X-linked Charcot-Marie-Tooth disease with myokymia: Report of a family
The clinical and electrophysiologic profiles of two brothers suffering from Charcot-Marie-Tooth disease are presented. Both had widespread muscle twitching in the legs which showed electrophysiologic features of myokymia. Pedigree analysis suggested an x-linked recessive form of inheritance. This appears to be the first report of an Indian family with x-linked Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) comprises inherited neuropathies, mostly inherited autosomally (CMT 1 and 2). Recent data suggests that approximately 10-16% of all cases of CMT are inherited in an x-linked (recessive or dominant) manner. These patients (designated as CMT X) form a distinct group with point mutation in the gene coding for Connexin 32 (CX 32). Over 130 different CX 32 mutations causing CMT X have been identified to date; these produce a wide spectrum of the severity of neurologic signs and symptoms, including weakness, muscle atrophy and sensory loss. We report herein the clinical characteristics of a family with CMT in two brothers with clear x-linked recessive inheritance.
The pedigree chart is shown in [Figure - 1]. No details of the paternal lineage of generation G1 could be obtained from the members interviewed.
Case 1 (GIII-3)
The index case, a 16-year-old boy, was born of a non-consanguineous marriage and had normal birth and developmental history. He presented with a 18-month history of progressive weakness and wasting of the distal muscles of all the four limbs, difficulty in walking, continuous muscle twitching in the legs, excessive sweating of the palms and soles and tremor of hands. Examination revealed normal higher mental and cranial nerve functions; symmetric wasting of distal muscles in the upper limbs with mild weakness (power 4/5); intact upper limb reflexes and sensations and a postural tremor of the hands. The legs were wasted symmetrically distally with power 3/5 and with pes cavus-like feet deformity. The patellar reflexes were brisk but ankle reflexes were absent. The sensation of vibration was absent in the legs and propriception was impaired. General senses were intact. Thigh and leg muscles revealed continuous muscle twitching but there was no cramp, pain or stiffness in the muscles. The twitching was present during sleep as well. The palms and soles were moist. There was no sphincteric impairment and no postural drop of blood pressure.
Basic hematological, biochemical and CSF studies were normal. Nerve conduction studies revealed moderate degrees of slowing of motor nerve conduction velocity (MNCV) in the upper limbs (range 31-38 m/sec) with prolonged distal latencies (> 5 m/sec) and reduced compound muscle action potential (CMAP) amplitudes (0.9-2.6 mv); F-responses were mostly absent. The sensory conduction velocities were within normal limits (55-58 m/sec) but sensory nerve action potential (SNAP) amplitudes were reduced (7-14 mv). In the lower limbs, MNCVs were significantly reduced (13-23 m/sec) with diminished CMAP amplitudes (0.3-1 mv), and prolonged distal latencies (> 7 m/sec), absent F-responses and absent sural SNAP. These findings suggested a predominantly demyelinating polyneuropathy with axonopathy. Autonomic testing revealed normal sympathetic skin responses in both hands.
Resting electromyography in the leg muscles revealed rhythmic firing of grouped muscle action potentials suggestive of myokymia [Figure - 2]. Volitional EMG revealed evidence of chronic partial denervation of the affected muscles.
Case 2 (GIII-4)
This 14-year-old brother of the index case presented with a 6-month history of difficulty in walking with muscle twitching in legs only and no pain or muscle cramp. On examination, his higher functions, cranial nerves and upper limbs were normal. The legs were symmetrically wasted and showed continuous muscle twitching. The sensations, except for vibration, were intact. The ankle reflexes were absent.
Electrophysiologic studies were similar to Case 1 but were of less severe degree. The MNCVs in the upper limbs were reduced (35-42 m/sec) with mildly prolonged distal latencies (> 3.5 m/sec), and CMAP amplitudes varied from 5-7 mv. The MNCVs in the legs were more affected (25-32 m/sec) and sural SNAPs were absent. Resting EMG of the leg muscles revealed myokymia and volitional EMG showed features of chronic partial denervation.
