Pes cavus and hereditary neuropathies: when a relationship should be suspected

Abstract

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

J Orthopaed Traumatol (2010) 11:195201 DOI 10.1007/s10195-010-0114-y

REVIEW ARTICLE

Pes cavus and hereditary neuropathies: when a relationship should be suspected

S. Piazza G. Ricci E. Caldarazzo Ienco

C. Carlesi L. Volpi G. Siciliano

M. Mancuso

Received: 7 May 2010 / Accepted: 25 September 2010 / Published online: 21 October 2010 The Author(s) 2010. This article is published with open access at Springerlink.com

Abstract The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the rst signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or conrm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a spy sign, discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Keywords Pes cavus Hereditary peripheral

neuropathy Neurological evaluation

Multidisciplinary management

Introduction

Pes cavus is a foot deformity characterized by a high arch of the foot that does not atten with weight bearing; the deformity can be located in the forefoot, midfoot, hindfoot, or in a combination of all these sites (Figs. 1, 2). Pes cavus is a common nding in the general population, with prevalence of approximately 10% [1].

Frequently, pes cavus may be a sign of an underlying neurological disorder, including spinal cord and peripheral nerve pathologies, such us spino-cerebellar ataxia and hereditary peripheral neuropathies. A previous retrospective analysis of patients undergoing pes cavus surgery [2] revealed that almost one-third of apparently idiopathic cases suffered from a neurological disease.

Herein, we discuss the hereditary peripheral neuropathies (HPN) in which pes cavus plays a key role as a spy sign. A clear, complete, and detailed review of clinical and molecular features of these rare disorders may be useful in clinical management and differential diagnosis of patients who present with pes cavus as almost single sign of disease.

Hereditary peripheral neuropathies (HPN) are a heterogeneous group of peripheral nerve disorders, clinically characterized by sensorial and/or motor impairment, with reduction or absence of deep tendon reexes [3].

Foot deformities, including pes cavus, hammer toes, and twisting of the ankle, are commonly present in some HPN forms, such as CharcotMarieTooth (CMT) disease, hereditary neuropathy with predisposition to pressure palsies (HNPP), and distal hereditary motor neuropathy (DHMN) [4], but are uncommon in the other HPN. We will therefore discuss only the clinical features and genetic basis of HPN associated with pes cavus.

S. Piazza G. Ricci E. Caldarazzo Ienco C. Carlesi

L. Volpi G. Siciliano M. Mancuso (&)

Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy e-mail: [email protected]

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Fig. 1 Pes cavus and main en griffe in a patient with CMT1A

Fig. 2 Pes cavus in a patient with CMT1A

HPN associated with pes cavus

CharcotMarieTooth disease

The most common form of HPN is hereditary motor and sensory neuropathy (HMSN), also called CharcotMarie Tooth (CMT) disease. Prevalence is estimated at about 1740 per 100,000 [5].

CMT is a genetically heterogeneous disorder (Table 1), classied into demyelinating (CMT1 and CMT4), axonal (CMT2 and CMT4), and intermediate (CMT, CMTX,

CMT2E) forms, and caused by mutations in several genes coding for structural myelin proteins, gap-junction proteins, cytoskeleton components, enzymes, or transcription factor. CMT is usually transmitted as an autosomal dominant trait, although rarer X-linked (CMTX) or recessive forms have been reported [6, 7]. CMT is a slow progressive disease, usually with onset in the second or third decade. Rarely, CMT arises in early infancy (DejerineSottas and congenital hypomyelination diseases) [8] with a severe phenotype characterized by hypotonia and delay in motor milestones. CMT onset may also occur later, generally with a less aggressive clinical course [9].

The most common features in classical CMT phenotype are skeletal deformities such as pes cavus with hammer toes; less frequent skeletal signs are pes planus, twisting of ankle and tripping, and painful foot callosities. Scoliosis could be present in 10% of affected people [10, 11]. Neurological examination shows characteristic signs of a sensorimotor peripheral neuropathy. Sensory signs are usually less prominent (70%) than motor ones [12]. The most frequent ndings [13] are ataxia, hypoesthesia, and loss of vibration, two-point discrimination, and joint position sense. Motor impairment, which usually became evident during the course of disease, is responsible for upper and lower limb weakness and atrophy, with main en griffe (Fig. 1) and inverted champagne bottle legs. Steppage gait and foot drop are the rst most common motor signs. Deep tendon reexes are diminished or absent [14]. Muscle cramps, cold feet, acrocyanosis, and postural tremor are frequent complaints.

