Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation

doi:10.4236/nm.2013.43023

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Neuroscience & Medicine, 2013, 4, 145-149

http://dx.doi.org/10.4236/nm.2013.43023 Published Online September 2013 (http://www.scirp.org/journal/nm)

145

Course of Atypical Manifestations of a Case of

Charcot-Marie-Tooth Disease over 35 Years of Clinical

Observation

Giuseppe Lanza1*, Luisa Vinciguerra1, Valentina Puglisi1, Daniela Modica1, Alfio Catalano1,

Giuseppe Zelante1, Riccardo Ricceri1, Lorenzo Lupo2, Salvatore Giuffrida1, Manuela Pennisi3

1Department “G. F. Ingrassia”, Section of Neurosciences, University of Catania, Catania, Italy; 2Department “G. F. Ingrassia”, MED

01, University of Catania, Catania, Italy; 3Department of Chemistry, University of Catania, Catania, Italy.

Email: *[email protected]

Received April 16th, 2013; revised May 20th, 2013; accepted June 5th, 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Introduction: Atypical manifestations of peripheral neuropathy are not rare, challenging the differential diagnosis. In the

past, the diagnosis of hereditary neuropathy was mainly based on the clinical and electromyographic (EMG) findings

and, occasionally, biopsy. Nowadays, the genetic tests allow us to identify more than 40 different genes/loci associated

with Charcot-Marie-Tooth (CMT) disease, although some subtypes are clinically indistinguishable. We have followed a

patient with a clinical diagnosis of apparent sporadic and atypical CMT and recently diagnosed genetically as distal

hereditary motor neuropathy, type V (dHMN-V). Case Report: Thirty-five years ago, a 16 years old patient complained

muscular weakness and wasting at the hands small muscles. Sporadic fasciculations were observed whereas deep ten-

don reflexes and sensation were normal. EMG examination revealed neurogenic muscular denervation in the distribu-

tion of C7, C8 and T1 segments bilaterally. Muscular biopsy of the left Biceps Brachii showed rare atrophic fibers and

some cellular atypia. The disease has undergone a clinical and EMG progression and diffusion over the years, involving

the lower limbs and leading to a bilateral steppage. A more slight diffuse axonal motor neuropathy was also identified

in the proband’s son and second cousin. The genetic study found a known missense mutation in BSCL2 gene related to a

dHMN-V. Interestingly, there was a remarkable intra-familiar phenotypic variability, especially in the clinical onset and

severity. Discussion: Atypical manifestations of hereditary neuropathies often overlap with other conditions. The pre-

sent case highlights how a comprehensive clinical evaluation and a careful follow-up have led to a correct diagnosis

even 35 years later and have allowed to identify other affected family members. The apparent lack of familiarity was

probably due to the very soft presentation in the proband’s relatives. Although the genetic study was not available at

that time, the first clinical diagnosis was not disavowed. The main differential diagnoses and a brief review of similar

reported cases are discussed.

Keywords: Hereditary Neuropathies; Clinical Overlap; Genetic Analysis; Phenotypic Variability

1. Introduction

Charcot-Marie-Tooth (CMT) neuropathy refers to a group

of hereditary disorders characterized by a chronic motor

and sensory polyneuropathy. The affected individual

typically has distal muscle weakness and atrophy often

associated with mild to moderate distal sensory loss, de-

pressed tendon reflexes, high-arched feet and weak ankle

dorsiflexion. However, atypical clinical manifestations

are not rare, often making the differential diagnosis with

other neurological disorders challenging. For instance,

some Hereditary Motor Neuropathies (HMN) presents

with distal weakness [1], thus, suggesting a clinical pic-

ture resembling CMT disease, although the HMN does

not usually show sensory disturbances.

In the past, classification of CMT spectrum disorders

was mainly based on the neurophysiological testing and,

occasionally, sural nerve or muscle biopsy. Nowadays,

genetic testing is available depending on inheritance pat-

terns and molecular genetics and more than 40 different

genes/loci are associated with CMT. However, there are

areas of overlap between different types of CMT and

some subtypes are clinically indistinguishable and are

*Corresponding author.

Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation

146

designated solely on molecular findings. Establishing the

specific cause of CMT hereditary neuropathy for a given

individual encompasses the medical history, physical and

neurological examination, nerve conduction and elec-

tromyographic (EMG) testing, as well as the use of mo-

lecular genetic testing when available.

We report a young patient with a clinical diagnosis of

apparent sporadic and atypical CMT, clinically followed

by the same Neurologist for approximately 35 years and

recently diagnosed genetically as distal HMN, type V

(dHMN-V).

2. Case Report

About 35 years ago, a young Neurologist diagnosed a

sporadic and atypical case of CMT disease in a 16 years

old Italian patient (F. C., proband) working as a bar-

tender. He complained muscular weakness at the upper

limbs and progressive muscular wasting almost exclu-

sively at the level of small muscles of both hands.

Herein is described the neurological examination as

reported at that time. Severe atrophy of the first and sec-

ond dorsal interosseous muscles of both hands, more

evident on the right side, a moderate atrophy of thenar

muscles and a slight atrophy of ipothenar muscles with-

out evident trophic abnormalities in other districts were

observed. Weakness, more evident in the distal muscle

groups, was tested in thumb opposition and in spread-

ing/closing finger movements. Sporadic fasciculations

were also observed and deep tendon reflexes were nor-

mal and symmetrical at both upper and lower limbs.

Hoffman and Babinski responses were not present. Nys-

tagmus, oculomotor deficits, lower cranial nerves im-

pairment and cerebellar signs were also absent. Eye fundi

and visual field were normal. There were no gait and

standing position disturbances and all types of sensation

were intact. The patient underwent to laboratory and in-

strumental investigations available at that time. Extensive

laboratory tests, including muscle enzymes level, were

unremarkable. Cerebrospinal fluid examination was nor-

mal and no oligoclonal bands were present. Electroen-

cephalogram (EEG), skull X-ray, cervical and thoracic

vertebral X-ray and myelography with iodinated contrast

material were unremarkable. EMG examination pointed

out severe and bilateral neurogenic muscular denervation

in the distribution of C7, C8 and T1 segments, with evi-

dence of fibrillation potentials. Biopsy of the left Biceps

Brachii muscle showed rare atrophic fibers tending to

angular shape (Figure 1(A)) and areas of both quantita-

tive and qualitative cellular atypia, such as enzymes de-

pletion and intermyofibrillar reticulum distortion at the

center of the fibers (Figure 1(B)). The clinical course

over the years was characterized by a slow progression of

the atrophic deficit at the upper limbs and, gradually,

muscular weakness became apparent at the lower limbs,

Figure 1. Proband’s le ft Biceps Brachii muscle biop sy (1978).

A. Hematoxylin-eosin × 150: atrophic fibers tending to an-

gular shape; (B) NADH-TR: intermyofibrillar reticulum

distortion.

leading to a bilateral steppage.

After 35 years of clinical follow-up, the neurological

evaluation showed severe distal muscles atrophy at the

four limbs, relevant gait and prehension impairment and

slight sensitive impairment. The electroneurographic ex-

amination revealed diffuse axonal motor neuropathy,

especially at the lower limbs. Thirty-five years after the

first observed case, the same Neurologist examined two

young patients complaining a recent history of motor

clumsiness at both hands, especially when writing. One

of them was the proband’s son (F. Al., 16 years old) and

the other was proband’s second cousin (F. An., 14 years

old). The EMG results were compatible with an axonal

motor neuropathy at the four limbs; median, tibial and

peroneal nerves were the most impaired whereas sensory

nerves were not involved (Tables 1 and 2). Muscle bi-

opsy was not performed because they underwent to ge-

netic test. The genetic studies led to the definitive diag-

nosis of dHMN-V. A known missense mutation 263A >

G was identified in BSCL2 gene of the examined patients

(proband, F.Al, F.An), resulting in the aminoacid substi-

tution N88S [2,3]. Therefore, clinical, instrumental and

genetic tests were performed in other family members.

