A PATIENT WITH NEUROFIBROMATOSIS TYPE 1 AND CHARCOT–MARIE–TOOTH DISEASE TYPE 1BERIC LANCASTER, MD, PhD, LAUREN B. ELMAN, MD, and STEVEN S. SCHERER, MD, PhD

Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce Street, 3W Gates Neurology, Philadelphia,Pennsylvania 19104, USA

Accepted 12 August 2009

ABSTRACT: We describe a patient with both neurofibromato-sis type 1 and Charcot–Marie–Tooth disease type 1B. Althoughone might expect an overwhelming tumor burden due to thecombination of these two disorders, the two mutations did notappear to interact.

Muscle Nerve 41: 555–558, 2010

Neurofibromatosis type 1 (NF1; OMIM162220) is an autosomal dominant disorder char-acterized by multiple tumor types, particularly neu-rofibromas. It is caused by loss-of-function muta-tions in the NF1 gene on chromosome 17.1 Thelarge size of the NF1 gene makes detection ofsome mutations problematic, but the most compre-hensive genetic testing available can detect NF1mutations in 95% of patients with NF1.2 NF1 isdiagnosed based on the presence of two or moreof the following criteria: multiple cafe-au-lait mac-ules, two or more neurofibromas (or one plexi-form neurofibroma), a family history of NF1, axil-lary/inguinal freckling, optic nerve glioma, two ormore Lisch nodules, or bone dysplasia.3 Charcot–Marie–Tooth disease type 1B (CMT1B; OMIM11820) is an autosomal dominant demyelinatingneuropathy caused by mutations in the myelin pro-tein zero gene (MPZ) on chromosome 1. Hereinwe describe a patient with both NF1 and CMT1B.

CASE REPORT

A 50-year-old man sought evaluation for 3 monthsof progressive foot numbness. He had been diag-nosed with NF1 in childhood on the basis of multi-ple neurofibromas, including a plexiform neurofi-broma that had been resected from his arm in

young adulthood. He had never been tested formutations in NF1. He was adopted and did notknow the health issues of his biological family. Hehad no children. He presented with multiple cafe-au-lait macules and multiple subcutaneous neurofi-bromas. There was mild weakness of toe extension(4þ/5), and he could not walk on his heels or tan-dem walk. Cold perception was decreased distal tothe knees, and vibration perception was absent onthe toes and decreased at the ankles. Reflexeswere absent at the ankles and 1þ elsewhere. Rom-berg’s sign was present. His CMT neuropathyscore4 was 12. Motor nerve conduction studiesshowed uniform and severe slowing and propor-tional prolongation of distal latencies, withdecreased amplitudes in the distal lower extremitymuscles (Table 1). Sensory nerve action potentials(SNAPs) were absent except for a radial SNAP thatwas severely decreased in amplitude and moder-ately slowed. Needle EMG showed length-depend-ent, chronic, active denervation (Table 2). The fol-lowing tests were normal: vitamin B12 levels; Lymeantibody; serum protein electrophoresis; and glu-cose tolerance test. Genetic testing for causes ofCMT1 and CMT4 (PMP22 duplication/deletion,and sequencing of PMP22, LITAF, EGR2, GJB1/CX32, PRX, GDAP1, and SH3TC2) was negativeexcept for a 449-1G>A in MPZ. This is a novelmutation that affects the splice site acceptor forexon IV (Fig. 1). It would be predicted to causeskipping of this exon, which encodes the trans-membrane domain of P0 (Fig. 2), the proteinencoded by MPZ.5

DISCUSSION

Peripheral nervous system symptoms, particularlymononeuropathies and radiculopathies related tonerve tumors, are well-recognized in NF1.6 Theassociation between NF1 and polyneuropathy isless clear. Approximately 1% of patients with NF1have a mild, predominantly sensory, indolentlyprogressive polyneuropathy that is not otherwiseexplained.7,8 Given the prevalence of idiopathicpolyneuropathy in the general population,9 someof these cases may be coincidental, so it has beensuggested that patients with NF1 who develop poly-neuropathy should be evaluated for an underlyingcause; neurofibromatous neuropathy is a diagnosisof exclusion.1