Electroneurography allows classication of CMT disease into two main forms: CMT1 or demyelinating form, characterized by a marked slowing in nerve conduction velocities (by denition, \38 m/s in upper limb motor nerves) and by a primary myelinopathy; and CMT2 or axonal form, in which nerve conduction values are preserved or only mildly slowed ([38 m/s in upper limb motor nerves) and the axon is the primary disease target [15]. The existence of a CMT subgroup showing nerve conduction velocity (NCV) values intermediate between CMT1 and CMT2 has been also reported [16, 17].

As previously reported, CMT diagnosis is based on clinical examination, electrophysiological ndings, and molecular testing. In selective cases, such as in patients with sporadic form or in whom molecular investigations result unable to demonstrate DNA defects, nerve biopsy might give relevant information for diagnosis and differential diagnosis. In particular, the typical histological marker of demyelinating neuropathies is represented by the presence of basal lamina onion bulbs, determined by concentric proliferation of Shawn cell cytoplasmic processes during the demyelination phenomenon and the remyelination tentative. In the advanced phase, loss of normal myelin covering (nude axon) has also been reported.

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Table 1 Genetic classication of hereditary motor and sensory neuropathies

Gene Inheritance Locus

HMSN1-CMT1

CMT1A: PMP-22 Dominant/sporadic 17p11

CMT1B: P0 protein Dominant lq22

CMT1C: LITAF Dominant 16pl3

CMT1D: EGR2 Dominant 10q21

CMT1E: P0 protein Dominant lq22

CMT1F: Neurolament light chain Dominant/sporadic 8p21

HMSN2-CMT2

CMT2A1: KIF1B Dominant lp36

CMT2A2: MFN2 Dominant lp36

CMT2B: RAB7 Dominant 3ql3-q22

CMT2C: TRPV4 Dominant 12q23-q24

CMT2D: GARS Dominant 7pl5

CMT2E: Neurolament light chain Dominant 8p21

CMT2F: HSPB1 Dominant/recessive 7q11-q21 CMT2G: Dominant 12ql2

CMT2I: PO Dominant lq22

CMT2J: PO Dominant lq22

CMT2L: HSPBE Dominant 12q24

AR-CMT2A Lam in A/C Recessive lq21.2

AR-CMT2E Med25 Recessive 19ql3.3

CMT2K: GDAP1 Dominant/recessive 8q21

HMSN3DSN/CHN

DSNA PMP-22 Dominant/recessive 17p11-2

DSNB MP2 Dominant/recessive lq22

DSNC EGRP2 Dominant 10q21/EGR2

DSND Dominant Sq23-24

DSN PRX Recessive 19ql3.1-13.2

DSN GDAP1 Recessive 8ql3-21.1

Congenital hypomyelination

CHA PMO-22 Dominant 17p11.2 CHB MP2 Dominant lq22

CHC EGRP2 Dominant/recessive 10q21

HMSN4-CMT4

CMT4A: GDAP1 Recessive 8q21

CMT4B1: MTMR2 Recessive 11q23

CMT4B2: SBF2 Recessive 11p15

CMT4C: SH3TC2 (KLAA1985) Recessive 5q32

CMT4D: NDRG1 Recessive 8q24

CMT4E: EGR2 Dominant/recessive 10q21

CMT4F: Periaxin Recessive 19ql3

CMT4H: FGD4 Recessive 12ql2

CMT4J FIG4 Recessive 6q21

HSMN5

Silver syndrome Seipin/BSCL2 Dominant 11ql3

Troyer syndrome SPG20 Recessive 13ql2.3

Hereditary motor and sensor neuropathy (http://www.ncbi.nlm.nih.gov/omim

Web End =http://www.ncbi. http://www.ncbi.nlm.nih.gov/omim

Web End =nlm.nih.gov/omim )

Large-caliber ber reduction and formation of isolated monostratied simple onion bulbs have been described in CMT2 [3].

