Chen, Zhongbo ORCID: 0000-0001-6668-7202, Maroofian, Reza, Basak, A. Nazli, Shingavi, Leena, Karakaya, Mert, Efthymiou, Stephanie, Gustavsson, Emil K., Meier, Leyla, Polavarapu, Kiran, Vengalil, Seena, Preethish-Kumar, Veeramani, Nandeesh, Bevinahalli N., Gunes, Nalan Gokce, Akan, Onur, Candan, Fatma, Schrank, Bertold, Zuchner, Stephan, Murphy, David, Kapoor, Mahima, Ryten, Mina, Wirth, Brunhilde, Reilly, Mary M., Nalini, Atchayaram, Houlden, Henry and Sarraf, Payam . Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies. Eur. J. Neurol.. HOBOKEN: WILEY. ISSN 1468-1331

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Abstract

Background and purpose Pathogenic variants in PLEKHG5 have been reported to date to be causative in three unrelated families with autosomal recessive intermediate Charcot-Marie-Tooth disease (CMT) and in one consanguineous family with spinal muscular atrophy (SMA). PLEKHG5 is known to be expressed in the human peripheral nervous system, and previous studies have shown its function in axon terminal autophagy of synaptic vesicles, lending support to its underlying pathogenetic mechanism. Despite this, there is limited knowledge of the clinical and genetic spectrum of disease. Methods We leverage the diagnostic utility of exome and genome sequencing and describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families originating from four different countries. We compare our phenotypic and genotypic findings with a comprehensive review of cases previously described in the literature. Results We found that patients presented with variable disease severity at different ages of onset (8-25 years). In our cases, weakness usually started proximally, progressing distally, and can be associated with intermediate slow conduction velocities and minor clinical sensory involvement. We report three novel nonsense and four novel missense pathogenic variants associated with these PLEKHG5-associated neuropathies, which are phenotypically spinal muscular atrophy (SMA) or intermediate Charcot-Marie-Tooth disease. Conclusions PLEKHG5-associated neuropathies should be considered as an important differential in non-5q SMAs even in the presence of mild sensory impairment and a candidate causative gene for a wide range of hereditary neuropathies. We present this series of cases to further the understanding of the phenotypic and molecular spectrum of PLEKHG5-associated diseases.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Chen, ZhongboUNSPECIFIEDorcid.org/0000-0001-6668-7202UNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Basak, A. NazliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shingavi, LeenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakaya, MertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gustavsson, Emil K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meier, LeylaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polavarapu, KiranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vengalil, SeenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preethish-Kumar, VeeramaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nandeesh, Bevinahalli N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gunes, Nalan GokceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akan, OnurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Candan, FatmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrank, BertoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuchner, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Murphy, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kapoor, MahimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryten, MinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reilly, Mary M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nalini, AtchayaramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarraf, PayamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-307856
DOI: 10.1111/ene.14649
Journal or Publication Title: Eur. J. Neurol.
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1468-1331
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PLEKHG5; GENE; FORMMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/30785

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