Charcot-Marie-Tooth (CMT) 1B

CMT1B Case Study

Two patients, father and son, presented since childhood with slowly progressive weakness, affecting the arms more than the legs, and numbness in the hands and feet (Thomas et al. 1994). There was no recurrent focal weakness, pain, or liability to pressure palsies. Findings were similar in father and son, but more pronounced in the former. Both had pes cavus deformity. The father had enlarged, firm peripheral nerves. Muscle strength was reduced to 4/5, being worse distally. Deep tendon reflexes were absent. Plantar responses were flexor. All sensory modalities were impaired. In addition, multiple living male and female relatives from four generations were affected.

Both patients underwent sural nerve biopsies and genetic testing; the father also underwent laboratory and electrodiagnostic studies. B12, folate, lead levels, MAG and GM1 antibody titers, and serum protein electrophoresis were all normal. No sensory or motor responses were obtained with surface recordings. Needle examination of the left median nerve revealed motor nerve conduction velocity of 11 m/s (normal >49 m/s), and a CMAP amplitude of 0.3 mV (normal >5 mV). Sensory responses and F waves were absent. Electromyography revealed minimal spontaneous activity with high amplitude motor unit potentials.

Sural nerve biopsy findings were similar in father and son. Semithin cross-sections of nerve showed a reduction of myelinated fiber density (Figure 1A,B). Many remaining fibers had thin myelin sheaths. Frequent small onion bulbs and scattered tomacula were found. The myelinated fiber density was 250/mm2 in the father and 3147/mm2 in the son. Histometric measurements showed a unimodal distribution of myelinated fibers with a shift of the peak to diameters between 1 and 4 µm in the father, and a bimodal distribution with one peak between 1 and 4 µm and a second peak at 6 µm in the son (Figure 2). Most of the fibers larger than 5 µm in diameter had tomacula. Teased fibers and longitudinal semithin sections revealed sausage-shaped expansions of myelin, located in both the paranodal and internodal regions in virtually all fibers (Figure 1C). Segmental remyelination was found in all teased myelinated nerve fibers. Ultrathin sections demonstrated that the tomacula consisted of closely apposed, redundant loops of myelin sheath wound around or layered on one side of a thinly myelinated fiber. Incorporation of the altered myelin protein zero into the myelin sheath was demonstrated immunohistochemically.

Myelin protein zero (MPZ) sequencing revealed a codon 96 mutation that substituted a positively charged lysine for a negatively charged glutamate in the extracellular region (Hayasaka et al. 1993; Su et al. 1993). This indicates that both patients have Charcot-Marie-Tooth disease type 1B.

Since the first description of tomacula in Charcot-Marie-Tooth disease type 1B patients (Thomas et al. 1994), the association of hypermyelination with mutations in the extracellular domain of MPZ has been confirmed. Meanwhile mutations in the intracellular domain and in or near the transmembrane domain have been associated with hypomyelination and myelin uncompaction (Gabreels-Festen et al. 1996; Nakagawa et al. 1999; Lagueny et al. 1999).

Figure legends

Figure 1. CMT1B. Light microscopical appearance of tomacula

Figure A

Figure B

A,B. Semithin cross-section shows a marked depletion of myelinated nerve fibers. Scattered onion bulbs consist of concentrically arranged Schwann cell processes, some without a central myelinated fiber. Several myelinated fibers in cross section (A) and longitudinal section (B) have a very thick myelin sheath and an irregular contour, suggesting that they are tomacula.

Figure C

C. Teased myelinated nerve fiber containing tomacula that consist of globular expansions of myelin measuring 30 to 50 µm in length.

References

1. Gabreels-Festen, A.A., Hoogendijk, J.E., Meijerink, P.H. et al., Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease. Neurology 1996; 47:761-765.
2. Lagueny, A., Latour, P., Vital, A. et al., Peripheral myelin modification in CMT1 B correlates with MPZ gene mutations. Neuromuscular Disorders 1999; 9:361-367.
3. Nakagawa, M., Suehara, M., Saito, A. et al., A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths. Neurology 1999; 52:1271-1275.
4. Su, Y., Brooks, D.G., Li, L. et al., Myelin protein zero gene mutated in Charcot-Marie-Tooth disease type 1 B patients. Proc Natl Acad Sci USA 1993; 90:10856-10860.
5. Thomas, F.P., Lebo, R.V., Rosoklija, G. et al, Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome. Acta Neuropathol 1994; 87:91-97.

This case study provided courtesy of Florian P. Thomas, M.D., Ph.D. of Saint Louis University, St. Louis, MO