Original Contribution |

Proximal Dominant Hereditary Motor and Sensory Neuropathy With Proximal Dominance Association With Mutation in the TRK-Fused Gene

Sang-Soo Lee, MD; Hye Jin Lee, MSc; Jin-Mo Park, MD; Young Bin Hong, PhD; Kee-Duk Park, MD; Jeong Hyun Yoo, MD; Heasoo Koo, MD; Sung-Chul Jung, MD; Hyung Soon Park, MD; Ji Hyun Lee, PhD; Min Goo Lee, MD; Young Se Hyun, MSc; Khriezhanou Nakhro, MSc; Ki Wha Chung, PhD; Byung-Ok Choi, MD
JAMA Neurol. 2013;70(5):607-615. doi:10.1001/jamaneurol.2013.1250.
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Importance Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) has been reported as a rare type of autosomal dominant adult-onset Charcot-Marie-Tooth disease. HMSN-P has been described only in Japanese descendants since 1997, and the causative gene has not been found.

Objectives To identify the genetic cause of HMSN-P in a Korean family and determine the pathogenic mechanism.

Design Genetic and observational analysis.

Setting Translational research center for rare neurologic disease.

Participants Twenty-eight individuals (12 men and 16 women) from a Korean family with HMSN-P.

Main Outcome Measures Whole-exome sequencing, linkage analysis, and magnetic resonance imaging.

Results Through whole-exome sequencing, we revealed that HMSN-P is caused by a mutation in the TRK-fused gene (TFG). Clinical heterogeneities were revealed in HMSN-P between Korean and Japanese patients. The patients in the present report showed faster progression of the disease compared with the Japanese patients, and sensory nerve action potentials of the sural nerve were lost in the early stages of the disease. Moreover, tremor and hyperlipidemia were frequently found. Magnetic resonance imaging of the lower extremity revealed a distinct proximal dominant and sequential pattern of muscular involvement with a clearly different pattern than patients with Charcot-Marie-Tooth disease type 1A. Particularly, endoneural blood vessels revealed marked narrowing of the lumen with swollen vesicular endothelial cells.

Conclusions and Relevance The underlying cause of HMSN-P proves to be a mutation in TFG that lies on chromosome 3q13.2. This disease is not limited to Japanese descendants, and marked narrowing of endoneural blood vessels was noted in the present study. We believe that TFG can affect the peripheral nerve tissue.

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Figure 1. Pedigree of the FC457 family. *Indicates an individual whose DNA was used for this study. Alleles of TFG (c.854C>T) as well as 6 microsatellites on 3q12-q25 are indicated in the rectangles beneath the identifiers of examined individuals. Alleles within parentheses were inferred. Although the II-9 affected man is the elder brother of the II-8 unaffected woman, II-9 is indicated on the right side of II-8 for the convenience of pedigree drawing. Mbp indicates megabase pair; square, male; circle, female; black-filled, affected; half-filled, unaffected but with TFG mutation; no fill, unaffected; arrow, proband; diagonal bar across symbol, deceased.

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Figure 2. Hip, thigh, and leg magnetic resonance images (MRIs) of a clinically unaffected individual (IV-17, A-D) and 3 symptomatic individuals (III-29, E-H; III-27, I-L; and III-23, M-P) with TFG mutation. A 23-year-old man (IV-17) did not experience any symptoms, and MRIs of the hip (A and B), thigh (C), and leg (D) revealed normal findings. A 48-year-old woman (III-29) with 2 years' disease duration showed atrophy and fatty changes in gluteus minimus and medius muscles (arrow, E) but relatively preserved gluteus maximus muscle (arrowhead, F). At the thigh level (G), the semitendinosus muscle (open arrowhead) was severely damaged, and vastus lateralis and sartorius muscles (arrowhead) were involved. On the leg (H), we found mild fatty changes in the gastrocnemius muscle (arrow); however, the tibialis anterior muscle (arrowhead) was not involved. A 51-year-old man (III-27; I-L) with 3 years' disease duration had more progression of fatty infiltrations than his younger sister (III-29). In a 56-year-old man (III-23; M-P) with 11 years' disease duration, we observed diffuse severe atrophy and fatty change of his whole lower limb muscles, including the hip (N). Very minimal muscle fiber remained in the adductor longus on his thigh (O), and the muscle fiber was relatively intact in the anterior compartment, especially the tibialis anterior muscles on the leg (P).

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Figure 3. Distal sural nerve biopsies and narrowed endoneural blood vessels. A, Transverse semithin sections of a patient (III-29) with toluidine blue stain revealed the absence of large myelinated fibers, with remaining medium and small fibers and occasional regenerating axonal clusters. B and C, Ultrastructural micrographs by electron microscope showed myelinated fibers with irregular thickness of myelin, thick myelinated fibers, and regenerating axonal clusters. D, Healthy control's (woman, age 38 years) endoneural blood vessels with intact vascular lumen. E, The endoneural blood vessels in the sural nerve of patient III-29, however, showed marked narrowing of the lumen with swollen vesicular endothelial cells. F, Patient III-27 displayed extensive edematous change of endothelial cells with an almost obstructed lumen. Concentric multilamella collections of basal lamina were prominent. Original magnifications: ×40 (A), ×3000 (B), ×7000 (C), ×6000 (D), ×10 000 (E), and ×8000 (F).

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Figure 4. Sequencing chromatograms and conservation analysis of c.854C>T (Pro285Leu) in TFG. A, Confirmation of the mutation by capillary sequencing. The heterozygous c.854C>T mutation was cosegregated in the affected individuals but was not found in the controls. B, Conservation analysis. The mutation site (arrow) and surrounding amino acid sequences are well conserved between the different species.

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Figure 5. In vitro expression of TFG in NSC-34 and HEK 293T cells. A, NSC-34 cells were transfected with green fluorescent protein (GFP)–tagged wild-type (WT) TFG. The green fluorescence image was obtained by fluorescent microscope. The TFG proteins are expressed in neurites (arrowheads). B, Cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Wild-type and mutant TFG vectors were transfected into the NSC-34 cells. Mock transfected cells were used as controls. C, Protein expression of WT and P285L (mutant) TFG in HEK 293T cells. D, Expression of GFP-tagged TFG in HEK 293T cells. In some cells, both WT and P285L TFG induced punctate or inclusion-like structures (arrowheads).




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