Abbreviations: CMT, Charcot–Marie–Tooth disease; CMT1, Charcot–Marie–Tooth disease type 1; CMT1A, Charcot–Marie–Tooth disease type1A; CMT1B, Charcot–Marie–Tooth disease type 1B; CMT1X, Charcot–Marie–Tooth disease X-linked; CMT4, Charcot–Marie–Tooth disease type4; EGR2, early growth response 2 gene, OMIM #129010; GDAP1, gangli-oside-induced differentiation protein 1 gene, OMIM #606598; GJB1/CX32,gap junction B1/connexin32 gene, OMIM #304040; LITAF, lipopolysaccha-ride-induced transcription factor gene, OMIM #603795; MPZ, myelin pro-tein zero gene, mutated in CMT1B, OMIM #159440; Mpz, mousehomolog of MPZ; NF1, neurofibromatosis type 1; NF1, neurofibromingene, OMIM #162200; Nf1, mouse homolog of NF1; OMIM, Online Men-delian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/); P0, myelinprotein zero, the protein encoded by MPZ; PMP22, peripheral myelin pro-tein 22 gene, duplicated in CMT1A, OMIM #601097; PRX, periaxin gene,OMIM #605725; SH3TC2, Sh3 domain and tetratricopeptide repeat do-main 2 gene, OMIM #608206

Correspondence to: E. Lancaster; e-mail: eric.lancaster@uphs.upenn.edu

VC 2009 Wiley Periodicals, Inc.Published online 13 November 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.21546

Key words: Charcot–Marie–Tooth disease; myelin protein zero;neurofibroma; neurofibromatosis type 1; neuropathy

Neurofibromatosis with CMT1B MUSCLE & NERVE April 2010 555

P0 is the most abundant myelin protein and isthe molecular glue of the myelin sheath. Morethan 100 different MPZ mutations have been iden-tified,10 and their associated phenotypes vary con-siderably.11 The mildest phenotypes result frommutations that likely cause simple loss-of-function(e.g., E71X, D75frameshift, and V102frameshift)and thereby produce a demyelinating neuropathyowing to haplotype insufficiency. That haplotypeinsufficiency of MPZ also causes a late-onsetdemyelinating neuropathy in mice12,13 stronglysupports the idea that the proper amount of P0 incompact myelin is crucial. The mutation found inour patient (449-1G>A) affects the splice siteacceptor of exon 4 and is associated with a mildphenotype. Two other mutations that affect thesame base, 449-1G>C14 and 449-1G>T,15,16 havebeen reported previously, but the clinical pheno-types of these patients were not described in suffi-cient detail to allow comparison to our patient. Allthree splice site mutations would be expected toresult in the loss of exon 4 and hence the trans-membrane domain of P0. If these P0 transcriptssplice to exon 5 or 6, then it is possible that somemutant P0 protein is made and produces morethan a simple loss of function. The severity of neu-ropathy in a 55-year-old patient from a family witha mutation at the þ2 site of intron 4 (c.614þ2T>G) with demonstrated skipping of exon 4

was similar to that of our patient (CMT neuropa-thy score 13). The motor conduction velocities inthis family (39–42 m/s in the upper extremities)were faster than those of our patient (17–27 m/s);this discrepancy could indicate that the 449-1G>Amutation results in more than a simple loss offunction (i.e., a dominant-negative effect) or, alter-nately, that the coexisting NF1 modifies ourpatient’s neuropathy.

NF1 and CMT each affect about 1 in 2500 per-sons, so that both diseases should occur togetherin about 1 of every 6 million persons. The co-occurrence of NF1 and CMT1 has been reported,17

including a prior report of 2 unrelated patientswith both CMT1A and NF1.18 In the latter cases,the patients had the typical PMP22 duplication(17p11.2p12); this should not affect the NF1 gene,which is on the opposite side of the centromere(17q11.2). Another family had both NF1 and coex-isting CMT, likely CMT1X based on the electro-physiological and clinical characteristics, butgenetic testing was not done.19 The case describedherein represents the first known co-occurrence ofCMT1B and NF1. Because MPZ mutations arefound in about 5% of individuals with CMT,20 thespecific coincidence of NF1 and CMT1B shouldoccur in about 1 in 125 million persons.

Neurofibromas are complex, with several celltypes, but several lines of evidence show Schwann

Table 1. NCS data.

Nerve (recording muscle) DL (ms)/DD (cm) Conduction velocity Amplitude

Motor nerve conductionR peroneal (EDB) 10.0 ms 13 m/s (ankle–knee); 17 m/s (across knee) 0.8 mVR tibial (AH) 8.3 ms 17 m/s 0.9 mVL peroneal (EDB) NRL tibial (AH) 9.9 ms 15 m/s 0.2 mVL peroneal (TA) 5.7 ms 19 m/s 3.3 mVL median (APB) 7.7 ms 22 m/s 5.6 mVL ulnar (ADM) 4.0 ms 27 m/s (forearm); 20 m/s (across elbow) 7.6 mV

Sensory nerve conductionL radial 2.5 ms/100 mm 39 m/s 8.4 lVL sural, L median (digit II–wrist), L ulnar, R sural NR

DL, distal latency; DD, distal distance; L, left; R, right; EDB, extensor digitorum brevis; AH, abductor hallucis; TA, tibialis anterior; APB, abductor pollicisbrevis; ADM, abductor digiti mimini; VM, vastus medialis; NR, no response.