There are no pharmacologic cures for CMT. A well-balanced diet and weight control can help minimize disability. Dietary supplements such as creatine, and

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co-enzyme Q have not been proven effective in treating CMT. Aerobic exercise and rehabilitation play an essential role in preserving quality of life of patients with CMT. A small percentage of patients with inherited neuropathy may respond to immunomodulatory therapy, such as prednisone or intravenous gammaglobulin (IVIG). Potentially neurotoxic medications, such as vincristine or cisplatinum, should be avoided [18]. Experimental studies showed that progesterone antagonist improves neuropathy in CMT1A rats, and it represents a promising pharmacologic target for CMT1A patients [19, 20].

DejerineSottas neuropathy and congenital hypomyelinating neuropathy

DejerineSottas (DSN) and congenital hypomyelinating (CHN) neuropathies are rare, severe, infantile-onset, demyelinating peripheral nerve diseases.

DSN is transmitted as an autosomal dominant or recessive trait (Table 1). Clinical onset occurs at up to 2 years of age, with motor and sensory impairment and skeletal deformities, more frequently represented by scoliosis. NCV of DSN patients is greatly compromised, with values \15 m/s. Sural nerve biopsies could show marked demyelination or predominant axonal loss [8, 18].

CHN, an autosomal dominant or recessive disease (Table 1), is characterized by severe hypotonia (oppy infant), dysphagia, and respiratory insufciency, usually occurring within the rst year of life. NCV is very slow (\10 m/s), and sural nerve biopsy presents pathological features similar to those of DSN [16, 17].

Hereditary neuropathy with liability to pressure palsies

The prevalence of hereditary neuropathy with liability to pressure palsies (HNPP) is estimated to be at least 16 per 100,000 [21].

HNPP is an autosomal dominant disorder due to a deletion in chromosome 17p11.2 which codes for peripheral myelin protein (PMP22), an integral membrane protein that is a major component of myelin in the peripheral nervous system [22].

Patients present acute and transient episodes of focal neuropathies, commonly affecting the ulnar, radial, and peroneal nerves and the brachial plexus. These episodes are typically painless, recurrent, and occur after trauma or pressure, or with no evident precipitating factor [23]. The palsies may be debilitating, last for days to weeks, and require installation of specic orthosis. Onset of HNPP is usually in adolescence, with a high degree of penetrance; however, clinically asymptomatic gene carriers are reported. Neurological examination could evidence hypoactive

deep tendon reexes and mild pes cavus, even in clinically asymptomatic patients [24].

With ageing, these patients can have a signicant clinical overlap with CMT1, as the repeated injuries to the nerve can prevent full reversal.

Electrophysiological examination shows prolonged motor and sensory nerve conduction velocities (NCV) [25] and conduction blocks that are characteristic of the affected nerves, especially over entrapment sites. NCV abnormalities are also present in those nerves apparently unaffected by palsy and in asymptomatic gene carriers [26].

Histological analysis of sural nerve biopsies shows segmental area of de- and remyelination. The pathological hallmark of HNPP is presence of tomacula, consisting of massive variable myelin overfolding [27]. In rare of HNPP patients nerve biopsy could be present only the axonal regeneration signs [28].

There is no specic treatment for HNPP. Current management consists of early detection and diagnosis of the disease, to reduce excessive force or repetitive movements, or to avoid static joint positions. Chemotherapeutic agents, such as vincristine, should be used with great caution [29].

Distal hereditary motor neuropathies

Distal hereditary motor neuropathies (dHMNs) are very rare genetic disorders (approximately prevalence rate of 1/100,000) [30], inherited as an autosomal dominant, autosomal recessive or X-linked trait [3133] (Table 2). dHMN usually presents as a classical peroneal muscular atrophy syndrome without sensory symptoms [34]. The clinical picture consists of progressive weakness and wasting of the extensor muscles of the toes and feet. Later,

Table 2 Genetic classication of distal hereditary motor neuropathies

Type Inheritance Gene/locus

HMN I AD Unknown

HMN II AD HSP27 (HSPB1)

HMN II AD HSP22 (HSPB8)

HMN III AR 11q13

HMN IV AR 11q13

HMN V AD GARS

HMN V AD BSC12

HMN VI AR IGHMBP2

HMN VIIA AD 2q14

HMN VIIB AD DCTN1

HMN/ALS4 AD SETX

HMN-J AR 9p21.1-p12

Congenital distal SMA AD 12q23-12q24

Distal hereditary motor neuropathies (http://www.ncbi.nlm.nih.gov/omim

Web End =http://www.ncbi.nlm.nih.gov/ http://www.ncbi.nlm.nih.gov/omim

Web End =omim )

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weakness and wasting also involve the distal upper limb muscles. Foot deformity is a common feature. Additional features are represented by involvement of hands, vocal cord paralysis, diaphragm paralysis, and pyramidal tract signs [35].

