Download Charcot-Marie-Tooth Disease Current Topics and Treatment Options

Charcot-Marie-Tooth Disease
Current Topics and Treatment Options
in Podiatric Medicine and Surgery
September 27, 2011
New York, NY
Hal Ornstein, DPM, FASPS, FAPWCA
Affiliated Foot and Ankle Center, LLP
4545 Highway 9 North
Howell, New Jersey 07731
(732) 905-1110
Fax (732) 905-7885
E-mail: [email protected]
www.footdoctorsnj.com
Many thanks to these individuals
for their assistance in preparing this manuscript
Katy Statler, DPM (Parts 1 & 2)
Sina Safar, DPM (Parts 1 & 2)
Sarah Kim, DPM (Part 3)
Jake Wynes, DPM and Jasen Langley, DPM
Introduction
Previous publications and various descriptions date back to the mid 1800s. In 1886, the
first discussions of Charcot-Marie-Tooth (CMT) were introduced by Jean-Martin Charcot and
his student Pierre Marie from France, with Howard Henry Tooth from England as further
contributor. Their work popularized the understanding of this disease and its effects in those
afflicted. CMT effects males more than females (prevalence as high as 1/2500) with an
autosomal dominant penetrance being the most common at 36/100,000 individuals. Family
history usually includes phenotypic presentation of thin legs and high arches. Charcot-MarieTooth has been studied as progressive in nature with manifestations as a peripheral nerve
disorder that results in diffuse degeneration of neuronal myelin sheath. Normally, the myelin
sheath facilitates rapid and efficient transmission of impulses along the nerve cells. The axon is a
long slender projection of a nerve cell, or neuron that conducts electrical impulses away from the
neuronal cell body, or soma (Figure 1). Histologically, onion bulb formation (focal myelin
swelling) is pathognomonic for this condition (Figure 2). When the myelin sheath and axon are
disrupted by CMT, the frequency of signal transduction and impulses slow down, thereby
causing muscle atrophy from diminished nerve signal transmission (decreased nerve
conduction). CMT is identified as a hereditary neuropathy which is sub-divided based on
phenotypic presentation. Hereditary Motor and Sensory Neuropathy (HMSN) and Sensory
Autonomic Neuropathies are defined as a group of disorders causing alterations in peripheral
nerves. Varying forms of CMT impact long term function and may exacerbate underlying
disabilities. Recognizing signs and symptoms early, along with implementing an efficient mode
of treatment through an interdisciplinary medical approach, allows for better patient outcomes
with respect to overall comfort and sustainable lifestyle.
Epidemiology, Pathophysiology, and Presentation
CMT currently affects approximately 125,000 people in the United States, mostly males.
There is no specific race predilection of this disorder; however African Americans are less likely
to be effected. With the most common phenotypic variant of CMT (CMT1A), initial
manifestations of this disorder are appreciated around the age of 30. The disease progression
may be quite variable yet approximately 70% of the autosomal dominant variants will develop
progressive atrophy, 23% will have atrophy arrest, and 7% of this population is left with
intermittent symptomatology. .
Several phenotypic variants of CMT exist including CMT1, CMT2, CMT3, CMT4,
dominant intermediate CMT, and CMTX. CMT1A / 2 are the most common autosomal
dominant inherited subtypes. Clinical findings with respect to age of onset, nerve conduction
tests, and physical exam help elucidate which variant is diagnosed. CMT1 is further broken
down into five subdivisions including CMT1A, B, C, D, and F. Approximately 40% of all
HMSN fall under the CMT1A subdivision. This autosomal dominant form presents with the
most prominent clinical characteristics and is associated with gene over expression at
chromosome 17, causing duplication of myelin protein 22 (PMP-22). Varying gene mutations
will govern phenotypic variation. An overabundance of PMP-22 leads to an abnormal structure
and function of the peripheral nerve sheath. The end result is atrophy and weakness of muscles
of the lower extremity.
CMT1B includes 5-10% of the cases of CMT. It is autosomal dominant in which there is
a point mutation of the gene that directs the manufacturing of myelin protein zero (MPZ).
Patients who fall under this subdivision experience similar symptoms of those who have
CMT1A, yet with increased peroneal muscular atrophy. At the present time phenotypic variants
CMT1C, CMT1D and CMTF carry similar characteristics of the other autosomal dominant
