The deformities in Charcot-Marie-Tooth disease are best understood as a result of relative imbalance rather than as the result of absolute weakness of the motor units powering the foot.7,10,12,14,16 For instance, the persistent strength of the toe extrinsics combines with the weakened intrinsics to produce clawtoe deformities, a feature common to most peripheral motor neuropathies. In a classic peripheral neuropathy, motor nerve dysfunction is proportional to the length of the nerve to the muscle it supplies. A constant feature of Charcot-Marie Tooth disease is selective denervation of the anterior and lateral compartments of the leg.7 Motor units in the posterior compartments usually are spared despite equally long nerve pathways.
Also unique to Charcot-Marie Tooth disease is the relative sparing of the peroneus longus,12 which overpowers the anterior tibialis and plantar flexes the first ray to create a forefoot cavus, one of the signature deformities of the disease. Peroneus longus-sparing was confirmed by Tynan et al, who described preservation of cross-sectional muscle on magnetic resonance imaging (MRI) relative to the anterior and lateral compartments.17
The extensor digitorum longus (EDL) and extensor hallucis longus (EHL) occasionally are spared as the toe extensors become accessory dorsiflexors, a role that accentuates the clawtoe deformities.7 For this reason the Jones procedure, a holdover from the days of polio surgery that transfers to the EHL to the first metatarsal to transform it into a foot dorsiflexor, continues to have a role in selected patients with Charcot-Marie Tooth disease. Extensor hallucis longus and EDL-sparing is neurologically puzzling as they are anterior compartment muscles located more distal than the affected anterior tibialis.
A rare inheritable peripheral nerve disorder is hereditary neuropathy with liability to pressure palsies (HNPP).11 The disease is marked by extreme sensitivity to nerve compression at multiple sites including the carpal tunnel, cubital tunnel, tarsal tunnel, and fibular neck.11 Hereditary neuropathy with liability to pressure palsies shares a common genetic link with the predominant variants of Charcot-Marie Tooth disease; both are caused by abnormalities in the production of peripheral myelin protein 22 (PMP-22).13 This suggests the sensitivity to nerve compression in HNPP also may play a role in the foot disorders of Charcot-Marie Tooth disease. If a subtle compressive palsy could explain the pattern of motor denervation in Charcot-Marie Tooth disease, the patterns of peroneal nerve branching about the fibular neck must show sufficient separation to explain the different neurologic patterns. The nerve anatomy must support sparing the peroneus longus and toe extensors.
I examined the branching patterns of the common peroneal nerve about the fibular neck to ascertain whether nerve branches emerge to the peroneus longus before the main nerve trunk passes the fibular neck, whether significant distance exists between the first branches to the peroneus longus and brevis, and whether the nerve to the anterior tibialis can be expected to be exceptionally vulnerable to compression.
MATERIALS AND METHODS
I dissected the common peroneal nerve and its branching patterns about the fibular head in 12 fresh cadaveric specimens. I also documented the origin of the nerve branches to the primary motor groups in the lateral and anterior compartments. All measurements were taken from where the common peroneal nerve crossed the posterior margin of the fibular neck. A micrometer was used to make all measurements recorded to the nearest millimeter.
The locations of the first branch points to the peroneus brevis, the peroneus longus, the anterior tibialis, and the toe extensors, and their qualitative position relative to the surface of the fibular neck. The peroneus longus is divided into a more proximal and more distal division by the main trunk of the nerve running through the muscle as it rounds the neck of the fibula. The first branches to both divisions were identified.
The peroneus longus was consistently the first muscle distal to the knee to be innervated by the common peroneal nerve. The main trunk of the nerve uniformly passed through the peroneus longus muscle on its path around the fibular head, dividing the muscle into superficial and deep components. Nine of 12 specimens had a branch to the superficial component of the peroneus longus at or proximal to the reference point where the nerve reached the bone. The first branch of the peroneal nerve was located 2.1 ± 6.7 mm proximal to the reference point. The branch then passed to the superficial portion of the muscle away from the fibula. A portion of the peroneus longus was supplied by a nerve branch not expected to be subject to substantial compression in nine of the 12 specimens (Fig 1).
The deep portion of the peroneus longus was supplied by multiple and variable nerve branches off the main trunk of the nerve as it passed through the muscle on its way to the peroneus brevis more distally. The location of the first branch varied and was a mean of 21.6 ± 22 mm distal to the reference point. Two to 10 subsequent branches were identified in this portion of the nerve.
The peroneus brevis was supplied by the largest branch of the nerve running through the length of the peroneus longus. Like the deep portion of the longus, it was supplied by multiple branches. On average, the first branch to the peroneus brevis muscle belly was 110.9 ± 19 mm distal to the reference point. The nerves to the peroneus longus and peroneus brevis were not directly applied to the surface of the fibula.