In dHMN patients, electromyography evidences signs of chronic denervation, and motor NCV study shows an amplitude reduction of compound muscle action potentials or a moderate decrease in velocity. Sensory nerve conductions and amplitudes were normal [4, 36].

Sural nerve biopsy has rarely been performed in dHMN patients and usually showed normal ndings [4]. Muscle biopsy shows neurogenic damage related to lower motor neuron degeneration [37].dHMN has no specic treatment. Patients need neurological follow-up to evaluate the diseases clinical progression and for referral to rehabilitation or orthopedic service for correct management of complications.

Etiopathogenesis of pes cavus in HPN

Pes cavus in HPN derives from plantar exion deformity of the rst metatarsal due to imbalance between the intrinsic muscles of the foot and the muscles of the leg. The exact physiopathological mechanisms responsible for pes cavus genesis in HPN is not entirely claried, even if two main hypotheses have been formulated [38].

The rst hypothesis assigns an important role in the pathogenesis of this skeletal deformity to overaction of the peronei in comparison with the antagonist tibialis anterior, secondary to the leg muscles amyotrophy pattern in the disease. In particular, it has been supposed that a weak peroneus brevis is overpowered by a relatively stronger tibialis posterior, causing adduction of the forefoot and inversion of the hindfoot. In addition, a weak tibialis anterior is overpowered by a stronger peroneus longus, causing plantarexion of the rst metatarsal and anterior pes cavus [12, 39 41]. The intrinsic foot muscles develop contractures, while the long extensor to the toe muscles, recruited to assist in ankle dorsiexion, causes claw toes deformity.

The second hypothesis is that precocious and primary involvement of intrinsic foot muscles is responsible for the pathogenesis of pes cavus, because the deformity is observed in the early stages of the disease, also when there is not yet evidence of leg muscle weakness [42]. A magnetic resonance imaging (MRI) study of amyotrophic leg and foot muscles performed in patients with CMT [43] reported precocious fatty inltration of intrinsic foot muscles, also when leg muscles are still preserved. The authors deduced that the weakness of the lumbricals and the other intrinsic foot muscles, due to selective denervation, could cause the dorsiexion of metatarsophalangeal joints,

initially responsible for the attening of the transverse arcus plantaris and the clawing of the toes. Dorsiexion of metatarsophalangeal joints during gait could also determine the wrapping around the metatarsal head of the plantar aponeurosis and the contraction of the short exors, with secondary shortening of the Achilles tendon and limitation of ankle dorsiexion. A subsequent MRI muscle study in CMT patients also seems to conrm a possible primary role of intrinsic foot muscle in pes cavus pathogenesis [44]. The sensitivity of MRI for detecting precocious denervation changes in early stages of HMN and CMT has been also recently conrmed [45].

In conclusion, the foot deformity pes cavus, secondary to plantar exion deformity of the rst metatarsal, could be associated to several neurological disorders, including spinal cord and peripheral nerve pathologies, such us spino-cerebellar ataxia and hereditary peripheral neuropathies.

In this article, we have reported the HPN in which pes cavus plays a key role as a spy sign [46, 47], as a precocious manifestation of HPN. Accurate clinical evaluation in patients with pes cavus is therefore necessary to exclude or conrm the presence of contemporary involvement of peripheral nerves [48, 49], especially in the early stage of

Fig. 3 When pes cavus might reveal HPN: a proposed diagnostic algorithm. NCS nerve conduction studies, HPN hereditary peripheral neuropathies

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the disease, when other signs of HPN may not yet be present or evident.

When should HPN be suspected in a patient with pes cavus? Clinical data suggestive of HPN are represented by evidence of: bilateral pes cavus, positive family history for pes cavus and/or gait impairment, distal muscle hypotrophy of limbs, and sensorial and/or motor dysfunction.

