Hereditary motor sensory neuropathies (HMSN) are characterized by degeneration of myelin and axons in motor and sensory nerves that cause clinically symmetrical weakness of distal muscles. HMSN are a group of genetically inherited disorders, predominantly by autosomal dominant or X-linked dominant genes. The hypertrophic or demyelinating form of HMSN is referred to as HMSN type I (HMSN-I), in which there is marked reduction in nerve conduction velocities. The majority of HMSN-I patients have DNA duplication on chromosome 17, where the human peripheral myelin protein-22 (PMP22) gene is located and clinical phenomena are limited to the peripheral nervous system (PNS) only, because the PMP22 gene is expressed only in PNS. However, there are studies reporting that a connexin-32 gene mutation may be responsible for demyelination and decreased conduction velocity, not only in the PNS but also in the central nervous system (CNS), especially in X-linked HMSN-I. There is also evidence with respect to pyramidal system involvement and visual and auditory system involvement.

Multiple sclerosis (MS) is classically defined as an autoimmune CNS disease limited to the white matter and characterized by demyelination, glial scarring and axonal damage. Another classical definition concerning MS is the sparing of the PNS. However, cases have been reported in which polyneuropathy (PNP) accompanies MS with no other etiological cause. In electrophysiological studies, it has been shown that PNP involvement could occur more frequently than expected in MS patients, but whether there is myelin damage in PNS of MS patients is not generally accepted yet.

In one study, severe demyelination was observed in peripheral nerves of 12 of 20 patients with MS and the authors concluded that malnutrition and avitaminosis were the etiological causes. However, in an other report PNP was observed in patients with MS and it was suggested that this was not a consequence of MS but occurred as a result of toxic and nutritional factors. The authors established that peripheral myelin was affected in sural nerve biopsies of MS patients who did not have clinical signs of PNP. The study presented by Rosenberg et al. (1993) showed clinical signs in the PNP such as widespread areflexia and hypoesthesia in stocking/glove distribution, in addition to a classical MS history.

In a study investigating the frequency of PNP associated with MS by clinical and electrophysiological methods, it was reported that 45.5% of the patients had subclinical PNP, predominantly sensorial. In an electrophysiological study using the “near nerve technique”, it was established that 64% of MS patients showed mild abnormalities in peripheral sensory conduction. It was suggested that this could be the result of both degenerating and regenerating nerve fibers due to chronic axonal denervation.

Matrix metalloproteinases (MMPs) have frequently been implicated to be important molecules in the pathogenesis of MS. It is known that MMPs cause CNS damage by degrading the blood-brain barrier together with adhesion molecules. A similar proteolytic process could also occur in the PNS of patients with MS.

Idiman et al. (2001) have reported increased immunostaining of some extracellular matrix (ECM) proteins and the integrin greek small letter alpha4 and ?4 receptors in a sural nerve biopsy of an MS patient. The increased immunostaining has been shown by clinical and electrophysiological methods to be associated with PNP. It was also reported that ECM reorganization was evidently increased and myelin sheaths were degenerated in a parallel with Schwann cell proliferation. In a parallel study, increased staining of vitronectin and its receptor was shown in MS.

Several hypotheses have been suggested to explain PNS dysfunction in MS. The most significant mechanism of myelin damage is the attack by immune cells of some proteins in the myelin structure. Central and peripheral myelin share common antigenic properties in different proportions. Although the cells producing myelin are different in the CNS and PNS, the corresponding myelin structures have a similar macromolecular organization. Both have a complex and compact spiral membrane structure with high electrical resistance and low capacitance. Myelin in CNS and PNS contains common proteins. For instance, some molecules like myelin basic protein, myelin associated glycoprotein, cerebroside, sulfatide and syfingomyelin could play a role in chronic change of CNS and PNS in patients with MS. There are immunohistochemical studies reporting a cross reaction between cultured cells of the CNS and PNS and how mutant superoxide dismutase protein lead to the death of motor neurons.

Although pathogenetic mechanisms are entirely different in these two diseases, the systems are similar with respect to demyelination, but immunohistochemical and ultrastructural studies on these two diseases are very limited. Therefore, the aim of the present study was to compare the immunohistochemical and ultrastructural changes in sural nerves in relation with HMSN-I and MS, which differ in their nature and pathogenesis.

Case I: 44-year-old male was first diagnosed to have PNP who, ten-years later, developed clinical features consistent with MS, with demyelinating lesions in white matter of the CNS.

Case II: 36-year-old male with HSMN-I who showed demyelination in the CNS with clinical and radiological evidence.

Sural nerve biopsies of the two patients were prepared for immunohistochemical and electron microscopical studies. Routine tissue preparation was performed in order to compare ultrastructure with immunohistochemical findings. Sections were cut for light and electron microscopy, respectively.

The biopsy materials were fixed with 4% paraformaldehyde and embedded in paraffin. Sections (5-?m thick) were deparaffinized and incubated for 10 min at 37 °C in methanol, which contained 3% H2O2 in order to block endogenous peroxidase activity. Afterwards, sections were washed with phosphate buffered saline (PBS, pH 7.2) at room temperature for 10 min. In order to prevent nonspecific staining, sections were incubated with a multispecies serum for 20 min at 37 °C. In the following step, sections were incubated with primary monoclonal antibodies against laminin (1:50 dilution; Dako, Glostrup, Denmark), fibronectin (1:1500 dilution; Dako), vimentin (1:100 dilution; Dako), collagen type IV (1:50 dilution; Dako) and S-100 protein (1:100 dilution; Dako) for 60 min at room temp. Sections were then washed and incubated with secondary antibodies (Dako) for 30 min at room temp. Thereafter, sections were washed with PBS and incubated with streptavidin–horseradish peroxidase complex (LSAB kit; Dako) for 30 min at room temp. To visualize bound antibodies, sections were incubated at room temperature for 10 min with the chromogen 3,3-diaminobenzidine (Dako), and finally sections were counterstained with hematoxylin, mounted with coverslips and examined under a light microscope. Details of the immunohistochemical techniques that were applied have been described in recent publications.