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First Reported Case of Charcot Marie Tooth Disease Type 4C in a Child from India with SH3TC2 Mutation but Absent Spinal Deformities

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First Reported Case of Charcot Marie Tooth Disease Type 4C in a Child from India with SH3TC2 Mutation but Absent Spinal Deformities [Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116] Case Report First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities Umesh Dinkar Kalane, Chaitanya Datar1, Anita Mahadevan2 Department of Pediatric Neurology, Deenanath Mangeshkar Hospital, 1Sahyadri Genetics and Tissue Engineering Facility, Pune, Maharashtra, 2Department of Neuropathology, NIMHANS, Bengaluru, Karnataka, India 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. Key words: Charcot Marie Tooth disease; HSMN4C; SH3TC2 Case Report or of other sensory symptoms. She had a normal intellect and attended school. A 10‑year old girl, first seen at 8 years of age, presented to us for evaluation of progressive weakness noticed since late On examination, she had lower limb weakness with ankle childhood. She was born of a 3rd degree consanguineous dorsi‑flexion and plantar‑flexion power of grade III. Her marriage and had an uneventful antenatal and perinatal proximal lower limb power was grade IV at knee flexion history. There was no family history of similar complaints. and extension, while power at hip flexion and extension There was no complaint of any major illness in the past. was also grade IV. In the upper limb, the distal power at the wrist was grade IV while proximal power in the upper Since she was 7 years of age, her parents noticed that she limbs was grade V (Medical Research Council grade). There had distal limb weakness, initially in the lower limbs with was areflexia in both lower and upper limbs. Mild pes frequent slipping of footwear. She then gradually developed cavus deformity was noted at presentation more in the upper limb distal weakness with difficulty in performing fine right foot compared to the left. Her sensory examination motor movements like writing and picking up small objects. was unremarkable. No other major dysmorphic features There were initially no complaints of frequent falls or were present and the other system examination was normal. difficulty in rising from a sitting position or in lifting heavy objects. There was no history of sphincteric involvement At the first visit, her routine hematology and biochemistry including liver function tests, serum electrolytes and blood Access this article online sugar were normal. Her creatine phophokinase was mildly Website: Quick Response Code raised and her fasting lipid profile was normal. www.neurologyindia.com DOI: Her nerve conduction velocity (NCV) study of the 10.4103/0028-3886.158222 motor nerves showed reduced amplitude without any PMID: conduction block or dispersion. The latencies were xxxxx prolonged with uniform slowing. The conduction velocities Address for correspondence: Dr. Umesh Dinkar Kalane, Flat No. 202, G Building, Wonder City Society, Katraz Serve No 75, Pune, Maharashtra, India. E-mail: [email protected] Neurology India / May 2015 / Volume 63 / Issue 3 395 [Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116] Kalane, et al.: A case report of Charcot-Marie-Tooth disease type 4c were in the range of 25‑40 m/S [Figures 1 and 2]. Her spectroscopy. The results of all these tests were normal. electromyography (EMG) study showed chronic denervation A repeat trial of steroids was again given for 2 months with partial re‑innervation, suggesting a chronic process of without much clinical benefit. demyelination. The nerve conduction screening study in rest of her family was normal. Biopsy of the sural nerve and vastus medialis muscle was performed. The sural nerve biopsy showed a loss Her cerebrospinal fluid (CSF) study showed raised (139 mg%) of myelinated fibers with remyelination, along with proteins with no cells. She was given intravenous methyl enveloped concentric lamellae of Schwann cell cytoplasm prednisolone 1 gm daily for 3 days and then oral prednisolone forming small onion bulbs which were seen scattered 2 mg/kg/day for 2 weeks. The steroids were tapered over the in all the fascicles admixed with fibers of normal myelin next 2 months and then omitted since there was no significant thickness. No inflammation was seen. This histopathological improvement in her motor power. presentation was suggestive of a demyelinating hypertrophic neuropathy [Figure 3]. The child did not attend the follow‑up outpatient clinic on a regular basis and only came back again after three years