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Table of Contents    
Year : 2015  |  Volume : 63  |  Issue : 3  |  Page : 395-398

First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities

1 Department of Pediatric Neurology, Deenanath Mangeshkar Hospital, Pune, Maharashtra, India
2 Sahyadri Genetics and Tissue Engineering Facility, Pune, Maharashtra, India
3 Department of Neuropathology, NIMHANS, Bengaluru, Karnataka, India

Date of Web Publication5-Jun-2015

Correspondence Address:
Umesh Dinkar Kalane
Flat No. 202, G Building, Wonder City Society, Katraz Serve No 75, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.158222

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 » Abstract 

Charcot Marie Tooth (CMT) disease is a group of hereditary motor sensory neuropathies with significant genetic heterogeneity. This disorder has been scarcely reported in the Indian literature. Here, we report a case of the rare but relatively more severe autosomal recessive CMT type 4C disease with a few features that are distinct from its regular presentation. Our patient was proven to have one of the common mutations in the SH3TC2 gene, which has so far not been described in Indian patients.

Keywords: Charcot Marie Tooth disease; HSMN4C; SH3TC2

How to cite this article:
Kalane UD, Datar C, Mahadevan A. First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities. Neurol India 2015;63:395-8

How to cite this URL:
Kalane UD, Datar C, Mahadevan A. First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities. Neurol India [serial online] 2015 [cited 2022 Oct 2];63:395-8. Available from: https://www.neurologyindia.com/text.asp?2015/63/3/395/158222

 » Case Report Top

A 10-year old girl, first seen at 8 years of age, presented to us for evaluation of progressive weakness noticed since late childhood. She was born of a 3 rd degree consanguineous marriage and had an uneventful antenatal and perinatal history. There was no family history of similar complaints. There was no complaint of any major illness in the past.

Since she was 7 years of age, her parents noticed that she had distal limb weakness, initially in the lower limbs with frequent slipping of footwear. She then gradually developed upper limb distal weakness with difficulty in performing fine motor movements like writing and picking up small objects. There were initially no complaints of frequent falls or difficulty in rising from a sitting position or in lifting heavy objects. There was no history of sphincteric involvement or of other sensory symptoms. She had a normal intellect and attended school.

On examination, she had lower limb weakness with ankle dorsi-flexion and plantar-flexion power of grade III. Her proximal lower limb power was grade IV at knee flexion and extension, while power at hip flexion and extension was also grade IV. In the upper limb, the distal power at the wrist was grade IV while proximal power in the upper limbs was grade V (Medical Research Council grade). There was areflexia in both lower and upper limbs. Mild pes cavus deformity was noted at presentation more in the right foot compared to the left. Her sensory examination was unremarkable. No other major dysmorphic features were present and the other system examination was normal.

At the first visit, her routine hematology and biochemistry including liver function tests, serum electrolytes and blood sugar were normal. Her creatine phophokinase was mildly raised and her fasting lipid profile was normal.

Her nerve conduction velocity (NCV) study of the motor nerves showed reduced amplitude without any conduction block or dispersion. The latencies were prolonged with uniform slowing. The conduction velocities were in the range of 25-40 m/S [Figure 1] and [Figure 2]. Her electromyography (EMG) study showed chronic denervation with partial re-innervation, suggesting a chronic process of demyelination. The nerve conduction screening study in rest of her family was normal.
Figure 1: Ulnar nerve conduction study: Uniform slowing of the conduction velocities from the ulnar nerve and no dispersion or conduction blocks. Conduction velocities were in between 20 and 40 m/s

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Figure 2: Median nerve conduction study: Uniform slowing of the conduction velocities from the median nerve and no dispersion or conduction blocks. Conduction velocities were in between 20 and 40 m/s

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Her cerebrospinal fluid (CSF) study showed raised (139 mg%) proteins with no cells. She was given intravenous methyl prednisolone 1 gm daily for 3 days and then oral prednisolone 2 mg/kg/day for 2 weeks. The steroids were tapered over the next 2 months and then omitted since there was no significant improvement in her motor power.

