Charcot–Marie–Tooth disease type 2F associated with biallelic <i>HSPB1</i> mutations

Abati, Elena; Magri, Stefania; Meneri, Megi; Manenti, Giulia; Velardo, Daniele; Balistreri, Francesca; Pisciotta, Chiara; Saveri, Paola; Bresolin, Nereo; Comi, Giacomo P.; Ronchi, Dario; Pareyson, Davide; Taroni, Franco; Corti, Stefania

doi:10.1002/acn3.51364

Cited by 7 publications

(6 citation statements)

References 40 publications

(118 reference statements)

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“…Five pathogenic or likely pathogenic mutations were identified in HSPB1 from six CMT2 or dHMN families ( Figure 1 A). A c.404C>T (p.S135F) was observed three times in one large dHMN family (FC189) and two CMT2 families (FC522 and FC567); many studies have reported this mutation as a genetic cause of CMT2F and dHMN2B [ 1 , 2 , 18 , 19 , 23 , 24 ]. A 6-year-old boy (VI-2) in the FC189 family and two girls (6 and 7 years old, III-1 and III-2) in the FC522 family had the p.S135F variant, but they were still not affected.…”

Section: Resultsmentioning

confidence: 99%

“…As a first report, a p.L99M homozygous mutation was reported in a consanguineous Pakistani patient with dHMN [ 2 ]. Then, a p.R140G homozygous mutation was reported in an Indian patient with distal vacuolar myopathy and motor neuropathy [ 3 ], and pS315F and p.R316L homozygous mutations were identified in the Republic of Cabo Verde and Iranian families with CMT2, respectively [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Lim

Jung

Lee

et al. 2022

Genes

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Small heat shock proteins (sHSPs) are ATP-independent chaperones that help correct the folding of denatured proteins and protect cells from stress. Mutations in HSPB1, HSPB8, and HSPB3 are implicated in inherited peripheral neuropathies (IPNs), such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathies (dHMN). This study, using whole exome sequencing or targeted gene sequencing, identified 9 pathogenic or likely pathogenic variants in these three sHSP genes from 11 Korean IPN families. Most variants were located in the evolutionally well conserved α-crystallin domain, except for p.P182S and p.S187L in HSPB1. As an atypical case, a patient with dHMN2 showed two compound heterozygous variants of p.R127Q and p.Y142H in HSPB1, suggesting a putative case of recessive inheritance, which requires additional research to confirm. Three HSPB8 variants were located in the p.K141 residue, which seemed to be a mutational hot spot. There were no significant differences between patient groups, which divided by sHSP genes for clinical symptoms such as onset age, severity, and nerve conduction. Early-onset patients showed a tendency of slightly decreased sensory nerve conduction values compared with late-onset patients. As a first Korean IPN cohort study examining sHSP genes, these results will, we believe, be helpful for molecular diagnosis and care of patients with CMT2 and dHMN.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Lim

Jung

Lee

et al. 2022

Genes

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“…In 2008, Houlden, H., et al first reported CMT2F inherited in the way of autosomal recessive (AR) (p.L99M) [ 4 ]. In the following years, studies and reports supplemented this conclusion [ 5 ]. The clinical phenotypes caused by HSPB1 gene mutation have certain heterogeneity in symptoms and onset age [ 6 ].…”

Section: Introductionmentioning

confidence: 89%

Heterogeneous Clinical Phenotypes of dHMN Caused by Mutation in HSPB1 Gene: A Case Series

et al. 2022

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Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation.

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“…One of the most common causes of dHMN are dominant mutations in HSPB1 , the prevalence of which vary between 5 and 10% in different series [3 ▪ –5 ▪ ,6,10]. Recessive inheritance has been reported in few cases [11,12]. Patients carrying the same HSPB1 mutation can be diagnosed with either dHMN or CMT2 [3 ▪ ].…”

Section: Classic Distal Hereditary Motor Neuropathiesmentioning

confidence: 99%

Hereditary motor neuropathies

Frasquet

Sevilla

2022

Current Opinion in Neurology

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Purpose of reviewDistal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field. Recent findingsDespite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1. Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways. SummaryDespite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials.

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Charcot–Marie–Tooth disease type 2F associated with biallelic HSPB1 mutations

Cited by 7 publications

References 40 publications

Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea

Heterogeneous Clinical Phenotypes of dHMN Caused by Mutation in HSPB1 Gene: A Case Series

Hereditary motor neuropathies

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