The anterior compartment musculature was supplied by two primary branches. The first, more proximal branch supplied the tibialis anterior. Like the nerve to the superficial portion of the peroneus brevis, this branch typically originated at or proximal to the posterior margin of the fibula. The mean origin was 1.6 ± 3.1 mm proximal to the reference point. However, the nerve to the tibialis anterior had a vulnerable course. It passed deep to apply directly to the periosteum of the fibular neck before wrapping around the bone to enter the anterior compartment. The nerve was applied to the surface of the bone for 17.2 ± 1.4 mm.
The second branch to the anterior compartment takes a more linear course through the lateral compartment before entering the anterior compartment and supplying the EDL and EHL. This nerve was applied to the surface of the bone for an average of 42.1 ± 10.4 mm before piercing the fascia to enter the anterior compartment.
Charcot-Marie-Tooth disease is a heterogeneous group of disorders caused by inheritable defects in any of several constituent proteins of the myelin sheath of the peripheral nerve.11 Although the disease is mostly compatible with a normal lifespan and considerable physical activity, associated foot deformities are a major source of pain and morbidity.7 Despite advances in our understanding of the disease during the last decade, there are no new treatment options beyond bracing and deformity-correcting surgery.
There are some limitations to this study. A larger number of specimens are required to fully document all potential branching patterns of the peroneal nerve about the fibular head. Such a detailed level of work eventually might be appropriate, but it would be of limited scientific interest in this context. This dataset is sufficient to suggest: (1) the discrete branches of the peroneal nerve are substantially segregated anatomically and mechanically; and (2) there is sufficient variability to potentially explain the variable features of the patterns of motor weakness in patients with Charcot-Marie Tooth disease. A descriptive anatomic study is inherently limited and is presented to show the potential for nerve compression as a contributor to the pathophysiologic features in Charcot-Marie Tooth disease. It is not reasonable to expect dissection of a cadaveric limb can provide anything beyond inference regarding the mechanical environment of a nerve. Other studies are required. Ultrastructural examination of the peroneal nerve branches in patients with Charcot-Marie Tooth disease or the murine model of the disease might show changes consistent with chronic compression. The most compelling would be a controlled surgical study of unilateral peroneal nerve release in patients early in their diagnosis.
Foot deformities associated with Charcot-Marie Tooth disease can be explained on a phenomenologic basis from the patterns of motor involvement, but the underlying causes of those patterns are not known. Nerve dysfunction in the disorder is not related to the length of the nerve. Comparing the relative cross-sectional areas of the motor units of the leg also fails to explain why strength in even relatively small distal muscles such as the flexor hallucis longus usually are spared until late in the disease, and such comparison can offer no explanation for sparing of the peroneus longus or toe extensors. Some clues to the problem may be present from the genetic data compiled on inheritable neuropathies during the last decade.
Although some cases of Charcot-Marie Tooth disease and HNPP are caused by point mutations in the gene for PMP-22,15 the phenotypic difference between the most common forms of the disease seems to be a gene dosage effect.13 The most common variant of Charcot-Marie Tooth disease is CMT-1A, accounting for approximately 60% of the total number of patients.11,13 It is caused by a recombination error resulting in a segmental trisomy along chromosome 17 (three copies of the PMP-22 gene are on the same chromosome).3 Hereditary liability to pressure palsy is caused by a gene deletion.11 The precise role of PMP-22 is unknown, but most evidence indicates it links layers of myelin in the nerve sheath.11 It is unclear why a dearth and abundance of PMP-22 can lead to nerve dysfunction, but it seems precise stoichiometry is critical for protein to perform its role.5
Charcot-Marie-Tooth disease is a heterogeneous disorder that encompasses various genetic defects.11 Only the most common forms of the disease are clearly linked to PMP-22 and can be compared with HNPP. Numerous defective gene products lead to different clinical presentations in the spectrum of this disease.11 As with PMP-22, our understanding of the normal function of these gene products is in its infancy. However, the genes identified in other forms of Charcot-Marie Tooth disease are suspected to play a role in sustaining nerve conduction.11
If the phenotypes of Charcot-Marie Tooth disease and HNPP are characterized by increased sensitivity to nerve compression, it would be reasonable to ask why seemingly opposite gene dosages could have qualitatively similar clinical results. The answer is not clear, but it seems that a precise stoichiometry of PMP-22 is required for functioning. In a mouse model of a similar gain-of-function gene duplication, excess PMP-22 combined with connexin and accumulated as intracellular myelin-like figures.5 The implication of this sequestration of connexin by PMP-22 on nerve function is unclear.5 It has been suggested that PMP-22 may play a role in the early development of the Schwann cell, and that these developmental abnormalities may be more critical in disease development.8 Electrical abnormalities in nerve conduction velocity are present by 2 years and are a hallmark of the disease in adulthood.6,9 The CMT-1A phenotype has been associated with presumed dysfunction of PMP-22 caused by point mutations and its overabundance caused by gene duplication.15 Whatever the role of PMP-22, it seems to be sensitive to perturbations in the structure or quantity of protein.