The child did not attend the follow-up outpatient clinic on a regular basis and only came back again after three years when she was 10 years of age. During this period, her weakness had progressively increased and she was now unable to get up from the floor. Her power had decreased in both upper and lower limbs. The pes cavus deformity of feet was evident bilaterally. There were no other deformities noted. Her repeat NCV/EMG study showed a similar uniform demyelination with no conduction blocks or dispersion and there was not much deterioration in her study despite her clinical worsening. Further work up in search for a metabolic cause included blood lactate, blood tandem mass spectroscopy, urinary gas chromatography and mass spectroscopy. The results of all these tests were normal. A repeat trial of steroids was again given for 2 months without much clinical benefit.

Biopsy of the sural nerve and vastus medialis muscle was performed. The sural nerve biopsy showed a loss of myelinated fibers with remyelination, along with enveloped concentric lamellae of Schwann cell cytoplasm forming small onion bulbs which were seen scattered in all the fascicles admixed with fibers of normal myelin thickness. No inflammation was seen. This histopathological presentation was suggestive of a demyelinating hypertrophic neuropathy [Figure 3].
Figure 3: Sural nerve and vastus medialis muscle biopsy showing significant loss of myelinated fibers with consequent endoneurial fibrosis; (a and b): There are several thinly myelinated remyelinating fibers with formation of "onion bulbs" which were seen scattered in all fascicles admixed with fibers of normal myelin thickness (a, inset), characteristic of a demyelinating hypertrophic neuropathy. The muscle biopsy revealed small groups of atrophic angulated fibers reflecting neurogenic atrophy (c)

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The possibility of Charcot Marie Tooth disease (HMSN) was considered based on the clinical and biopsy presentation. Since this disorder is known to show significant genetic heterogeneity, targeted gene panel study by NextGen Sequencing was considered to screen for nearly 54 genes responsible for the various types of CMT.

A homozygous nonsense variation c. 2710C>T in exon 11 of SH3TC2 gene was detected on gene sequencing. This variation resulted in the premature termination of the protein at position 904 (p.R904Ter) because of the generation of a stop codon. This variation has been described in the literature and also by disease databases as being pathogenic. Sanger sequencing and parental studies further verified the variation.

 » Discussion Top

The term "Charcot-Marie-Tooth (CMT) disease" includes a clinically and genetically heterogeneous group of disorders which are the most common inherited neuromuscular disorders with an estimated prevalence of one in 2500 individuals. Not only does CMT disease present with a significant genetic heterogeneity but it may also segregate with different Mendelian patterns-autosomal dominant (AD), autosomal recessive (AR) or X-linked. [1] The AR CMT phenotypes are usually more severe and have an earlier onset of the weakness than the AD CMT phenotype. [2],[3]

CMT4C disease is an early-onset autosomal recessive demyelinating form. It is known to have a variable presentation with the milder form presenting with only scoliosis and foot deformities like pes cavus/planus while the severe forms present with a predominantly childhood onset severe neuropathy with respiratory and cranial nerve involvement along with spine and foot deformities. [4] Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often the inaugural symptoms heralding the onset of the disease. The spinal deformities are particularly a fairly consistent feature of CMT4C disease as has been noted in a large cohort of patients by Azzedine et al. who found that almost 27 of the 28 patients of CMT4C disease belonging to the age group 2-10 years showed the spinal deformity, with nearly 13 having had to undergo surgery at a young age. Thus, spine deformities have been considered to be a hallmark of CMT4C disease. [4],[5]

Our patient presented with distal muscle weakness along with a pes cavus deformity but did not have sensory issues and spinal deformity until the age of 10 years. There was no respiratory insufficiency or hypoventilation. The patient, however, did have very slow NCVs, elevated CSF protein, and hypertrophic nerves with onion bulb formation.