Table 2. EMG data.

EMG muscleSpontaneous

activity (Fibs/PSWs)

Motor unit morphology Recruitment

Duration Amplitude Polyphasic Ratio Pattern

VM Nl Nl Nl Nl Nl NlVL Nl Nl Nl increased 15–25% Nl NlTA Nl Nl Increased 15–25% Nl 40–60%Gastroc (medial) L 1þ Fibs Nl Nl Nl Nl 60–80%EHL L 1þ Fibs Nl Increased Nl Nl 20–40%

L, left; Fibs, fibrillation potentials; PSWs, positive sharp waves; AH, abductor hallucis; TA, tibialis anterior; VM, vastus medialis; VL, vastus lateralis; Gastroc,gastrocnemius medial head; EHL, extensor hallucis longus; Nl, normal.

556 Neurofibromatosis with CMT1B MUSCLE & NERVE April 2010

cells are the primary cell type affected by NF1 muta-tions.21 First, the Schwann cells in the tumors, butnot other cell types, show loss of heterozygosity forNF1.22 Second, Schwann cells from neurofibromasinvade through basement membranes and triggerangiogenesis.23,24 Third, the conditional deletion ofNF1 only in Schwann cells results in neurofibromasinitiated by non-myelinating Schwann cells (thoseassociated with unmyelinated axons).25,26 AlthoughSchwann cell proliferation has not been specificallymeasured in CMT1B, demyelination and remyelina-tion are always, to the best of our knowledge,accompanied by Schwann cell proliferation27; this

has been demonstrated for insults as varied as sys-temic tellurium intoxication,28 intraneural lysoleci-thin injection, or genetic mutation in PMP22.29–32

Although one might suspect that conditions associ-ated with increased Schwann cell proliferation,such as CMT1,33 would result in an overwhelmingdisease burden, this did not appear to be the casein our patient or in the other published cases ofpatients with both CMT1 and NF1.17–19 Conversely,even if Schwann cells that are haplo-insufficient forNF1 have increased proliferation,34 this conse-quence has not yet been detected in patients withCMT1.

This work was supported the National Institutes of Health (RO1NS43174 and NS55284 to S.S.S. and T32 DA022605-01 to E.L.).The authors thank Dr. Dev Batish (Athena Diagnostics) for a help-ful discussion and Figure 1.

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typic clustering in MPZ mutations. Brain 2004;127:371–384.12. Shy ME, Arroyo E, Sladky J, Menichella D, Jiang H, Xu W, et al. Het-

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15. Choi BO, Lee MS, Shin SH, Hwang JH, Choi KG, Kim WK, et al.Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Ko-rean Charcot–Marie–Tooth neuropathy patients. Hum Mutat 2004;24:185–186.

16. Song S, Zhang Y, Chen B, Wang M, Wang Y, Yan M, et al. Mutationfrequency for Charcot–Marie–Tooth disease type 1 in the Chinesepopulation is similar to that in the global ethnic patients. GenetMed 2006;8:532–535.

17. Roos KL, Pascuzzi RM, Dunn DW. Neurofibromatosis, Charcot–Marie–Tooth disease, or both? Neurofibromatosis 1989;2:238–243.

18. Lupski JR, Pentao L, Williams LL, Patel PI. Stable inheritance of theCMT1A DNA duplication in two patients with CMT1 and NF1. Am JMed Genet 1993;45:92–96.

FIGURE 1. Mutation analysis. Electrophoretogram shows the

DNA sequence at the 50 boundary of exon 4 for both the patient

(upper panel) and a control (lower panel). [Color figure can be

viewed in the online issue, which is available at www.

interscience.wiley.com.]

FIGURE 2. The predicted consequences of the MPZ mutation

as shown by a schematic of the P0 protein. Each circle repre-

sents an amino acid residue. The patient’s mutation is predicted

to result in the failure of exon 3 to splice exon 4 (which encodes

the amino acids indicated by the solid black circles, including

the transmembrane domain. The N- and C-termini are shown.

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28. Berciano MT, Calle E, Fernandez R, Lafarga M. Regulation ofSchwann cell numbers in tellurium-induced neuropathy: apoptosis,supernumerary cells and internodal shortening. Acta Neuropathol1998;95:269–279.

