Novel variants broaden the phenotypic spectrum of PLEKHG5‐associated neuropathies

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 i...

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Bibliographic Details
Published in:European journal of neurology 2021-04, Vol.28 (4), p.1344-1355
Main Authors: Chen, Zhongbo, Maroofian, Reza, Başak, A. Nazlı, Shingavi, Leena, Karakaya, Mert, Efthymiou, Stephanie, Gustavsson, Emil K., Meier, Leyla, Polavarapu, Kiran, Vengalil, Seena, Preethish‐Kumar, Veeramani, Nandeesh, Bevinahalli N., Gökçe Güneş, Nalan, Akan, Onur, Candan, Fatma, Schrank, Bertold, Zuchner, Stephan, Murphy, David, Kapoor, Mahima, Ryten, Mina, Wirth, Brunhilde, Reilly, Mary M., Nalini, Atchayaram, Houlden, Henry, Sarraf, Payam
Format: Article
Language:English
Subjects:
Atrophy
Autophagy
Charcot-Marie-Tooth disease
Charcot-Marie-Tooth Disease - genetics
Consanguinity
Disease
Gene sequencing
Genes, Recessive
Genomes
Genotype
genotype–phenotype association
Guanine Nucleotide Exchange Factors
hereditary motor neuropathy
hereditary sensory and motor neuropathy
Humans
Mutation
Nervous system
Neuromuscular diseases
peripheral nerve disease
Peripheral nervous system
Peripheral neuropathy
Phagocytosis
Phenotype
Spinal muscular atrophy
Synaptic vesicles
Tooth diseases
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Summary: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. We describe novel biallelic variants in PLEKHG5 in 13 individuals from nine unrelated families extending the phenotypic and molecular spectrum of PLEKHG5‐associated disease. PLEKHG5 pathogenic variants should be considered in motor‐predominant hereditary neuropathies, usually starting proximally, and can be associated with minor sensory involvement.
ISSN:1351-5101
1468-1331
DOI:10.1111/ene.14649