In 1996, LeGuern et al. had assigned the locus for CMT4C to chromosome 5q23-33 in two consanguineous Algerian families with a typical childhood/adolescent onset CMT disease having the presence of the associated feature of pes cavus and scoliosis in many individuals. There was also a discrepancy observed between the rapid worsening of deformities and the relatively slow progression of the motor deficit. [4] Later, mutations in a single gene, namely the SH3TC2 (also called KIAA1985) on chromosome 5q32, were shown to be responsible for the occurrence of CMT4C disease. Since then, approximately 19 SH3TC2 mutations have been identified in Caucasian non-Gypsy families from Turkey, Germany, Italy, Greece, Iran and UK. [3],[4],[5],[6] Majority of these mutations have been identified in the 11 th exon of the gene which encodes for perhaps one of the important TPR5 domains of the protein. [6],[7],[8] Thirteen of the 19 mutations described by Azzedine et al. in 2005 and Senderek et al. in 2003, directly or indirectly affected the structure or the number of this important TPR domain. [5],[8] Azzedine et al. searched for the SH3TC2 gene mutations in 10 consanguineous CMT families. These families revealed eight new mutations and one recurrent mutation R954X. Six of the 10 mutations detected were found in exon 11. [5]

The mutation detected in our patient was also within the 11 th exon of the SH3TC2 gene, which caused a change of arginine to a premature stop codon at position 904 of the protein (R904X). This mutation has been previously described in literature in many populations worldwide but never in the Indian population. It was reported in a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. Of the 412 patients tested for p.R904X, the mutation was found in 8 patients (1.94%), of whom 6 were homozygous and 2 were heterozygous. [7],[8] Significant intrafamilial variability in the disease course makes it difficult to identify genotype-phenotype correlations as discussed by Azzedine et al., but its characteristic hallmark, the spinal deformities, were absent in our case. [5]

This is the first reported study of the recessive CMT4C disease in the Indian population with a confirmed mutation. The absence of scoliosis at the initial presentation and the asymmetric limb involvement were the distinctive features.

 » References Top

Shy M, Lupski JR, Chance PF, Klein CJ, Dyck PJ. Hereditary motor and sensory neuropathies: An overview of clinical, genetic, electrophysiologic and pathologic features. Dyck PJ, Thomas PK, eds. Peripheral neuropathy 4 th edn. Philadelphia: Elsevier Saunders;2005: 1623-58.  Back to cited text no. 1
Harding AE, Thomas PK. Autosomal recessive forms of hereditary motor and sensory neuropathy. J Neurol Neurosur Psy 1980; 43:669-78.  Back to cited text no. 2
Thomas PK. Autosomal recessive hereditary motor and sensory neuropathy. Curr Opin Neurol 2000; 13:565-8.  Back to cited text no. 3
LeGuern E, Guilbot A, Kessali M, Ravisé N, et al. Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33.Hum Mol Genet 1996; 5:1685-8.  Back to cited text no. 4
Azzedine H, Ravisé N, Verny C, Gabrëels-Festen A, Lammens M, et al. Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 2006; 67:602-6.  Back to cited text no. 5
Yger M, Stojkovic T, Tardieu S, Maisonobe T, et al. Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C. J Peripher Nerv Syst 2012;17:112-22.  Back to cited text no. 6
Colomer J1, Gooding R, Angelicheva D, King RH, et al. Clinical spectrum of CMT4C disease in patients homozygous for the p.Arg1109X mutation in SH3TC2. Neuromuscul Disord 2006;16:449-53.  Back to cited text no. 7
Senderek J, Bergmann C, Stendel C, Kirfel J, et al. Mutations in a gene encoding a novel sh3/tpr domain protein cause autosomal recessive Charcot-Marie-Tooth Type 4C neuropathy. Am J Hum Genet 2003;73:1106-19.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3]

This article has been cited by
1 Clinical and Genetic Analysis of an Asian Indian Family with Charcot-Marie-Tooth Disease Type 4C
Raji P. Grewal,Leema Reddy Peddareddygari,Kinsi Oberoi
Case Reports in Neurology. 2018; : 38
[Pubmed] | [DOI]


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