forms of CMT with variation in genes which mediate their function.
CMT2 (axonal) typically presents with a later onset (ages 35-85) and is associated with
mildly reduced NCV/EMG findings and less nerve hypertrophy / onion bulb formation compared
to CMT1. Clinically these patients will present with decreased deep tendon reflexes and variable
types of foot deformity. Sensory deficits are more common than motor with loss of vibration
and proprioception being the most common findings. In this population it is important to
evaluate these patients for trophic ulcerations secondary to diminished protective sensation
(Figure 9). CMT2A is the most common; however subtypes A through I exist with more on the
research horizon. Many of these subtypes are mediated by genes providing support to axonal
function and depend on mode of inheritance and clinical features.
Dejerine-Sottas Disease is a rare and severe demyelinating neuropathy, which falls under
the category of CMT3 with autosomal dominant and recessive forms causing the disease. PMP22, EGR2, and MPZ genes have been studied. Age of onset (contrary to CMT2), is during
infancy and manifests with hypotonia, delayed motor development, sensory loss in a distal to
proximal progression with concomitant muscle weakness. CMT3 may be further complicated
clinically by presentation areflexia, ataxia and lower extremity contractures. NCV findings are
severely diminished with respect to amplitude and frequency.
CMT4 is an autosomal recessive form of CMT, manifesting with primarily sensory
neuropathy. It is the most rare with the most clinical severity with increased distal muscle
weakness and significant Pes Cavus (high arch) foot deformity. Patients generally become nonambulatory once they reach adolescence. The main gene target has not yet been identified;
however research has determined that axonal dysfunction is less likely due to mutations in
structural myelin proteins.
Lastly, CMTX is another form of CMT which is the second most common variant, that
effects approximately 3.6/100,000 individuals in the United States and is diagnosed in 10-20% of
all cases. CMTX is caused by a point mutation in the connexin-32 gene on the X chromosome.
Both sexes may be affected, yet males who inherit one mutated gene maternally, show moderate
to severe symptoms of the disease beginning in late childhood or adolescence; whereas the Y
chromosome that males inherit paternally do not contain the connexin-32 gene mutation.
Females who inherit one mutated gene from one parent and one normal gene from the other
parent typically have a variable symptomatology. CMTX presents with gait disturbance, loss of
deep tendon reflexes at the ankles with retained L4 reflexes in 50% of females. NCV results
show mildly diminished conduction, as compared to NCV results of CMT1A patients.
Phenotypic subtypes 1-5 exist with varying clinical presentations. Podiatric manifestations are
primarily seen in CMTX2 with atrophy, distal weakness, areflexia, and Pes Cavus foot
deformity.
CMT patients often complain of foot pain, clumsiness (spinal ataxia) with or without
frequent falls, recurrent ankle sprains, and various other gait disturbances. Sensory deficits are
primarily with proprioception and vibratory sensation. Subjectively, patients may complain of
instability, discomfort, and ankle fatigue. Common presentation of the lower extremity is
demonstrated by an “inverted champagne bottle” and “stork leg” deformity (Figure 3). In CMT,
the longest axons of the sciatic nerve are preferentially targeted first with muscles of smallest
bulk showing initial atrophy. The lateral compartment muscle group of the leg is affected first,
followed by the anterior compartment, and (in severe cases) the posterior muscle group.
Pertinent anatomy is reviewed here with primary involvement of the Peroneus Brevis
(PB) muscle, which is the main everter of the foot (attaching to the base of the fifth metatarsal
bone). With significant demyelination this muscle is put into a mechanical disadvantage when
the arch is elevated and the thereby this muscle is unable to assist in flattening the arch. The
Peroneus Longus (PL) is one of the last muscles to atrophy or weaken. PL inserts proximally
onto the first metatarsal and functions to plantarflex (lower) the first metatarsophalangeal joint
(MPJ) downward and its function are maintained until the later stages of the disease.
Progression in to the anterior compartment involving the Tibialis Anterior (TA) muscle and
