Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Novel Variants Broaden the Phenotypic Spectrum of Plekhg5-Associated Neuropathies Publisher Pubmed



Chen Z1, 2 ; Maroofian R2 ; Basak AN3 ; Shingavi L4 ; Karakaya M5 ; Efthymiou S2 ; Gustavsson EK1 ; Meier L5 ; Polavarapu K4, 6, 7, 8 ; Vengalil S4 ; Preethishkumar V4 ; Nandeesh BN9 ; Gokce Gunes N10 ; Akan O11 Show All Authors
Authors
  1. Chen Z1, 2
  2. Maroofian R2
  3. Basak AN3
  4. Shingavi L4
  5. Karakaya M5
  6. Efthymiou S2
  7. Gustavsson EK1
  8. Meier L5
  9. Polavarapu K4, 6, 7, 8
  10. Vengalil S4
  11. Preethishkumar V4
  12. Nandeesh BN9
  13. Gokce Gunes N10
  14. Akan O11
  15. Candan F12
  16. Schrank B13
  17. Zuchner S14
  18. Murphy D2
  19. Kapoor M2
  20. Ryten M1
  21. Wirth B5
  22. Reilly MM2
  23. Nalini A4
  24. Houlden H2
  25. Sarraf P15
Show Affiliations
Authors Affiliations
  1. 1. Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom
  2. 2. Department of Neuromuscular Disease, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom
  3. 3. School of Medicine, Neurodegeneration Research Laboratory, KUTTAM-NDAL, Koc University, Istanbul, Turkey
  4. 4. Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
  5. 5. Institute of Human Genetics, Center for Molecular Medicine and Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne, Germany
  6. 6. Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
  7. 7. Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
  8. 8. Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
  9. 9. Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
  10. 10. Neurology Department, Ankara Training and Research Hospital, University of Health Sciences, Ankara, Turkey
  11. 11. Neurology Department, Okmeydani Training and Research Hospital, Istanbul, Turkey
  12. 12. Neurology Department, Goztepe Training and Research Hospital, Medeniyet University, Istanbul, Turkey
  13. 13. Department of Neurology, DKD Helios Kliniken, Wiesbaden, Germany
  14. 14. Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miler School of Medicine, Miami, FL, United States
  15. 15. Department of Neuromuscular Diseases, Iranian Centre of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: European Journal of Neurology Published:2021


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. © 2020 European Academy of Neurology
Related Docs
View other Related Docs
1. Biallelic Variants in Ogdh Encoding Oxoglutarate Dehydrogenase Lead to a Neurodevelopmental Disorder Characterized by Global Developmental Delay, Movement Disorder, and Metabolic Abnormalities, Genetics in Medicine (2023)
2. Homozygous Variants in Wdr83os Lead to a Neurodevelopmental Disorder With Hypercholanemia, American Journal of Human Genetics (2024)
3. Novel Disease-Causing Variants in a Cohort of Iranian Patients With Metachromatic Leukodystrophy and in Silico Analysis of Their Pathogenicity, Clinical Neurology and Neurosurgery (2021)
4. Bi-Allelic Loss of Function Variant in the Nrcam Gene Is Associated With Motor-Predominant Axonal Polyneuropathy; the Second Report, Molecular Genetics and Genomic Medicine (2023)
5. Co-Existence of Phenylketonuria Either With Maple Syrup Urine Disease or Sandhoff Disease in Two Patients From Iran: Emphasizing the Role of Consanguinity, Journal of Pediatric Endocrinology and Metabolism (2016)
6. Molecular Characterization of Qdpr Gene in Iranian Families With Bh4 Deficiency: Reporting Novel and Recurrent Mutations, JIMD Reports (2015)
7. Adult-Onset Very-Long-Chain Acyl-Coa Dehydrogenase Deficiency (Vlcadd), European Journal of Neurology (2020)
8. Genetic Homozygosity in a Diverse Population: An Experience of Long Qt Syndrome, International Journal of Cardiology (2020)
Experts (# of related papers)
View all Related Experts
Abbas Tafakhori (4)
Ali Reza Tavasoli (4)
Other Related Docs
9. Catecholaminergic Polymorphic Ventricular Tachycardia (And Seizure) Caused by a Novel Homozygous Likely Pathogenic Variant in Casq2 Gene, Gene (2024)
10. Ellis-Van Creveld Syndrome: Report of a Case and Recurrent Variant, Journal of Gene Medicine (2020)
11. A Bioinformatics Approach to Prioritize Single Nucleotide Polymorphisms in Tlrs Signaling Pathway Genes, International Journal of Molecular and Cellular Medicine (2016)
12. Waardenburg Syndrome Type 2A in a Large Iranian Family With a Novel Mitf Gene Mutation, BMC Medical Genomics (2021)
