Figure 38-1 Sural nerve features. A, Considerable reduction in myelinated nerve fiber density. Few axons with disproportionately thin myelin sheaths, minor onion bulb formation (black arrows). Sporadic nerve fibers with focally folded myelin (white arrow). Semithin section, toluidine blue; scale bar = 25 μm. B, EM micrograph of an axon surrounded by focally folded myelin. Ultrathin section; scale bar = 4 μm. C, Nonmyelinated axon surrounded by a Schwann cell with prominent, often plump cytoplasmic protrusions (white arrow). Occasionally, basal lamina remnants (black arrow) and loops were found in the vicinity of such nerve fibers, indicating Schwann cell degeneration associated with process retraction. A denervated Schwann cell process indicative of incipient onion bulb formation is marked by (S). Ultrathin section; scale bar = 1 μm. D, A myelinated nerve fiber presumably cross-sectioned at a level close to a node of Ranvier showing cytoplasmic Schwann cell protrusions and focal detachment of Schwann cell basal lamina (black arrow). Extended, flat or often plump cytoplasmic processes of Schwann cells of unmyelinated nerve fibers (white arrows). (M): Membranous extracellular matrix structure of unknown significance. Ultrathin section, scale bar = 2 μm.

The peculiar ultrastructural phenotype prompted molecular genetic analysis of the KIAA1985/SH3TC2 gene. Sequencing of the coding exons disclosed compound heterozygosity for the common nonsense mutation c.2860C>T, R954X^2,³ and a so far unreported missense mutation c.686T>A, L229Q. Because the latter variant was undetectable in a large number of control chromosomes and causes a nonconservative exchange of an evolutionary conserved residue, L229Q represents a pathogenic mutation.

CONCLUSIONS

The current case combines several typical features of CMT4C including primary involvement of the distal legs, sensory symptoms, foot deformity, demyelinating phenotype with reduced nerve conduction velocities, and autosomal recessive mode of inheritance.^4,⁵ However, onset of the disease was late, and scoliosis, a regular feature of previously reported cases,³^–⁵ ⁶ was absent.

Sural nerve biopsy confirmed the diagnosis of chronic demyelinating neuropathy. As in other reported cases, onion bulbs consisting of Schwann cell processes were rare and numerous Schwann cells of mostly unmyelinated nerve fibers had extended atypical cytoplasmic processes. However, only incipient basal lamina onion bulb formation was found. Moreover, even though the cytoplasmic Schwann cell protrusions were numerous, most of them were relatively short and many of the longer ones were plump and often broad-based, unlike the ones reported previously.^3,^4,⁶

Together, these findings suggest an abortive CMT4C phenotype, both on the clinical and the cellular level. In line with this hypothesis, the novel KIAA1985/SH3TC2 sequence variant c.686T>A, L229Q is a missense mutation. Residual protein function may account for the mild clinical and histopathologic phenotype and late onset of the disease. In addition, our results support the notion that KIAA1985/SH3TC2 is involved in the regulation of the interaction of Schwann cells with the extracellular matrix. Finally, the present case demonstrates that morphologic analysis in seemingly sporadic cases of peripheral neuropathy might reveal changes indicative of an autosomal recessive type of hereditary neuropathy.

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