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.
Received April 16th, 2013; revised May 20th, 2013; accepted June 5th, 2013
Copyright © 2013 Giuseppe Lanza et al. This is an open access article distributed under the Creative Commons Attribution License,
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
L
0.6
0.8
40
56
11
11
49
52
0.2
0.2
-
28
0.1
0.1
33
33
17
16
39
43
6
7
41
45
11
9
35
35
F. Al. R
L
1
1
54
57
17
16
58
59
0.1
0.1
30
29
1
2
40
42
33
49
49
49
29
26
42
41
14
9
40
37
F. An. R
L
0.7
0.7
40
47
15
9
61
53
0.9
2
42
50
10
8
43
42
54
45
43
47
20
44
39
43
18
21
39
38
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
R
F. C. R
L
-
-
N
N
-
-
↓
↓
-
-
↓
↓
-
-
↓
↓
-
-
N
N
-
-
↓
↓
-
-
↓
↓
-
-
↓
↓
F. Al. R
L
-
-
N
N
-
-
↓
↓
+F
+F
↓
↓
+F
+F
↓
↓
-
-
N
N
+F
+F
↓
↓
F
F
↓
↓
-
-
↓
↓
F. An. R
L
-
-
N
N
-
-
↓
↓
+
+
↓
↓
-
-
↓
↓
-
-
N
N
+
+
↓
↓
-
-
N
N
+
+
↓
↓
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.
REFERENCES
[1] J. Irobi, P. De Jonghe and V. Timmerman, “Molecular
Genetics of Distal Hereditary Motor Neuropathies,” Hu-
man Molecular Genetics, Vol. 13, No. 2, 2004, pp. R195-
R202.
[2] C. Windpassinger, M. Auer-Grumbach, J. Irobi, H. Patel,
E. Petek, G. Horl, et al., “Heterozygous Missense Muta-
tions in BSCL2 Are Associated with Distal Hereditary
Motor Neuropathy and Silver Syndrome,” Nature Genet-
ics, Vol. 36, No. 3, 2004, pp. 271-276.
doi:10.1038/ng1313
[3] D. Ito and N. Suzuki, “Seipinopathy: A Novel Endoplas-
mic Reticulum Stress-Associated Disease,” Brain, Vol.
132, 2009, pp. 8-15.
[4] M. Bonduelle, “Aran-Duchenne? Duchenne-Aran? The
Quarrel around Progressive Muscular Atrophy,” Revue
Neurologique Société de Neurologie de Paris, Vol. 146,
No. 2, 1990, pp. 97-106.
[5] J. Magrè, M. Delépine, E. Khallout, T. Gedde-Dahl, L.
Van Maldergem, E. Sobel, et al., “Identification of the
Gene Altered in Berardinelli-Seip Congenital Lipodystro-
phy on Chromosome 11q13,” Nature Genetics, Vol. 28,
No. 4, 2001, pp. 365-370. doi:10.1038/ng585
[6] K. Sivakumar, T. Kyriakides, I. Puls, G. A. Nicholson, B.
Funalot, A. Antonellis, et al., “Phenotypic Spectrum of
Disorders Associated with Glycyl-tRNA Synthetase Mu-
tations,” Brain, Vol. 128, No. 10, 2005, pp. 2304-2314.
doi:10.1093/brain/awh590
[7] V. Rakocević-Stojanović, V. Milić-Rasić, S. Perić, J. Ba-
ets, V. Timmerman, I. Dierick, et al., “N88S Mutation in
the BSCL2 Gene in a Serbian Family with Distal Heredi-
tary Motor Neuropathy Type V or Silver Syndrome,”
Journal of the Neurological Sciences, Vol. 296, No. 1-2,
2010, pp. 107-109. doi:10.1016/j.jns.2010.06.015
[8] B. P. van de Warrenburg, H. Scheffer, J. J. van Eijk, M. H.

Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation
149
Versteeg, H. Kremer, M. J. Zwarts, et al., “BSCL2 Muta-
tions in Two Dutch Families with Overlapping Silver
Syndrome-Distal Hereditary Motor Neuropathy,” Neuro-
muscular Disorders, Vol. 16, No. 2, 2006, pp. 122-125.
doi:10.1016/j.nmd.2005.11.003
[9] M. Auer-Grumbach, B. Schlotter-Weigel, H. Lochmüller,
G. Strobl-Wildemann, P. Auer-Grumbach, R. Fischer, et
al., “Phenotypes of the N88S Berardinelli-Seip Congeni-
tal Lipodystrophy 2 Mutation,” Annals of Neurology, Vol.
57, No. 3, 2005, pp. 415-424. doi:10.1002/ana.20410
[10] B. Chen, R. Zheng, X. Luan, W. Zhang, Z. Wang and Y.
Yuan, “Clinical and Pathological Study of Distal Motor
Neuropathy with N88S Mutation in BSCL2,” Neuropa-
thology, Vol. 29, No. 5, 2009, pp. 543-547.
doi:10.1111/j.1440-1789.2009.01011.x
[11] B. Rohkamm, M. M. Reilly, H. Lochmüller, B. Schlotter-
Weigel, N. Barisic, L. Schöls L, et al., “Further Evidence
for Genetic Heterogeneity of Distal HMN Type V, CMT2
with Predominant Hand Involvement and Silver Syn-
drome,” Neurological Sciences, Vol. 263, No. 1-2, 2007,
pp. 100-106. doi:10.1016/j.jns.2007.06.047