The maternal grandfather of the index case (GI-1) was reported to have wasted legs and an awkward gait starting at 15 years of age. He lived up to 70 years, needing help to walk in the later years. None of his 6 daughters were symptomatic. The youngest daughter aged 37 years (GII-6), mother of the index case had no muscle wasting, weakness or twitching in her limbs. Electrophysiology and electromyography were normal. None of her other sisters and their siblings could be examined.
The father of the index case showed no clinical or electrophysiological abnormality.
The historically unaffected brother (GIII-1 aged 22 yrs) and sister (GIII-2 aged 20 yrs) of the index case showed normal electrophysiological results.
The diagnosis of CMT in the two brothers was suggested by the positive family history, slow progression, presence of distal symmetrical muscle weakness with atrophy, ankle areflexia, foot abnormality and slowed MNCVs. The diagnosis of an acquired form of neuropathy (like CIDP) was not considered in view of the familial occurrence and normal CSF findings. The inheritance pattern had been clearly x-linked recessive with history of a similar illness affecting the maternal grandfather and having normal parents (clinically and electrophysiologically). It is interesting that the sibships of the mother were all females and hence none were affected. An x-linked dominant inheritance could be excluded as the mother and her sisters were unaffected. Similarly, an autosomal recessive inheritance seemed unlikely as none on the paternal side of the index case had the disease. The theoretical possibility of an autosomal dominant disease with variable penetrance seemed on the whole unlikely judging by the sparing of all the female members of the family and the absence of any electrophysiological abnormality in either of the parents of the affected subjects.
NCV studies were suggestive of a demyelinating neuropathy mostly, but NCV values were of intermediate severity. This is known in CMT X patients (vide infra). An important clinical point of interest had been the presence of widespread muscle twitching only in the legs of both the patients. There was no pain, muscle cramps or stiffness and electrophysiology confirmed myokymia with rhythmic firing of grouped motor unit potentials (MUPs). In contrast to fasciculation potentials, there were groups of MUPs firing in bursts at a regular rate. There had been no waxing and waning thus excluding myotonic discharge, and no continuous muscle fiber activity as in neuromyotonia. The presence of myokymic discharges had not been specifically discussed in relation to CMT. However, these are known to occur with peripheral neuropathies like the GB syndrome. Myokymia only represents a hyperexcitable neuronal or peripheral nerve disorder irrespective of its etiology. No further details of the pathophysiology of myokymia in relation to CMT are available in the literature reviewed.
Interest in CMT X is of relatively recent origin. CX 32 is expressed in myelinating schwann cells, but unlike PMP 22 (the missing protein in CMT IA), is not found in compact myelin. CX 32 is found mainly in areas of loosely compact or uncompacted myelin, such as paranodal loops, where it presumably functions as a gap junction protein. Interestingly, many individuals with CMT X in contrast to CMT IA, have nerve conduction velocities that are only of intermediate severity,, and nerve biopsies that often show prominent axonal loss., Some mutations in CX 32 may not directly disrupt the structure of myelin but rather interfere with the communication between the schawann cells and the axons they ensheath, leading to secondary axonal degeneration. Because of the wide variety of clinical phenotypes in patients with CMT X, the differences in clinical severity are probably related to the type of mutation and its effect on the CX 32 function. The effects of known mutations in CMT X kindreds on CX 32 function are not well understood, and the molecular mechanisms underlying neuropathy in CMT X have not been studied in detail. Few clinical or molecular details are available on the 200 or more CMT X mutations, including missense and nonsense mutations, deletions and insertions that span almost all regions of the CX 32 molecule. The unusual finding of myokymia in the present cases seems to have resulted from a rather uncommon form of such mutation.
The authors are grateful to the Medical Director, B. R. Singh Hospital and Research Centre, Eastern Railways, Calcutta, for his kind permission to publish this case report.