|Year : 2014 | Volume
| Issue : 4 | Page : 259-262
Unusual manifestations of Charcot-Marie-Tooth disease: A clinical observation
Akhila Kumar Panda
Department of Neurology, BLK Super Speciality Hospital, New Delhi, India
|Date of Web Publication||16-Oct-2014|
Akhila Kumar Panda
Department of Neurology, BLK Super Speciality Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuromuscular disorder. Careful assessment of clinical presentations, mode of inheritance, electrophysiological studies, and genetic analysis form the basis for the diagnosis of CMT. CMT4 is a group of progressive motor and sensory axonal demyelinating neuropathies. It is distinguished from other forms of CMT by autosomal recessive pattern of inheritance, variable clinical manifestations, electrophysiological study, nerve biopsy, and specific genetic studies. Here, we report an interesting case of hereditary neuropathy with recessive inheritance pattern who presented with combined clinical phenotypes of 4B1, 4C, and 4D subtypes. The histopathological study revealed onion bulb appearance suggestive of demyelination and remyelination phenomenon. The overlapping clinical manifestation may create a diagnostic challenge which would be confirmed by specific molecular analysis.
Keywords: Charcot-Marie-Tooth disease, hypoglossal palsy, onion bulb appearance
|How to cite this article:|
Panda AK. Unusual manifestations of Charcot-Marie-Tooth disease: A clinical observation. Int J Health Allied Sci 2014;3:259-62
|How to cite this URL:|
Panda AK. Unusual manifestations of Charcot-Marie-Tooth disease: A clinical observation. Int J Health Allied Sci [serial online] 2014 [cited 2020 Feb 25];3:259-62. Available from: http://www.ijhas.in/text.asp?2014/3/4/259/143068
| Introduction|| |
Individuals with Charcot-Marie-Tooth disease More Details type 4 (CMT4) usually have the clinical characteristics of progressive distal muscle weakness and atrophy associated with sensory loss. It is frequently associated with hand and foot deformity with an earlier onset and more severe progression than the autosomal dominant variants. The subtypes of CMT4 are based on clinical characteristics, ethnic background, neuropathological findings, and genetic analysis. There are 10 subtypes of type 4 of CMT.  CMT4A is the most common cause of autosomal recessive variant. ,, This case illustrates overlapping clinical phenotype of different subgroups of CMT such as type 4B1, 4C, and 4D. Though genetic analysis for specific CMT4 is not commercially available in developing countries, but characteristic clinical presentations with autosomal recessive pattern of inheritance, typical electrophysiological study, and nerve biopsy finding may suggest the close mimic of this group.
| Case report|| |
This case illustrates a 10-year-old boy born of consanguinity belongs to low socioeconomic family from North India. He had normal birth and development without any in-utero complications. At 6 years of age, he developed slowly progressive walking difficulty more marked in narrow path, crowded places, uneven surfaces and while attempting to walk back ward. He used to hold his feet firmly to the ground due to sense of insecurity. The imbalance was more marked in dark as well as upon eye closure especially while bathing and washing face. Subsequently, he developed thinning as well as numbness in distal aspects of both the feet up to mid legs with cotton wool sensation. At 9 years of age, he developed deformities of the hands and feet that is, claw hand and pes cavus with hammer toes. His parents also noticed bifacial weakness and incomplete closure of eyelids during sleep. He had constant pursing of lips with difficulty in closing mouth. He could not keep mouth full of water or drink with straw. He had difficulty to produce labial sound "p or t." Subsequently, he complained of difficulty in making bolus formation while taking food. However, he denied visual blurring, double vision, drooping of eyelids, hearing loss, swallowing difficulty, fatigability, any diurnal or seasonal variation. He had no history suggesting proximal limb weakness, fasciculation, hand in-coordination, tremor or evidence of autonomic involvement. He has average scholastic performance. Though disabled, he could maintain his daily routine activities unassisted. His elder sister of 15 years of age studying at 7 th standard has similar complaints which started at the age of 7 years. None of the other family members in three generations had similar illness.
General physical and other systemic examinations were normal. Nervous system examination showed a normal cognition and behavior. Cranial nerve examinations revealed bilateral lower motor neuron facial weakness [Figure 1], bulbar and labial dysarthria, the bilateral lower motor neuron hypoglossal palsy that is, tongue was hypotonic, atrophic, weak and associated with fasciculation [Figure 2]. Other cranial nerves were normal. Motor system examination revealed claw hands with wasting of intrinsic muscles of hands, hammer toes, wasted extensor digitorum brevis, intrinsic foot muscles extending up to distal one-third of leg. Muscle power with medical research grading (MRC) showed the following; weak intrinsic hand muscles, finger extensors were weaker than finger flexors, normal power around wrist, elbow and shoulder joints. In lower limb, ankle dorsi-flexors (MRC grade 4/5), plantar flexion, inversion, eversion (MRC grade 3/5) with bilateral foot drop, power around bilateral knee and hip was MRC grade 5/5. There was generalized areflexia with flexor plantar response and absent superficial as well as primitive reflexes. Sensory examination revealed impaired vibration below bilateral ankle with intact other modalities with positive Romberg's sign and high steeping gait due to bilateral foot drop. Cerebellar, autonomic, and peripheral nerve examinations were noncontributory.
|Figure 1: Bilateral facial weakness with inability to show teeth and incompletely buried eyelashes during attempted forceful eye closure|
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Examination of his elder sister of 15 years of age revealed bilateral pes cavus, hand deformity (claw hands), tongue atrophy, bifacial weakness with distal weakness of both upper and lower limb and impaired vibration below ankle. Clinical examinations of his both parents were normal.