Extensors (Extensor Digitorum / Hallucis Longus – EDL / EHL: respectively), account for
another deformity regarded as equinous which usually manifests as foot drop and “high steppage
gait,” as the foot is unable to clear the ground during gait. Late atrophy of the PL, and an
inability of PB muscle to function combined with intrinsic muscle wasting and atrophy provides
an unstable construct for gait leading to a severe Pes Cavus/ Equinocavovarus deformity (high
arch).
The greater the degree of varus (inversion) combined with intrinsic muscle wasting
accounts for the greater likelihood for ankle instability and digital contractures of the
interphalangeal joints (IPJ) referred to as a “claw toe deformity.” This can be further
complicated by injury to the lateral foot as a result of this adapted alignment of the foot. Less
commonly, studies have reported that the PL is primarily weakened in 42% of cases with
weakening of the Tibialis Posterior (TP) muscle in approximately 20% of cases. Atrophy of the
TP muscle will result in a variant of CMT with Pes Planovalgus (flat foot), as this muscle is
primarily involved in inverting the foot with resistance to pronatory influence.
Diagnosis
There are various ways of diagnosing CMT including: Deep Tendon Reflex (DTR)
assessment which using a reflex hammer will assess the ability of the nerve to stimulate muscles
effectively. When this finding is decreased or absent, further tests can be administered to further
confirm diagnosis. Nerve Conduction Velocity (NCV), Electromyography (EMG), Manual
Muscle Test (MMT), Nerve Biopsies, and Genetic testing are all the most common modalities of
diagnosing CMT. Advanced imaging (such as Magnetic Resonance Imaging – MRI), has yet to
show promise with respect to diagnosing CMT, yet has prognostic value in CNS imaging to
establish rehabilitation potential for these patients. Some studies advocate for its use in
demonstrating muscle atrophy secondary to demyelination with correlation with MMT.
Clinically, the patient presentation is highly reliable in diagnosing one with CMT.
Brewerton and colleagues first associated individuals with symptomatic high arch feet and
neurologic abnormality. Their study found that 2/3 of the study population presented with these
findings. The history and physical will reveal various findings such as the pathologic foot
structure (Pes Cavus / Cavovarus or Equinovarus), presence of digital contractures (claw toe
deformity), tripod of foot (suggestive of a rigid forefoot deformity), lateral ankle instability, and
gait abnormality. Gait abnormality will require a complete biomechanical exam evaluating the
patient for pelvic elevation or pelvic tilt, followed by observation for characteristic shuffling of
the feet, high steppage (or Marionette Gait), and signs of excessive ankle / rearfoot inversion.
Nerve conduction velocity (NCV) are suggestive when findings are less than 60% of
normal with respect to decreased frequency of axonal nerve propagation. The EMG will
correlate little with the clinical findings. Sural nerve biopsies may show demyelination of large
nerve fibers showing histologic findings of redundant Schwann cells, collagen deposition, and
fibroblast proliferation).
Treatment
Conservative treatments for CMT primarily involve the use of various forms of
accommodative bracing and supportive measures for palliative care of symptoms and should
include a multi-disciplinary approach with incorporation of Physical Therapy / Physical
Medicine and Rehabilitation (PMR). The National Institute of Neurological Disorders and
Strokes (NINDS) is one of many research institutions currently striving to identify mutant genes
and proteins that lead to the various subtypes of CMT.
Currently, no systemic treatments are available for CMT1 yet ongoing research has
shown promise in both human and murine models. Sereda and colleagues have shown that
progesterone antagonists will reduce PMP-22 over expression and may therefore slow the
progression of nerve demyelination. Vitamin C (Ascorbic Acid) has also been studied in vivo in
both animals and humans and has shown no effect in a randomized control trial of 81 children
and 179 adult patients with CMT1. Finally, Neurotrophin 3 has been studied and shown to
improve axonal regeneration of peripheral nerves in mouse models after PMP-22 duplication.
One recent study looked at 10 affected children (ages 3-14) with CMT1A and examined the
effects of injection Botulinium toxin – A into the TP or PL muscle would prevent progression of