When one or more of these signs are present, the patient should be subjected to neurological evaluation to complete the HPN diagnostic algorithm, based on electroneurographysiological studies and, subsequently, molecular analysis (see Fig. 3).

Conict of interest None.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

1. Japas LM (1968) Surgical treatment of pes cavus by tarsal vosteotomy: preliminary report. J Bone Joint Surg Am 50:927944

2. Brewerton DA, Sandifer PH, Sweetnam DR (1963) Idiopathic pes cavus: an investigation into its aetiology. Br Med J 14:659661

3. Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charco-Marie-Tooth disease. Lancet Neurol 8:654667

4. Irobi J, Dierick I, Jordanova A, Claeys KG, De Jonghe P, Timmerman V (2006) Unraveling the genetics of distal hereditary motor neuronopathies. Neuromolecular Med 8:131146

5. Martyn CN, Hughes RAC (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62:310318

6. Boerkoel CF, Takashima H, Lupski JR (2002) The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy. Curr Neurol Neurosci Rep 2:7077

7. Pareyson D, Testa D, Morbin M, Erbetta A, Ciano C, Lauria G, Milani M, Taroni F (2003) Does CMT1A homozygosity cause more severe disease with root hypertrophy and higher CSF proteins? Neurology 60:17211722

8. Chance PF, Lupski JR (1994) Inherited neuropathies: Charcot Marie Tooth disease and related disorders. Baillieres Clin Neurol 3:373385

9. Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J (2004) Phenotypic clustering in MPZ mutations. Brain 127:371384

10. Holmes JR, Hansen ST (1993) Foot and ankle manifestations of Charcot Marie Tooth disease. Foot Ankle 14:476486

11. Banchs I, Casasnovas C, Albert A, De Jorge L, Povedano M, Montero J, Martnez-Matos JA, Volpini V (2009) Diagnosis of Charcot-Marie-Tooth disease. J Biomed Biotechnol 2009:985415

12. Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Dyck PJ, Thomas PK (eds) Peripheral neuropathy, 4th edn. Elsevier Saunders, Philadelphia, pp 16231658

13. Szigeti K, Lupski JR (2009) Charcot-Marie-Tooth disease. Eur J Hum Genet 17:703710

14. Mann RA, Missirian J (1988) Pathophysiology of Charcot Marie Tooth disease. Clin Orthop 234:221228

15. Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy (types I and II). Brain 103:259280

16. Birouk N, LeGuern E, Maisonobe T, Rouger H, Gouider R, Tardieu S, Gugenheim M, Routon MC, Lger JM, Agid Y, Brice A, Bouche P (1998) X linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology 50:10741082

17. Zchner S, Noureddine M, Kennerson M, Verhoeven K, Claeys K, De Jonghe P, Merory J, Oliveira SA, Speer MC, Stenger JE, Walizada G, Zhu D, Pericak-Vance MA, Nicholson G, Timmerman V, Vance JM (2005) Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nature Genet 37:289294

18. Grandis M, Shy ME (2005) Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol 7:2331

19. Sereda MW, Meyerzu Hrste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT1A). Nat Med 9:15331537

20. Koenig HL, Schumacher M, Ferzaz B, Thi AN, Ressouches A, Guennoun R, Jung-Testas I, Robel P, Akwa Y, Baulieu EE (1995) Progesterone synthesis and myelin formation by Schwann cells. Science 268:15001503

21. Meretoja P, Silander K, Kalimo H, Aula P, Meretoja A, Savontaus ML (1997) Epidemiology of hereditary neuropathy with liability to pressure palsies (HNPP) in south western Finland. Neuromuscul Disord 7:529532

22. Snipes GJ, Suter U, Welcher AA, Shooter EM (1992) Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J Cell Biol 117:225238

23. Pareyson D, Taroni F (1996) Deletion of the PMP22 gene and hereditary liability to pressure palsies. Curr Opin Neurol 9:348354

24. Chance PF (1999) Overview of hereditary neuropathy with liability to pressure palsies. Ann N Y Acad Sci 14(883):1421

25. Earl CJ, Fullerton PM, Wakeeld GS, Schutta HS (1964) Hereditary neuropathy with liability to pressure palsies. Q J Med 33:481498

26. Mouton P, Tardieu S, Gouider R, Birouk N, Maisonobe T, Dubourg O, Brice A, LeGuern E, Bouche P (1999) Spectrum of clinical and electrophysiological features in HNPP patients with the 17p11.2 deletion. Neurology 52:14401446