The possibility of Charcot Marie Tooth disease (HMSN) was when she was 10 years of age. During this period, her considered based on the clinical and biopsy presentation. weakness had progressively increased and she was now Since this disorder is known to show significant genetic unable to get up from the floor. Her power had decreased heterogeneity, targeted gene panel study by NextGen in both upper and lower limbs. The pes cavus deformity of Sequencing was considered to screen for nearly 54 genes feet was evident bilaterally. There were no other deformities responsible for the various types of CMT. noted. Her repeat NCV/EMG study showed a similar uniform demyelination with no conduction blocks or dispersion A homozygous nonsense variation c. 2710C>T in exon and there was not much deterioration in her study despite 11 of SH3TC2 gene was detected on gene sequencing. her clinical worsening. Further work up in search for a This variation resulted in the premature termination metabolic cause included blood lactate, blood tandem of the protein at position 904 (p.R904Ter) because of mass spectroscopy, urinary gas chromatography and mass Figure 1: Ulnar nerve conduction study: Uniform slowing of the conduction Figure 2: Median nerve conduction study: Uniform slowing of the conduction velocities from the ulnar nerve and no dispersion or conduction blocks. velocities from the median nerve and no dispersion or conduction blocks. Conduction velocities were in between 20 and 40 m/s Conduction velocities were in between 20 and 40 m/s 396 Neurology India / May 2015 / Volume 63 / Issue 3 [Downloaded free from http://www.neurologyindia.com on Tuesday, June 09, 2015, IP: 61.16.135.116] Kalane, et al.: A case report of Charcot-Marie-Tooth disease type 4c 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] a b 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. c Figure 3: Sural nerve and vastus medialis muscle biopsy showing significant In 1996, LeGuern et al. had assigned the locus for CMT4C loss of myelinated fibers with consequent endoneurial fibrosis; (a and b): to chromosome 5q23‑33 in two consanguineous Algerian There are several thinly myelinated remyelinating fibers with formation of “onion bulbs” which were seen scattered in all fascicles admixed with families with a typical childhood/adolescent onset CMT fibers of normal myelin thickness (a, inset), characteristic of a demyelinating disease having the presence of the associated feature of hypertrophic neuropathy. The muscle biopsy revealed small groups of pes cavus and scoliosis in many individuals. There was atrophic angulated fibers reflecting neurogenic atrophy (c) also a discrepancy observed between the rapid worsening of deformities and the relatively slow progression of the the generation of a stop codon. This variation has been motor deficit.[4] Later, mutations in a single gene, namely described in the literature and also by disease databases as the SH3TC2 (also called KIAA1985) on chromosome 5q32, being pathogenic. Sanger sequencing and parental studies were shown to be responsible for the occurrence of CMT4C further verified the variation. disease. Since then, approximately 19 SH3TC2 mutations have been identified in Caucasian non‑Gypsy families from Discussion Turkey, Germany, Italy, Greece, Iran and UK.[3‑6] Majority of these mutations have been identified in the 11th exon of the The term “Charcot–Marie–Tooth (CMT) disease” includes a gene which encodes for perhaps one of the important TPR5 clinically and genetically heterogeneous group of disorders domains of the protein.[6‑8] Thirteen of the 19 mutations which are the most common inherited neuromuscular described by Azzedine et al. in 2005 and Senderek et al. disorders with an estimated prevalence of one in 2500 in 2003, directly or indirectly affected the structure or individuals. Not only does CMT disease present with a the number of this important TPR domain.[5,8] Azzedine significant genetic heterogeneity but it may also segregate et al. searched for the SH3TC2 gene mutations in 10 with different Mendelian patterns‑autosomal dominant consanguineous CMT families. These families revealed eight [1] (AD), autosomal recessive (AR) or X‑linked. The AR CMT new mutations and one recurrent mutation R954X. Six of the phenotypes are usually more severe and have an earlier onset 10 mutations detected were found in exon 11.[5] of the weakness than the AD CMT phenotype.[2,3] The mutation detected in our patient was also within the CMT4C disease is an early‑onset autosomal recessive 11th exon of the SH3TC2 gene, which caused a change of demyelinating form.
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