Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies

Zhongbo Chen, Reza Maroofian, A. Nazlı Başak, Leena Shingavi, Mert Karakaya, Stephanie Efthymiou, Emil K. Gustavsson, Leyla Meier, Kiran Polavarapu, Seena Vengalil, Veeramani Preethish-Kumar, Bevinahalli N. Nandeesh, Nalan Gökçe Güneş, Onur Akan, Fatma Candan, Bertold Schrank, Stephan Zuchner, David Murphy, Mahima Kapoor, Mina RytenBrunhilde Wirth, Mary M. Reilly, Atchayaram Nalini, Henry Houlden, Payam Sarraf

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1344-1355
Number of pages12
JournalEuropean Journal of Neurology
Issue number4
StatePublished - Apr 2021


  • Charcot-Marie-Tooth disease
  • genotype–phenotype association
  • hereditary motor neuropathy
  • hereditary sensory and motor neuropathy
  • peripheral nerve disease
  • spinal muscular atrophy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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