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In CMT4A, nerve biopsies reveal a marked reduction of myelinated nerve bers, severe hypomyelination, and basal lamina onion bulbs (Figs 9 8 and 9 9)133,135 140 Hypomyelination, loss of myelinated

Figure 9 8 CMT4 A Semithin transverse section through sural nerve from two patients (A and B), showing a pronounced depletion of myelinated bers Remaining bers are of very small size, sometimes assembled in regenerative clusters *Note the proliferation of Schwann cells in circular fashion forming onion bulbs, particularly around cluster (black arrowhead) Some bers are thinly myelinated (open arrowheads) Bar = 10 m (With permission from Sevilla T, Cuesta A, Chumillas MJ, et al Clinical, electrophysiological and morphological ndings of Charcot Marie Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene Brain 2003;126(Pt 9):2023 2033, Fig 2, p 2027)

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Figure 9 9 CMT4 A EM (A) A cluster of small myelinated bers is surrounded by a concentric array of Schwann cell processes with which numerous unmyelinated axons are associated (B) A myelinated ber undergoing active axonal degeneration along with several groups of unmyelinated bers fully encircled by a single Schwann cell Bars = 2 m (With permission from Sevilla T, Cuesta A, Chumillas MJ, et al Clinical, electrophysiological and morphological ndings of Charcot Marie Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene Brain 2003;126(Pt 9):2023 2033, Fig 5, p 2029)

Use the following vocabulary terms to complete the following sentences Not all terms will be used 133 MHz 233 MHz 800 MHz 1 GHz CD-ROM drive oppy disks installation network drive upgrade Upgrade Advisor Windows 2000 Professional Windows XP Home Edition Windows XP Professional

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Figure 9 10 CMT4 F (A) Light microscopy Cross semithin epon section of the sural nerve Loss of myelinated bers of all diameters, small onion bulb structures, and tomacula (B) Electron microscopy Onion bulb formations, ber with focally folded myelin Inset: A naked axon with myelin infoldings surrounded by an onion bulb of mixed type (With permission from Kabzinska D, Drac H, Sherman DL, et al Charcot Marie Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene Neurology 2006;66(5):745 747, Fig 1, p 746)

nerve bers, basal lamina onion bulbs, and numerous bers with excessively folded myelin sheaths are features of CMT4B25,142,143 Some have characterized these focal myelin thickenings as tomacula,142 while others have advocated that these are histologically distinct from tomacula143 In CMT4C, there is a marked reduction of large-diameter myelinated nerve bers with relative sparing of small- and intermediate-diameter bers145 The remaining axons are thinly myelinated and surrounded by Schwann cell proliferation forming classic onion bulbs CMT4F is characterized by severe axonal loss, with remaining axons being hypomyelinated and associated with onion bulbs (Fig 9 10)146 148 In addition, occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and the axon are appreciated in CMT4F152

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CMT4A is caused by mutations in the GDAP1 gene located on chromosome 8q13 q2184,133 141,154 Both neurons and Schwann cells express GDAP1, which may explain why mutations may be associated with electrophysiological and histopathological features of either an axonal or a demyelinating neuropathy155,156 GDAP1 is located in the mitochondrial outer membrane and helps regulate the mitochondrial network and belongs to a group of proteins, such as mitofusion-2, which when abnormal lead to CMT

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