Cavovarus deformity. Their findings were that Botulinum toxin was safe yet did not affect foot
morphology at 24 months.
Given the relative slow progression of this disease, conservative goals are centered on
mechanically controlling the deformity. These treatment modalities are reserved for individuals
with a controllable deformity or who are deemed poor surgical candidates. This can be
accomplished with extra-depth accommodative shoes with multi-density inlays. The benefit of
this intervention, will provide support of boney prominences and prevent progression of claw toe
deformity by limiting deforming forces secondary to muscle atrophy. The use of custom mold
orthoses in conjunction may provide added benefit in controlling triplanar deformity through
support of the sagittal plane (plantarflexed forefoot and 1st metatarsal declination), the frontal
plane (rearfoot varus and increased lateral column cavus), and transverse plane deformity
(forefoot adduction at the midfoot) . Further, custom Molded Ankle Foot Orthoses (MAFO) may
be implemented to provide control at the ankle level and assist with drop foot deformity by
allowing clearance of the ground during gait and provide a stable construct for propulsion during
the last phase of the gait cycle. Proper orthotic devices can greatly reduce the chance of tripping
and will help reduce injuries during physical therapy.
Physicians have been able to treat CMT patients symptomatically, by physical and
occupational therapy as well as by managing pain, fatigue and orthopaedic issues. CMT
patients may benefit from physical therapy in various ways especially when working towards
relieving functional deterioration. Classically, rehabilitation programs involve a range of
exercises including picking up marbles, towel rolling, extensor strengthening exercises, and
much more. Strength training may assist patients in decreasing severity of contracture from
muscle imbalance. Not only does this training help improve function of weakened muscles but it
also helps to maximize the strength of uninvolved muscles. Studies show that even a small
increase of strength in effected muscle can result in significant improvement on patients. This
leads to greater tolerance of activities such as writing, and ambulation. It is important to note that
the results from physical therapy will differ from patient to patient. Progress can be slow with
certain patients, while for others’ it may produce a major increase in muscle strength and
resistance. Not knowing the ultimate outcome can cause physical therapy to become an
exhausting process for CMT patients; however, it is very important for patients to be compliant
with the physical therapy program, in order to notice significant improvements in their condition.
Many patients with CMT disease become sedentary which may precipitate deterioration
of the muscles but also deterioration of their overall health. Although excessive training is
contraindicated in CMT patients due to potential injuries that may occur during this type of
training, studies have shown that mild to moderate training can improve overall strength and
health by decreasing heart disease, body fat, and lowering blood pressure; while increasing
muscular and cardiovascular endurance. It is important to consult a physical therapist who can
design an exercise program specific for individual’s needs and thus help to avoid injuries. It is
also important to manage fatigue in CMT patients because more energy is spent during exercises
than that of a comparable healthy individual. When physical therapy is started in the early stages,
it can have a dramatic effect in delaying nerve deterioration and muscle weakness.
Some CMT patients experience weakness in their arms and hands, causing difficulty with
gripping and finger movement. Occupational therapy can make significant difference in the
quality of life by using assistive devices such as special rubber grips on doorknobs or clothing
with snaps instead of buttons.
Typically, suboptimal results have been reported for non surgical management of rigid
deformities. When the decision is made to treat a patient surgically with CMT, it is important to
factor in several elements including which of the motor units remaining are functional, how
flexible or rigid the established deformities are, and whether ligamentous laxity is present. Goals
of surgery are that all fixed deformities must be corrected to include muscle / tendon imbalances
in order to prevent recurrence.
Typical Deformities Outlined:

Forefoot Deformities

Toe/ digit Deformities

Metatarsal Deformities

Midfoot Deformities

Rearfoot Deformities

Ankle / Equinus Deformities

Dropfoot Deformities

Tendon Deformities

Muscle imbalances
Correcting these deformities before any further progression takes place will have a
positive impact on the outcome of the surgical procedures. Many patients who have a flexible
form of a Cavovarus deformity (Figure 4) and plantarflexed 1st ray (figure 6) associated with
CMT have been surgically treated with reconstruction involving tendon transfers with or without
1st metatarsal / midfoot / calcaneal osteotomy (taking a wedge of bone from the first metatarsal,
midfoot, or calcaneus with realignment) and lesser digit stabilization procedures (lesser toe
fusions) (Figure 7). The long term results show positive outcomes with having a lower
progression of degenerative changes in comparison of those who had a triple arthrodesis
(multiple fusions instead of reconstruction) performed in a span of twenty four years. The goal of
the reconstruction compared to the arthrodesis was to efficiently correct the Cavovarus deformity
with respect to function, radiographic changes, and gait/walking patterns. A triple arthrodesis
procedure was concluded to be left as a last resort / salvage procedure when all other procedures
fail (Figure 8). The triple arthrodesis procedure has greater chance of not uniting, foot alignment
errors, and various forms of immobility issues secondary to arthritic changes at adjacent joints.
Concluding remarks
In closing, CMT is a challenging progressive disease process with a variable phenotypic
presentation. Presently, there is no cure which will alter the course of the disease, but patients
should be aware that there are alternatives available to minimize the manifestation of the disease.
It is crucial to assess the patient with respect to patient goals, quality of life, and what
interventions a physician can provide to the patient. Once the disease is identified treatment
should then be assumed by the primary care physician, neurologist, podiatric surgeon, physical
medicine rehabilitation specialist or physical therapist, and even genetic counselor. Patients with
Identifying the apex and characteristics of the deformity, along with associated muscular
imbalances provide the best chance for optimal prognosis. For instance, young patients tend to
benefit from early surgical procedures to include reconstructive approaches; whereas patients
who suffer from severe or multi-planar deformities may respond best to triple arthrodesis and
adjunctive tendon transfers. It is imperative to treat this debilitating pathology through a
methodical and inter-disciplinary approach to achieve the best possible patient outcomes.
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Figure Legend
Figure 1. Neuronal structure of non-pathologic axon
Figure 2. Onion bulb formation. Electron micrograph of sural nerve from an individual
with CMT 1A showing characteristic concentric Schwann cell cytoplasmic processes
surrounding a myelinated axon (adapted from Benstead TJ, Grant IA. Charcot-MarieTooth Disease and Related Inherited Peripheral Neuropathies. Can. J. Neurol. Sci. 2001;
28: 199-214)
Figure 3. Clinical presentation of CMT patient with classic “stork leg” appearance and
Equinocavovarus foot alignment and claw toe deformity. (Adapted from McGlamry’s
Comprehensive Textbook of Foot and Ankle Surgery. Third Ed. Section 5: Chapter 34
Charcot- Marie- Tooth Disease. 2001; 1071-1089)
Figure 4. Clinical photograph of patient with noticeable Pes Cavus foot deformity.
Figure 5. Diagram of subtalar joint (STJ), midtarsal joint (MTJ), and forefoot with first
ray including the 1st metatarsal bone and its associated phalanges (proximal, middle, and
distal).
Figure 6. Radiographic assessment with increased calcaneal inclination angle, talar
dorsiflexion, and first metatarsal declination.
Figure 7. Forefoot reconstruction consisting of interphalangeal joint arthrodesis 1-4,
arthroplasty 5th digit, and dorsiflexory base wedge osteotomy of the 1st metatarsal (Adapted
from McGlamry’s Comprehensive Textbook of Foot and Ankle Surgery. Third Ed. Section
5: Chapter 34 Charcot- Marie- Tooth Disease. 2001; 1071-1089)
Figure 8. (A) Post operative patient who underwent triple arthrodesis and dorsiflexory
base wedge osteotomy with tibialis posterior tendon transfer. (B) 1 year post operatively
with hardware removed. No arthritic findings / symptomatology.
Figure 9. (A,B) Fibrinous partial thickness ulceration to lateral forefoot at boney
prominence secondary to CMT neuropathy CMT and associated drop foot