorithm for Genetic Testing in suspected CMT patients
Charcot-Marie Tooth disease (CMT) Diagnosis
Genetic screening for relatives: optional
Genetic counseling:
Prenatal testing for pregnancies at increased risk is possible for some types of CMT only if the disease-causing mutation in the family is already known
Charcot-Marie Tooth disease (CMT) Management
No cure
No disease-modifying therapy is available
Supportive care
Genetic counselling
Most important goal for patients with CMT is to maintain movement, muscle strength, and flexibility
PT/OT and moderate activity are usually recommended, but overexertion should be avoided
Daily stretching exercises early in the course of the disease may help delay ankle contractures
Charcot-Marie Tooth disease (CMT) Management
Orthoses (bracing): to help stabilize ankles
Ankle-foot orthoses (AFOs)
Appropriate footwear
Podiatrist referral as indicated
Orthopedic surgery (straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability)
Fall precautions
Avoid exacerbating factors(Emotional stress, periods of prolonged immobility, pregnancy, medications like vincristine)
Charcot-Marie Tooth disease (CMT) Management-Research
Progesterone antagonist- used in animal models reduced overexpression of PMP22 and slowed disease progression
Ascorbic acid (vitamin C):
-promote myelination and appeared promising in an animal model of CMT1A
-Ascorbic acid therapy reduced the expression of PMP22
-remyelination, amelioration of the CMT1A phenotype, and prolonged
lifespan
-However, there was no clear benefit of ascorbic acid in a 12 month
randomized controlled trial of 81 children with CMT1A or in a similar trial of
179 adults with CMT1A
-Since disease progression in CMT1A is typically slow, trials with longer
treatment periods may be necessary to detect benefit
Charcot-Marie Tooth disease (CMT) Management-Research
Neurotrophin-3 (NT3):
-Improved axonal regeneration and associated myelination in both a xenograft model of Schwann cells with a PMP22 duplication and in a mouse model with a PMP22 point mutation
-A single-blinded pilot clinical trial involving eight patients with
CMT1A found that NT3 treatment for six months was associated
with improved sural nerve myelinated fiber regeneration
compared with placebo treatment.
-Clinical applicability of these observations remains to be
proven.
Charcot-Marie Tooth disease (CMT) Management-Research
Anesthesia:
-Regional anesthesia has been controversial
-may have an increased susceptibility to further nerve damage with the use of
local anesthetic agents
-a number of small case series and case reports have described uneventful
outcomes with regional anesthesia, including both peripheral nerve and
neuraxial blocks
Charcot-Marie Tooth disease (CMT) Research
PUBMED ID: 25519680
Orphanet J Rare Dis. 2014 Dec 18;9:199. doi: 10.1186/s13023-014-0199-0.
An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A
Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, Péréon Y, Dubourg O, Pouget J, Micallef J, Franques J, Lefebvre MN, Ghorab K, Al-Moussawi M, Tiffreau V, Preudhomme M, Magot A, Leclair-Visonneau L, Stojkovic T, Bossi L, Lehert P, Gilbert W, Bertrand V, Mandel J, Milet A, Hajj R, Boudiaf L, Scart-Grès C, Nabirotchkin S, Guedj M, Chumakov I, Cohen D
Clinical Trials.gov
Active study: NCT02579759Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT) (PLEO-CMT)
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