It is relatively easy to measure the locations of the branch points of the nerve. However, the mechanical stimuli each nerve branch receives from its surrounding structures is harder to quantify. Several features of the anatomic dissection suggest different mechanical environments. First, the nerve to the tibialis anterior appeared remarkably vulnerable to compression as it wrapped tightly around the fibular neck. It took a sharp turn and was directly opposed to the periosteum along its entire course past the fibular neck. Although the branches of the EHL and EDL were longer and had more contact with bone for a greater distance, they took a less tortuous course to their destination. Second, nerve branches to the peroneus longus were proximal to the passage of the common peroneal nerve past the fibular neck. The peroneus longus was innervated much more distally than the peroneus brevis, and also had a portion of its nerve supply that completely avoided the presumed area of greatest compression.
Clinical management of patients with Charcot-Marie Tooth disease can be frustrating. The disease is progressive and deformities often recur,7 and fusions performed to obviate this possibility have a substantial morbidity.18 Gene therapy is in the remote future and may be limited in a disease that, in cases of new mutations or recombination errors, often fails to be recognized until adolescence. If hypersensitivity to localized nerve compression exists in Charcot-Marie Tooth disease, it suggests that surgical decompression may be beneficial. Surgical decompression of the peroneal nerve in Charcot-Marie Tooth disease has not been studied. Data on nerve decompression in patients with Charcot-Marie Tooth disease focus on pain relief.1,2,4 Trigeminal neuralgia has been addressed with nerve decompression in patients with this disease.4 Some authors suggest nerve decompression at the wrist can be clinically effective in patients with late-stage Charcot-Marie Tooth disease and well-established pain symptoms.1,2 Other than pain, the upper extremity manifestations of Charcot-Marie Tooth disease rarely require surgical attention, and no attempts at nerve decompression to preserve motor function have been reported. The progression of deformity is usually more urgent in the foot.7
I thank Brent Parks for laboratory assistance.
1. Brown RE, Zamboni WA, Zook EG, Russell RC. Evaluation and management of upper extremity neuropathies in Charcot-Marie-Tooth disease. J Hand Surg Am
2. Chalekson CP, Brown RE, Gelber DA, Haws MJ. Nerve decompression at the wrist in patients with Charcot-Marie-Tooth disease. Plast Reconstr Surg
3. Chance PF, Abbas N, Lensch MW, Pentao L, Rao BB, Patel PI, Lupski JR. Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17. Hum Mol Genet
4. de Matas M, Francis P, Miles JB. Microvascular decompression for trigeminal neuralgia in Charcot-Marie-Tooth disease. J Neurosurg
5. Dickson KM, Bergeron JJ, Shames I, Colby J, Nguyen DT, Chevet E, Thomas DY, Snipes GJ. Association of calnexin with mutant peripheral myelin protein-22 ex vivo: a basis for “gain-of-function” ER diseases. Proc Natl Acad Sci USA
6. Garcia A, Combarros O, Calleja J, Berciano J. Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood: a longitudinal clinical and electrophysiologic study. Neurology
7. Guyton GP, Mann RA. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin
8. Hanemann CO, Muller HW. Pathogenesis of Charcot-Marie-Tooth 1A (CMT1A) neuropathy. Trends Neurosci
9. Hanson P, Deltombe T. Preliminary study of large and small peripheral nerve fibers in Charcot-Marie-Tooth disease, type I. Am J Phys Med Rehabil
10. Holmes JR, Hansen ST Jr. Foot and ankle manifestations of Char-cot-Marie-Tooth disease. Foot Ankle
11. Lupski JR. Charcot-Marie-Tooth disease: a gene dosage effect. Hosp Pract
12. Mann RA, Missirian J. Pathophysiology of Charcot-Marie-Tooth disease. Clin Orthop Relat Res
13. Murakami T, Garcia CA, Reiter LT, Lupski JR. Charcot-Marie-Tooth disease and related inherited neuropathies. Medicine (Balti-more)
14. Olney B. Treatment of the cavus foot. Deformity in the pediatric patient with Charcot-Marie-Tooth. Foot Ankle Clin
. 2000;5: 305-315.
15. Roa BB, Garcia CA, Lupski JR. Charcot-Marie-Tooth disease type 1A: molecular mechanisms of gene dosage and point mutation underlying a common inherited peripheral neuropathy. Int J Neurol
16. Sabir M, Lyttle D. Pathogenesis of pes cavus in Charcot-Marie-Tooth disease. Clin Orthop Relat Res
17. Tynan MC, Klenerman L, Helliwell TR, Edwards RH, Hayward M. Investigation of muscle imbalance in the leg in symptomatic fore-foot pes cavus: a multidisciplinary study. Foot Ankle
. 1992;13: 489-501.
18. Wukich DK, Bowen JR. A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease. J Pediatr Orthop