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

Lee, Sang Soo; Lee, Hye Jin; Park, Jin Mo; Hong, Young Bin; Park, Kee Duk; Yoo, Jeong Hyun; Koo, Heasoo; Jung, Sung Chul; Park, Hyung Soon; Lee, Ji Hyun; Lee, Min Goo; Hyun, Young Se; Nakhro, Khriezhanou; Chung, Ki Wha; Choi, Byung Ok

doi:10.1001/jamaneurol.2013.1250

Cited by 41 publications

(32 citation statements)

References 21 publications

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“…Exome sequencing was performed for the proband of FC307 family according to Lee et al [22]. Functionally significant variants (missense, nonsense, exonicindel and splicing site variants) were first selected from WES data, and then novel or uncommon variants (MAF ≤0.01) registered in the dbSNP137 [23] and 1000 Genomes database [24] were chosen.…”

Section: Methodsmentioning

confidence: 99%

Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Kim

Hong

Park

et al. 2013

Orphanet J Rare Dis

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BackgroundMutations in the Pleckstrin homology domain-containing, family G member 5 (PLEKHG5) gene has been reported in a family harboring an autosomal recessive lower motor neuron disease (LMND). However, the PLEKHG5 mutation has not been described to cause Charcot-Marie-Tooth disease (CMT).MethodsTo identify the causative mutation in an autosomal recessive intermediate CMT (RI-CMT) family with childhood onset, whole exome sequencing (WES), histopathology, and lower leg MRIs were performed. Expression and activity of each mutant protein were analyzed.ResultsWe identified novel compound heterozygous (p.Thr663Met and p.Gly820Arg) mutations in the PLEKHG5 gene in the present family. The patient revealed clinical manifestations of sensory neuropathy. Fatty replacements in the distal lower leg muscles were more severe than in the thigh muscles. Although the symptoms and signs of this patient harboring slow nerve conduction velocities suggested the possibility of demyelinating neuropathy, a distal sural nerve biopsy was compatible with axonal neuropathy. Immunohistochemical analysis revealed that the patient has a low level of PLEKHG5 in the distal sural nerve and an in vitro assay suggested that the mutant proteins have a defect in activating the NF-κB signaling pathway.ConclusionsThis study identifies compound heterozygous PLEKHG5 mutations as the cause of RI-CMT. We suggest that PLEKHG5 might play a role in the peripheral motor and sensory nervous system. This study expands the phenotypic spectrum of PLEKHG5 mutations.

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Section: Methodsmentioning

confidence: 99%

Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Kim

Hong

Park

et al. 2013

Orphanet J Rare Dis

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“…Motor nerve conduction studies were within normal limits in our patients. In contrast, electrodiagnostic studies in HMSN2A, HMSN2K and HMSN‐P revealed axonal neuropathy with low amplitudes of CMAP in the motor nerves. The sensory nerves were severely involved as the amplitudes of SNAP could not be recorded in the investigated nerves in this study.…”

Section: Discussionmentioning

confidence: 71%

“…16 An autopsy study of HMSN-P patients revealed obvious loss of neurons in the dorsal root ganglion, anterior horn of the spinal cord, hypoglossal and facial nuclei of the brainstem. [17][18][19] Limited study of sural nerve biopsy revealed absence of large myelinated fibers with occasional regenerating axonal clusters in HMSN-P. 20 Here, we report sural nerve pathology and clinical characteristics in two unrelated Chinese families with motor neuron…”

Section: Introductionmentioning

confidence: 82%

Sural nerve pathology in TFG‐associated motor neuron disease with sensory neuropathy

Meng

et al. 2019

Neuropathology

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The tropomyosin‐receptor kinase fused gene (TFG) functions in vesicles formation and egress at the endoplasmic reticulum (ER). A heterozygous missense mutation c.854C > T (p.Pro285Leu) within TFG has been reported as causative for hereditary motor and sensory neuropathy with proximal predominance. Here, we describe two unrelated Chinese pedigrees with 13 affected members harboring the same variant. The clinical, electrophysiological and pathological findings are consistent with motor neuron disease with sensory neuropathy. The main symptoms were painful muscle cramps, slowly progressive proximal predominant weakness, muscle atrophy, fasciculation and distal sensory disturbance. Electromyography revealed widespread denervation and reinnervation. Sural nerve biopsy revealed severe loss of myelinated fibers. Electron microscopy revealed aggregation of ER with enlarged lumen and small vesicles in the remaining myelinated and unmyelinated axons. The mitochondria are smaller in Schwann cells and axons. Some unmyelinated axons showed disappearance of neurofilament and microtubular structures. This is the first report of c.854C > T mutation within TFG in Chinese population. Our findings not only extend the geographical and phenotypic spectrum of TFG‐related neurological disorders, but also confirm the abnormalities of ER and mitochondria in sural nerves.

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“…In contrast with traditional genetic approaches for the isolation of disease-causing mutations, which have taken considerable time and effort, recent advent of next-generation sequencing (NGS) has broadened and accelerated the genetic analysis of various disorders. For example, a mutation in the TRK-fused gene, which causes hereditary motor and sensory neuropathy with proximal dominance, eluded isolation for 15 years, until the application of NGS (1,2). In addition, the application of whole-exome sequencing (WES) to clinically and genetically heterogeneous diseases has been effective in unveiling their genetic causes.…”

Section: To the Editormentioning

confidence: 99%

Application of variant‐calling algorithms for Mendelian disorders: lessons from whole‐exome sequencing in Charcot–Marie–Tooth disease

Hong

Jung

et al. 2013

Clinical Genetics

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

Cited by 41 publications

References 21 publications

Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Sural nerve pathology in TFG‐associated motor neuron disease with sensory neuropathy

Application of variant‐calling algorithms for Mendelian disorders: lessons from whole‐exome sequencing in Charcot–Marie–Tooth disease

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