Overall, the genetic study was performed in 13 subjects:

the 263 A > G missense mutation (AAT > AGT), typi-

cally observed in dHMN-V [1,4], was identified in 10

patients. Some of the examined relatives have never

consulted a Neurologist because of the very mild clinical

presentation with a minimal impairment in the activity of

daily living. For instance, the father of the proband’s

cousin had a subtle atrophy of the hand muscles without

any weakness so that he continued to work as a dentist

without difficulty.

3. Discussion

Distal HMN defines a group of hereditary disorders

characterized by distal muscular weakness and atrophy.

The subtype dHMN-V affects in particular the upper

limbs, especially the small hand muscles. Interestingly, a

remarkable intra-familial phenotypic variability in the

clinical onset and severity is often observed, thus often

Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation

147

Table 1. Nerve conduction studies results of the examined patients.

MMN UMN PMN TMN MSN USN SN

Patient

A CV A CV A CV A CV A CV A CV A CV

Normal

values >5 >50 >5 >50 >4 >41 >5 >40 >10 >41 >8 >40 >6 >35

F. C. R

0.6

0.8

0.2

0.1

F. Al. R

0.1

F. An. R

0.7

0.9

MMN = Median Motor Nerve; MSN = Median Sensory Nerve; UMN = Ulnar Motor Nerve; USN = Ulnar Sensory Nerve; PMN = Peroneal Motor Nerve; TMN

= Tibial Motor Nerve; SN = Sural Nerve. R = right; L = left; A = amplitude: motor (mV); sensory (µV); CV = conduction velocity (m/s); - = not recordable;

bold numbers = abnormal values.

Table 2. Electromyography results of the examined patients.

BB EDC APB FDI VM TA MG EDB

Patient

SA R SA R SA RSA RSA RSA R SA R SA

F. C. R

↓

F. Al. R

↓

F. An. R

↓

BB = biceps brachii; EDC = extensor digitorum communis; APB = abductor pollicis brevis; FDI = first dorsal interosseous; VM = vastus medialis; TA = tibialis

anterior; MG = medial gastrocnemius; EDB = extensor digitorum brevis; SA = spontaneous activity; R = recruitment; − = absent; N = normal; + = fibrillations;

F = fasciculations; ↓ = reduced. R = right; L = left;

challenging the differential diagnosis.

In this context, the main differential diagnosis to be

taken into account is the Progressive Muscular Atrophy,

a rare subtype of Amyotrophic Lateral Sclerosis formerly

known as “Aran-Duchenne disease” at that time [4]. The

clinical presentation, the lack of familiarity and the EMG

data seemed to support this hypothesis. However, based

on the young age of onset, the non-progressive clinical

course as well as the instrumental and neuropathological

findings, a diagnosis of lower motor neuron disease was

unlikely. At first, inheritance seemed to be excluded

since similar clinical presentation was not referred nei-

ther in his parents or in other family members. The early

upper limbs involvement, and especially the lack of sen-

sory impairment, suggested the diagnosis of sporadic and

atypical CMT disease.

Distal HMN-V also shares clinical and genetic features

with another hereditary neuropathy, the CMT2D, and

with the hereditary spastic paraplegia 17 also known as

Silver syndrome. Clinically, CMT2D is characterized by

an early onset [6] and a predominant upper limbs in-

volvement in terms of muscular weakness and cramps,

progressive wasting of small hand muscles and sensory

disturbances, the latter being typically absent in the

dHMN-V. Silver syndrome [3], a rare autosomal domi-

nant neurodegenerative disorder, has variable onset and,

although presenting with amyotrophy of the small hand

muscles, is mainly characterized by spasticity and other

pyramidal signs at the lower limbs and, subsequently,

foot deformities and slight sensory complaints can also

occur [2]