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FAMILIAL, DEMYELINATING SENSORY AND MOTOR POLYNEUROPATHYWITH CONDUCTION BLOCKSTEPHEN N. SCELSA, MD

Neuromuscular Division, Department of Neurology, Beth Israel Medical Center, Albert Einstein College of Medicine, PhillipsAmbulatory Care Center, 10 Union Square East, Suite 5D, New York, New York 10003, USA

Accepted 25 August 2009

ABSTRACT: Both multifocal, demyelinating features and pred-nisone responsiveness are rare in Charcot–Marie–Tooth (CMT)disease. We report a mother and son with a prednisone-respon-sive, multifocal, demyelinating, predominantly sensory polyneu-ropathy that was associated with an isoleucine92valinepolymorphism of lipopolysaccharide-induced TNF-alpha factor(LITAF). The mother had a multifocal, acquired, demyelinatingsensory and motor polyneuropathy (MADSAM)-like presenta-tion. The son developed left peroneal neuropathy during acuteLyme disease with a subsequent relapsing, MADSAM-like ill-ness, despite antibiotic treatment. Both shared prednisoneresponsiveness and multifocal, demyelinating features electro-physiologically. MADSAM may be familial (FaDSAM) andrespond to prednisone.

Muscle Nerve 41: 558–562, 2010

Reports of Charcot–Marie–Tooth (CMT) dis-ease with multifocal, demyelinating features thatresemble chronic, inflammatory polyradiculoneur-

opathy (CIDP) are rare.1–4 There are only isolatedcase reports of prednisone-responsiveness in suchpatients.1,5 The association of these disorders isthought to reflect the chance development of, orhereditary predilection for, CIDP in patients withCMT.1 Lipopolysaccharide-induced TNF-alpha Fac-tor (LITAF) missense mutations cause CMT1C, anautosomal dominant, demyelinating polyneurop-athy.6 Electrophysiologic features are demyelinat-ing, and occasional patients (2 of 38) showed dif-ferential slowing and temporal dispersion that ismore typical of an acquired demyelinatingpolyneuropathy.6 A recent case report raised thepossibility that a second CMT-causing mutation ina distinct gene may modify the CMT phenotype.Two different sequence variations in the LITAFgene occurred in a patient with the peripheralmyelin protein 22 (PMP22) duplication and pro-duced a more severe phenotype.7 One variationwas the LITAF polymorphism isoleucine92valine.

Lewis–Sumner syndrome—multifocal, acquired,demyelinating sensory and motor polyneuropathy(MADSAM)—is a multifocal CIDP variant thatresponds to both prednisone and intravenousimmunoglobulin.8,9 The electrophysiologic signa-ture is multifocal motor conduction block withsensory conduction abnormalities.

We report a mother and son with a prednisone-responsive, multifocal, predominantly sensory,demyelinating polyneuropathy that resembledLewis–Sumner syndrome (MADSAM) and was

Abbreviations: ACE, angiotensin-converting enzyme; AFB, acid fastbacilli; AIDP, acute inflammatory demyelinating polyradiculoneuropathy;AMAN, acute motor axonal neuropathy; ANA, antinuclear antibodies;ANCA, anti-neutrophil cytoplasmic antibody; CIDP, chronic inflammatorydemyelinating polyradiculoneuropathy; CMT, Charcot–Marie–Tooth dis-ease; Cx32, connexin32 (gap junction protein 1); BUN, blood urea nitro-gen; CBC, complete blood count; EGR2, early growth response gene;ELISA, enzyme-linked immunoassay; ESR, estimated sedimentation rate;LITAF, lipopolysaccharide-induced TNF-alpha factor; MADSAM, multifocal,acquired, demyelinating, sensory, and motor polyneuropathy; MAG, mye-lin-associated glycoprotein; MFN2, mitofusin2; MMTCS, manual muscletesting composite score; MPZ, myelin protein zero; MRC, MedicalResearch Council; NFL, light-chain neurofilament protein, PMP22, periph-eral myelin protein 22; RF, rheumatoid factor; TNF, tumor necrosis factor;TRAPS, tumor necrosis factor receptor–associated periodic syndrome;VDRL, venereal diseases research laboratory

Correspondence to: S.N. Scelsa; e-mail: sscelsa@chpnet.org

VC 2009 Wiley Periodicals, Inc.Published online 25 November 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.21558

Key words: Charcot–Marie–Tooth disease; hereditary; Lewis–Sumnersyndrome; MADSAM; polyneuropathy

558 FaDSAM Polyneuropathy MUSCLE & NERVE April 2010