TY - JOUR
T1 - Novel variants broaden the phenotypic spectrum of PLEKHG5-associated neuropathies
AU - Chen, Zhongbo
AU - Maroofian, Reza
AU - Başak, A. Nazlı
AU - Shingavi, Leena
AU - Karakaya, Mert
AU - Efthymiou, Stephanie
AU - Gustavsson, Emil K.
AU - Meier, Leyla
AU - Polavarapu, Kiran
AU - Vengalil, Seena
AU - Preethish-Kumar, Veeramani
AU - Nandeesh, Bevinahalli N.
AU - Gökçe Güneş, Nalan
AU - Akan, Onur
AU - Candan, Fatma
AU - Schrank, Bertold
AU - Zuchner, Stephan
AU - Murphy, David
AU - Kapoor, Mahima
AU - Ryten, Mina
AU - Wirth, Brunhilde
AU - Reilly, Mary M.
AU - Nalini, Atchayaram
AU - Houlden, Henry
AU - Sarraf, Payam
N1 - Funding Information:
Zhongbo Chen is funded by the Leonard Wolfson Clinical Research Fellowship in Neurodegenerative Disease. This work has been funded by the Deutsche Forschungsgemeinschaft (Wi 945/19‐1; RTG1960) and CMMC (C18) to Brunhilde Wirth , a CMMC clinical scientist award to Mert Karakaya, and a Köln‐Fortune doctoral fellowship to Leyla Meier. A. Nazlı Başak is grateful to the Suna and İnan Kıraç Foundation for its invaluable support and both the Foundation and Koç University‐KUTTAM for the stimulating research infrastructure and environment supplied.
Publisher Copyright:
© 2020 European Academy of Neurology
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - Charcot-Marie-Tooth disease
KW - genotype–phenotype association
KW - hereditary motor neuropathy
KW - hereditary sensory and motor neuropathy
KW - peripheral nerve disease
KW - spinal muscular atrophy
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U2 - 10.1111/ene.14649
DO - 10.1111/ene.14649
M3 - Article
C2 - 33220101
AN - SCOPUS:85097626548
VL - 28
SP - 1344
EP - 1355
JO - European Journal of Neurology
JF - European Journal of Neurology
SN - 1351-5101
IS - 4
ER -