What is a case study of Charcot-Marie-Tooth (CMT) disease type 1B?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, MSc, PhD, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Answer

A clinical vignette is as follows:

Two patients, father and son, presented with slowly progressive weakness since childhood, affecting the arms more than the legs, and numbness in the hands and feet. They denied recurrent focal weakness, liability to pressure palsies, or pain. Multiple living male and female relatives from 4 generations were affected.

Findings were similar in father and son but were more pronounced in the former. Both had pes cavus. The father had enlarged firm peripheral nerves. Muscle strength was reduced to four fifths and was worse distally. Deep tendon reflexes were absent. Plantar responses were flexor. All sensory modalities were impaired. Laboratory studies in the father revealed vitamin B-12, folate, and lead levels that were within the reference range and normal findings on myelin-associated glycoprotein and GM1 antibody titers and serum protein electrophoresis. No sensory or motor responses were obtained with surface recordings. Needle examination of the left median nerve revealed motor nerve conduction velocities of 11 m/s (lower reference range value is 49 m/s) and a compound motor action potential (CMAP) amplitude of 0.3 mV (lower reference range value is 5 mV). Sensory responses and F waves were absent. Electromyography (EMG) 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. Many remaining fibers had thin myelin sheaths. Frequent small onion bulbs and scattered tomaculae (as shown below) 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 µm and 4 µm in the father and a bimodal distribution with one peak between 1 µm and 4 µm and a second peak at 6 µm in the son.

Light microscopy of tomaculae, which are typical o Light microscopy of tomaculae, which are typical of hereditary neuralgic amyotrophy (HNA) and hereditary neuropathy with predisposition to pressure palsies (HNPP) but are also associated with certain MPZ mutations in Charcot-Marie-Tooth disease type 1B (CMT1B). (A) Semithin cross-section shows myelinated nerve fiber loss with scattered onion bulbs (arrowheads). Several myelinated fibers have a thick myelin sheath and an irregular contour (large arrow). (B) Semithin longitudinal section demonstrating tomaculae in continuity with myelinated fibers. The myelin sheath is inappropriately thin, probably as a result of segmental remyelination or hypomyelination. (C) Teased myelinated nerve fiber containing tomaculae that consist of globular expansions of myelin measuring 30-50 µm in length.

Most of the fibers larger than 5 µm in diameter had tomaculae. Teased fibers and longitudinal semithin sections revealed sausage-shaped expansions of myelin, located in both the paranodal and internodal regions in virtually all fibers. Segmental remyelination was found in all teased myelinated nerve fibers. Ultrathin sections demonstrated that the tomaculae consisted of closely apposed redundant loops of myelin sheath wound around or layered on one side of a thinly myelinated fiber. MPZ mutation was found in both father and son.


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