Neurofibromatosis 2 with peripheral neuropathies: Electrophysiological, pathological and genetic studies of a Taiwanese family

Abstract

The objective of this study was to assess peripheral nerve involvement and DNA mutation of the neurofibromatosis type 2 (NF2) gene (NF2) in a Taiwanese family with classic NF2. Eleven members (six symptomatic and five asymptomatic) of a family carrying NF2 underwent clinical examination, neuroimaging, and electrophysiological analysis. Mutation and linkage analyses were conducted on DNA samples prepared from peripheral blood (all individuals), a sural nerve biopsy specimen (one symptomatic member), and a tumor specimen (another symptomatic member). Six of the 11 members were diagnosed with classic NF2. DNA sequencing of the tumor specimen demonstrated a frameshift mutation with 756delC on exon 8 of NF2. Three affected subjects showed clinical variability of the neuropathic disorders. Electrophysiological studies demonstrated variation in the disease pattern and severity of peripheral nerve involvement in five affected subjects. The morphometric assessment of the sural nerve biopsy specimen showed a marked reduction in both large myelinated and unmyelinated fibre density and increased density of non-myelinating Schwann cell nuclei. Apart from numerous pathological nuclei of isolated Schwann cells, multiple profiles of non-myelinating Schwann cell subunits were apparent in the endoneurium. Schwann cell proliferation in association with first-hit mutation of the merlin gene might be responsible for the NF2-associated neuropathy. Sural nerve biopsy showed a progressive neuropathy in the disease. Further, we suggest nonmyelinating Schwann cells are involved in NF2 neuropathy.

Muscle action potential scans and ultrasound imaging in neurofibromatosis type 2

“…The pathogenesis of neuropathy in NF2 patients is unclear. One possible factor is the cumulative nerve compression caused by small tumors (schwannomas) or fascicular microlesions, as discussed in earlier studies . Our data provide some support for this view.…”

“…The low amplitudes of the CMAP in some patients, together with normal CVs (Fig. ), are in accordance with the description of an “axonal” type of neuropathy in NF2 patients . In comparison to conventional techniques, however, the CMAP scan analyses can provide more quantitative data about the number of functionally intact motor axons in peripheral nerves and can help to quantify the extent of denervation.…”

“…). These lesions may be small tumors (schwannomas) composed of proliferating Schwann cells, as described in histological studies of sural nerve biopsies in NF2 patients . Visualization of nerve schwannomas has been described by ultrasound imaging, and a case report of a single NF2 patient has been published .…”

“…Symptoms of neuropathy are common in NF2, as there are paresthesias, sensory loss, weakness, and muscle atrophy. Neuropathic pain, however, occurs in only rare cases . The aim of this study was to test novel methods that may help to quantify and follow‐up NF2‐associated neuropathy.…”

Nerve ultrasound shows subclinical peripheral nerve involvement in neurofibromatosis type 2

“…Peripheral neuropathy, with or without local nerve compression by a tumor, is reported in up to 66% of patients, although evidence is scarce . Subclinical peripheral nerve involvement has also been reported based on nerve conduction studies (NCS), but this information is even more scarce . This feature may be of importance, however, as neuropathic complaints could develop in the course of the disease.…”