Routine blood parameters including viral markers for human immune deficiency virus, hepatitis B and C were negative. Magnetic resonance imaging of brain and visual evoked potential was normal. Brain auditory evoked response revealed wave I, III, V, and I-III were abnormally prolonged. Nerve conduction test showed decreased conduction velocity of upper limb (median and ulnar) and both tibial nerve to <20 m/s; with prolonged distal latencies, decreased compound muscle action potential amplitude and nonrecordable sensory nerve action potential [Figure 3]. Repetitive nerve stimulation test of distal as well proximal group of muscles and orbicularis oculi were negative. Biopsy of left sural nerve revealed "onion bulb" formation, fibrocystic proliferation, and increased endoneurial connective tissue. Genetic testing could not be done due to unavailability and nonaffordability.
|Figure 3: Nerve conduction study showed uniform moderate conduction slowing with conduction velocity <24 m/s in both upper limb, prolonged distal motor latency and absent sensory potentials in both upper and lower limb suggestive of demyelinating hereditary neuropathy|
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Nerve conduction study of his elder sister showed demyelinating pattern with upper limb conduction studies below 15 m/s with absent response in lower limb. Sensory potentials are not obtainable. Nerve biopsy was not done assuming same phenotype as her younger brother. Nerve conduction velocity (NCV) studies of his parents were within normal limit.
The progression of disease course is slow in most of the subtypes. Management is mainly symptomatic. Patients should avoid neurotoxic drugs. There is no definite treatment available for any form of the disease. Various drugs like progesterone, ascorbic acid have been tried in animal as well human model without any success. Neurotrophins in CMT1A and corticosteroids in some CMT2 patients with MPZ mutations may be beneficial. ,,] Special shoes, ankle-foot orthoses, forearm crutches or canes for gait stability, exercise within the individual's capability, stretching exercises to reduce the deformities may help the patient to live with the disease.
| Discussion|| |
Charcot-Marie-Tooth disease is the most common inherited or genetic neuropathy affecting approximately 1 in 2500 people.  Characteristics clinical pictures, electrophysiological and nerve biopsy findings classify inherited neuropathy into two main groups: (1) The demyelinating form, or CMT1 and (2) the axonal form of CMT disease, or CMT2. Both CMT1 and majority subtypes of CMT2 showed autosomal dominant pattern of inheritance. Apart from this, CMT3 and 4 and X-linked form have also been described with variable clinical manifestations and inheritance pattern.
Charcot-Marie-Tooth type 4 and its subtypes are heterogeneous group of disorders with autosomal recessive pattern of inheritance. The exact incidence is not known. There are 10 subtypes of type 4 described so far. The different clinical features of CMT4 were described in [Table 1]. The diagnosis is usually carried out by correlation of various clinical manifestations, nerve conduction study (NCV), nerve biopsy findings, and specific genetic analysis. Common to all these subgroups are disturbances in myelination. NCV usually slowed with conduction velocity in upper limb is 20-30 m/s. Nerve biopsy may reveal features of demyelination and remyelination with onion bulbs appearance as in CMT1.  The following gene mutation found in CMT and its various subtypes; CMT1A with PMP22 duplication or point mutations; CMT1B with MPZ point mutations; CMT3 (Dejerine-Sottas disease) including PMP22, MPZ, and EGR2 mutations, CMT4 subtypes that is, GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SH3TC2 (CMT4C), NDRG1 (CMT4D).  Majority of them are not commercially available in developing countries.
|Table 1: Clinical features of subgroups of Charcot-Marie Tooth disease type 4 (CMT 4)|
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In the present report, the patient in his first decade of life, presented with history of consanguinity with autosomal recessive pattern of inheritance with predominant sensory ataxia, hand and feet deformity, bifacial weakness and bilateral lower motor neuron hypoglossal nerve palsy with pathological, and electrophysiological proven demyelinating inherited neuropathy with abnormal BAER. Facial weakness, abnormal BAER, and prominent sensory ataxia are demonstrated in type 4B1 variant and tongue atrophy with tongue fasciculations are described in type 4C variant of CMT. ,, To our knowledge, the clinical spectrum described in our patient has not been described under any one single subtype rather the clinical phenotype has shown overlapping features of type 4B1, 4C, and 4D. Although extensive genetic test are not available in this country, this keen phenotypic observation with overlapping clinical manifestations may give a clue for a different entity of inherited neuropathy. Furthermore, inclusion of more number of similar cases with definite molecular analysis may disclose the true etiology and will be helpful in categorization of this entity.
| Conclusion|| |
Charcot-Marie-Tooth disease type 4 is a heterogeneous group of inherited neuropathy with autosomal recessive pattern of inheritance with variable clinical spectrum. The present case demonstrated overlapping clinical pictures of type 4B1, 4C, and 4D with neurophysiologic and histopathology proven inherited genetic neuropathy which has rare documentation in clinical practice. Molecular and genetic studies may give proper insight into the exacting subtypes.
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[Figure 1], [Figure 2], [Figure 3]