27. Madrid R, Bradley WG (1975) The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy): studies on the formation of the abnormal myelin sheath. J Neurol Sci 25:415448

28. Sessa M, Nemni R, Quattrini A, Del Carro U, Wrabetz L, Canal N (1997) Atypical hereditary neuropathy with liability to pressure palsies (HNPP): the value of direct DNA diagnosis. J Med Genet 34:889892

29. Kalfakis N, Panas M, Karadima G, Florosku P, Kokolakis N, Vassilopoulos D (2002) Hereditary neuropathy with liability to pressure palsies emerging during vincristine treatment. Neurology 59:14701471

30. Radhakrishnan K, Thacker AK, Maloo JC (1988) A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya. J Neurol 235:422424

31. Nelson JN, Amick LD (1966) Heredofamilial progressive spinal muscular atrophy: a clinical and electromyographic study of a kinship. Neurology 16:306

123

J Orthopaed Traumatol (2010) 11:195201 201

32. Emery AEH (1971) Review: the nosology of the spinal muscular atrophies. J Med Genet 8:481495

33. Takata RI, Martins CES, Passosbueno MR, Abe KT, Nishimura AL, Da Silva MD, Monteiro A Jr, Lima MI, Kok F, Zatz M (2004) A new locus for recessive distal spinal muscular atrophy at Xq13.1q21. J Med Genet 41:224229

34. Harding AE (1993) In: Dyck PJ, Thomas PK, Grifn JW, Low PA, Poduslo JF (eds) Peripheral Neuropathy. W.B. Saunders, Philadelphia, pp 10511064

35. Irobi J, De Jonghe P, Timmerman V (2004) Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet 1:195202

36. Frequin ST, Gabreels FJ, Gabreels-Festen AA, Joosten EM (1991) Sensory axonopathy in hereditary distal spinal muscular atrophy. Clin Neurol Neurosurg 93:323326

37. Timmerman V, Raeymaekers P, Nelis E, De Jonghe P, Muylle L, Ceuterick C, Martin JJ, Van Broeckhoven C (1992) Linkage analysis of distal hereditary motor neuropathy type II (distal HMN II) in a single pedigree. J Neurol Sci 109:4148

38. Burns J, Ouvrier R (2006) Pes cavus pathogenesis in Charcot-Marie-Tooth disease type 1A. Brain 129:E50; author reply E51

39. Tynan MC, Klenerman L, Helliwell TR, Edwards RH, Hayward M (1992) Investigation of muscle imbalance in the leg in symptomatic forefoot pes cavus: a multi disciplinary study. Foot Ankle 13:489501

40. Guyton GP, Mann RA (2000) The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin 5:317326

41. Berciano J, Garca A, Combarros O (2003) Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication. Muscle Nerve 27:3439

42. Sabir M, Lyttle D (1983) Pathogenesis of pes cavus in Charcot-Marie-Tooth disease. Clin Orthop Relat Res 175:173178

43. Gallardo E, Garca A, Combarros O, Berciano J (2006) Charcot-Marie-Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles. Brain 129:426437

44. Chung KW, Suh BC, Shy ME, Cho SY, Yoo JH, Park SW, Moon H, Park KD, Choi KG, Kim S, Kim SB, Shim DS, Kim SM, Sunwoo IN, Choi BO (2008) Different clinical and magnetic resonance imaging features between Charcot-Marie-Tooth disease type 1A and 2A. Neuromuscul Disord 18:610618

45. Del Porto LA, Nicholson GA, Ketheswaren P (2010) Correlation between muscle atrophy on MRI and manual strength testing in hereditary neuropathies. J Clin Neurosci 2010 Apr 15 Apr 15 Epub ahead of print

46. Carter GT, England JD, Chance PF (2004) Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management. IDrugs 7:151159

47. Pareyson D, Scaioli V, Laura M (2006) Clinical and electro-physiological aspects of Charcot-Marie-Tooth disease. Neuro-molecular Med 8:322

48. Berciano J, Gallardo E, Garca A, Infante J, Mateo I, Combarros O (2006) Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study. J Neurol Neurosurg Psychiatry 77:11691176

49. Reilly MM, Shy ME (2009) Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry 80: 13041314

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