Literature reports some families with a phenotypic and

genetic diagnosis of dHMN-V. In 2010 Rakocevic-

Stoianovic et al. [7] described the first three Serbian

family members with a BS CL 2 mutation showing vari-

able expression within the family: a 55-year-old woman

with distal muscle weakness and atrophy in her legs and

hypereflexia (except for ankle reflexes); her 25 year-old

son with lower limbs stiffness and hyporeflexia; her 55

year-old cousin with a more prominent involvement of

leg muscles and mild asymmetrical weakness of hand

muscles. Sensory nerve conduction velocities were nor-

mal whereas compound muscle action potential ampli-

tudes were markedly reduced in all patients; concentric

Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation

148

needle EMG showed chronic denervation in distal mus-

cles. In 2006, van de Warrenburg et al. [8] reported the

first two Dutch families with BSCL2 mutations and un-

derscored the phenotypic spectrum of BSCL2 gene muta-

tions with an overlap between Silver syndrome, dHMN-

V and dHMN-II, highlighting the variable phenotypic

patterns between and within the families. Despite a rather

early onset in the second or first decade, disease progres-

sion was usually slow and mildly impacts the daily living

functions. The heterogeneous clinical presentations in-

cluded: foot muscle weakness and atrophy, with or with-

out gradually evolving pyramidal tract signs or hand

muscle involvement; predominant involvement of hand

muscles, with minimal or no lower limb involvement and

the early or late presence of Babinski’s sign; predomi-

nant spastic paraparesis with minimal distal lower limb

involvement. Therefore, although the phenol-type may

eventually become compatible with Silver syndrome va-

riant (with predominant foot rather than hand muscle

involvement), the dHMN-II or dHMN-V resembling fea-

tures are often encountered in early stages and pyramidal

tract signs might even remain absent.

In a report of 90 patients with the N88S mutation [9],

the following distribution of clinical subtypes was ob-

served: 4.4% (still) unaffected; 20% subclinically/very

mildly affected; 31.1% dHMN-type V; 14.5% classical

Silver syndrome; 20% CMT like phenotype (either spinal

form or hereditary motor sensory neuropathies-II de-

pending on the absence or presence of sensory abnor-

malities, respectively); 10% a pure spastic paraparesis.

More recently, a Chinese family over four generations

with seipinopathy was studied [10]. Six family members

were dHMN-II with predominant weakness of lower ex-

tremities, whereas one was accompanied by pyramidal

signs. Other three women were dHMN-V with predomi-

nant hands atrophy.

Taken together, these findings interestingly highlight

the view that the phenotype of motor neuropathies asso-

ciated with BSCL2 mutations is broader than Silver syn-

drome and dHMN-V [1]. In this context, Irobi et al. [1]

reported two families, one with members affected by

marked spasticity in the lower limbs and very striking

distal amyotrophy that always started in the legs and the

other with distal amyotrophy sometimes starting and pre-

dominating in the legs, but no pyramidal tract signs. Fur-

ther evidence for genetic heterogeneity of dHMN-V,

CMT2 with predominant hand involvement and Silver

syndrome came from Rohkamm et al. [11], confirming

that most likely only two mutations (N88S, S90L) in

exon 3 of BSCL2 may lead to dHMN-V or Silver syn-

drome phenotypes whereas mutations in other genes

(such as GARS, HSPB1 and HSPB8) are not a common

cause of dHMN-V, Silver syndrome and CMT2D.

4. Conclusion

Some atypical manifestations of CMT disease, such as

the apparent lack of familiarity, the predominant upper

limbs involvement at the onset, together with no tendon

reflexes or sensation abnormalities, intrigued a young

Neurologist 35 years ago. Although the genetic study

was not available at that time, a comprehensive diagnos-

tic work-up and a continuous clinical observation, in ad-

dition to modern advanced diagnostic procedures such as

genetic analysis, allowed us to delineate a definitive diag-

nosis and to identify other family members affected by a

rare hereditary neuropathy. The apparent lack of famili-

arity that led to the diagnosis of atypical and sporadic

CMT in the past was probably due to the very soft pres-

entation and course of the disease in the proband’s rela-

tives, highlighting the impressive intra-familiar variabil-

ity that might characterize these conditions. In conclu-

sion, 35 years later, the same Neurologist has not dis-

avowed his first diagnosis.

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