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Multiple sclerosis associated with duplicated CMT1A: a report of two cases
  1. Sezione di Neurologia Clinica, Dipartimento di Scienze Neurologiche e della Visione, Universita’ di Verona, Italy
  1. Dr Giuseppe Moretto, Sezione di Neurologia Clinica, Policlinico Borgo Roma, 37134 Verona, Italy.

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The concomitant involvement of both the peripheral and central nervous system myelin is rare and may occur in the course of inherited lysosomal storage diseases. In inflammatory autoimmune diseases of the peripheral nervous system or CNS, a mild involvement of central or peripheral myelin has sometimes been reported.1 2 In such conditions, a single pathogenetic mechanism has been tentatively considered as responsible for the nervous tissue damage and the association of peripheral nervous system and CNS demyelinating disorders due to different pathogenetic mechanisms has never been reported.

We describe two patients with definite multiple sclerosis and hereditary peripheral neuropathy of Charcot-Marie-Tooth type 1A (CMT1A).

Patient 1, a 38 year old woman, was admitted to hospital because of episodes of gait disturbances and optic neuritis. Neurological examination showed ataxia, lower limb weakness, bilateral Babinski’s sign, increased tendon reflexes, mild sensory loss in all four limbs, impaired bladder function, and bilateral pes cavus. Her CSF showed an IgG index of 0.89 and IgG oligoclonal bands. Electrophysiology disclosed features of CNS and peripheral nervous system demyelination (table).

Patient 2, a 30 year old woman, had had recurrent episodes of hemiparesis and paraparesis, optic neuritis, and facial palsy since the age of 22. When admitted to our department, she had spastic paraplegia, absent ankle tendon reflexes, bilateral Babinski’s sign, distal loss of vibration in the legs, impaired visual acuity, internuclear opthalmoplegia, and ataxic speech. Bilateral pes cavus was found in the patient as well as in several members of her family. Her CSF showed an IgG index of 0.98 and IgG oligoclonal bands. Brain MRI showed diffuse foci of demyelination in the white matter of the cerebral hemispheres and in the spinal cord. Neurophysiological studies disclosed aspects of CNS and peripheral nervous system demyelination (table).

In both patients sural nerve biopsy showed loss of myelinated fibres and aspects of demyelination and remyelination with onion bulb formation.

Genetic molecular analysis was performed by CHEF-DRIII pulsed fields gel electrophoresis of the CMT1A Sac II junction fragment.3 The detection of the novel junction fragment of 500 kb in both cases indicated the presence of duplication.

Both patients had clinically definite multiple sclerosis; in addition, the neurophysiological, neuropathological, and genetic analysis investigations disclosed a demyelinating and remyelinating neuropathy of CMT1A.

The involvement of the peripheral nervous system in the course of multiple sclerosis has been previously reported.1 2 The authors suggested the diagnosis of chronic inflammatory polyradiculoneuropathy (CIDP) as the consequence of a peripheral nervous system invasion by the same pathological process affecting the CNS. Our patients did not fulfill laboratory criteria for CIDP. In addition, the anamnestic presence of foot abnormalities in family members suggested inherited neuropathy. Finally, the detection of characteristic genetic alterations in chromosome 17 confirmed the diagnosis of CMT1A.

Aspects of CNS involvement have been reported in CMT1 and also in hereditary neuropathy with liability to pressure palsy,4the last being caused by a reciprocal deletion of the region duplicated in CMT1A; these changes have been tentatively attributed to an increased or decreased expression of peripheral myelin protein (PMP) 22 within the CNS. However, this is the first report describing an association of multiple sclerosis and CMT1A. CMT1A encompasses most of the cases of CMT and is associated with a duplication in chromosome 17 p11.2-12 where the PMP22 gene is located. PMP22 is mainly expressed in the peripheral nervous system, but it shares similarities with other proteins of the CNS such as the proteolipid protein. In duplicated CMT1A, myelin development is normal, but an overexpression of PMP22 may affect the maintenance of the peripheral nervous system myelin, which undergoes progressive destruction.5

The present finding raises the question whether the concomitant presence of CMT1A and multiple sclerosis represents a chance association or whether the genetic defect responsible for the peripheral neuropathy can play a part in triggering the autoimmune disorder of CNS myelin. We speculate that the PMP22 overexpression may also involve its antigenic properties, thus inducing modifications of self tolerance. In this context, the partial homology among peripheral nervous system and CNS proteins, such as the proteolipid protein, could account for the occurrence of autoimmune disorders targeted to the CNS myelin.

We suggest that patients with multiple sclerosis must be carefully evaluated for the presence of peripheral nervous system involvement. In such circumstances, neurophysiological, neuropathological, and genetic analyses may greatly contribute towards a correct diagnosis.


This work was supported by grant 750 95 from Telethon Italy.


Table 1

Neurophysiological studies

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