13. Leu226trp Cacna1a Variant Associated With Juvenile Myoclonic Epilepsy With and Without Intellectual Disability, Clinical Neurology and Neurosurgery (2022)
14. Autosomal Dominant Deficiency of the Interleukin-17F in Recurrent Aphthous Stomatitis: Possible Novel Mutation in a New Entity, Gene (2018)
15. Dysfunction of the Ciliary Armc9/Togaram1 Protein Module Causes Joubert Syndrome, Journal of Clinical Investigation (2020)
16. Genome-Wide Association Study of Long Covid, Nature Genetics (2025)
17. A Comprehensive Overview of Nf1 Mutations in Iranian Patients, NeuroMolecular Medicine (2024)
18. Identification of a Novel Stop Loss Mutation in P2rx2 Gene in an Iranian Family With Autosomal Nonsyndromic Hearing Loss, Iranian Biomedical Journal (2021)
19. Flt3l Governs the Development of Partially Overlapping Hematopoietic Lineages in Humans and Mice, Cell (2024)
20. Identification of Six Novel Mutations in Iranian Patients With Maple Syrup Urine Disease and Their in Silico Analysis, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis (2016)
21. Rpe65 and Retinal Dystrophy: Report of New and Recurrent Mutations, Journal of Gene Medicine (2020)
22. Autozygosity Mapping of Methylmalonic Acidemia Associated Genes by Short Tandem Repeat Markers Facilitates the Identification of Five Novel Mutations in an Iranian Patient Cohort, Metabolic Brain Disease (2018)
23. Maple Syrup Urine Disease Mutation Spectrum in a Cohort of 40 Consanguineous Patients and Insilico Analysis of Novel Mutations, Metabolic Brain Disease (2019)
24. Exome-Wide Copy Number Variation Analysis Identifies a Col9a1 in Frame Deletion That Is Associated With Hearing Loss, European Journal of Medical Genetics (2019)
25. Beta Thalassemia in 31,734 Cases With Hbb Gene Mutations: Pathogenic and Structural Analysis of the Common Mutations; Iran As the Crossroads of the Middle East, Blood Reviews (2016)
26. Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of Cnksr2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (Mrxshg), American Journal of Medical Genetics, Part A (2025)
27. Detection of Variants in Dystroglycanopathy-Associated Genes Through the Application of Targeted Whole-Exome Sequencing Analysis to a Large Cohort of Patients With Unexplained Limb-Girdle Muscle Weakness, Skeletal Muscle (2018)
28. Prdm12 Is Transcriptionally Active and Required for Nociceptor Function Throughout Life, Frontiers in Molecular Neuroscience (2021)
29. Digenic Mutations in Junctional Epidermolysis Bullosa in an Iranian Family, Cell Journal (2021)
30. Genotypes of European and Iranian Patients With Type 3 Von Willebrand Disease Enrolled in 3Winters-Ips, Blood Advances (2021)
31. Identification of a Novel Frameshift Mutation in the Tecta Gene in an Iranian Family With Autosomal Nonsyndromic Hearing Loss, Acta Medica Iranica (2021)
32. Brown-Vialetto-Van Laere Syndrome and Fazio-Londe Syndrome: A Novel Mutation and in Silico Analyses, Journal of Clinical Neuroscience (2020)
33. Crystallographic Modeling of the Pnpt1:C.1453A>G Variant As a Cause of Mitochondrial Dysfunction and Autosomal Recessive Deafness; Expanding the Neuroimaging and Clinical Features, Mitochondrion (2021)
34. Genetic Testing of Leukodystrophies Unraveling Extensive Heterogeneity in a Large Cohort and Report of Five Common Diseases and 38 Novel Variants, Scientific Reports (2021)
35. Whole-Genome Sequencing Reveals Host Factors Underlying Critical Covid-19, Nature (2022)
36. In Silico Analysis for Determining the Deleterious Nonsynonymous Single Nucleotide Polymorphisms of Brca Genes, Molecular Biology Research Communications (2019)
37. Mutation in Twinkle in a Large Iranian Family With Progressive External Ophthalmoplegia, Myopathy, Dysphagia and Dysphonia, and Behavior Change, Archives of Iranian Medicine (2016)
38. Biallelic Ndc1 Variants That Interfere With Aladin Binding Are Associated With Neuropathy and Triple A-Like Syndrome, Human Genetics and Genomics Advances (2024)
39. Expanding the Clinical and Neuroimaging Features of Nkx6-2-Related Hereditary Spastic Ataxia Type 8, European Journal of Medical Genetics (2020)
40. Whole Exome Sequencing Reveals a Xpnpep3 Novel Mutation Causing Nephronophthisis in a Pediatric Patient, Iranian Biomedical Journal (2020)
41. In Silico Analysis of Novel Mutations in Maple Syrup Urine Disease Patients From Iran, Metabolic Brain Disease (2017)