Neurological update: hereditary neuropathies

Kramarz, Caroline; Rossor, Alexander M.

doi:10.1007/s00415-022-11164-1

Cited by 9 publications

(8 citation statements)

References 28 publications

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“…Biallelic pathogenic variants in SORD have been recently identified as a common cause of HMN/CMT2 neuropathy, possibly accounting for ∼10% of undiagnosed HMN/CMT2 cases. 95 , 96 Close to 70% of described individuals had no familiar history.…”

Section: Early Onset Neuronopathiesmentioning

confidence: 99%

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Zambon

Pini

Bosco

et al. 2022

Brain

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Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement. Their cumulative estimated prevalence is 2.14/100.000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive, and X-linked inheritance. Despite the advances of next generation sequencing, more than 60% of patients with HMN remain genetically uncharacterised. Of note, we are increasingly aware of the broad range of phenotypes caused by pathogenic variants in the same gene and of the considerable clinical and genetic overlap between HMN and other conditions, such as Charcot-Marie-Tooth type 2 (CMT2; axonal), spinal muscular atrophy with lower extremities predominance (SMA-LED), neurogenic arthrogryposis multiplex congenita (AMC), and juvenile amyotrophic lateral sclerosis (ALS). Considering that most HMN present during childhood, in this review we primarily aim to summarise key clinical features of paediatric forms, including recent data on novel phenotypes, to help guide differential diagnosis and genetic testing. Secondly, we describe newly identified causative genes and molecular mechanisms, and discuss how the discovery of these is changing the paradigm through which we approach this group of conditions.

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Section: Early Onset Neuronopathiesmentioning

confidence: 99%

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Zambon

Pini

Bosco

et al. 2022

Brain

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“…When the SORD enzyme is lost, sorbitol accumulates in cells leading to toxicity. Aldose reductase is an enzyme that produces sorbitol from glucose and its activity can be inhibited by already FDA-approved compounds that are now under investigation in clinical trials along with natural history studies [ 105 ].…”

Section: Inherited Peripheral Neuropathies (Ipns)mentioning

confidence: 99%

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Zambon,

Falzone,

Bolino

et al. 2024

Cell. Mol. Life Sci.

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Neuromuscular diseases encompass a heterogeneous array of disorders characterized by varying onset ages, clinical presentations, severity, and progression. While these conditions can stem from acquired or inherited causes, this review specifically focuses on disorders arising from genetic abnormalities, excluding metabolic conditions. The pathogenic defect may primarily affect the anterior horn cells, the axonal or myelin component of peripheral nerves, the neuromuscular junction, or skeletal and/or cardiac muscles. While inherited neuromuscular disorders have been historically deemed not treatable, the advent of gene-based and molecular therapies is reshaping the treatment landscape for this group of condition. With the caveat that many products still fail to translate the positive results obtained in pre-clinical models to humans, both the technological development (e.g., implementation of tissue-specific vectors) as well as advances on the knowledge of pathogenetic mechanisms form a collective foundation for potentially curative approaches to these debilitating conditions. This review delineates the current panorama of therapies targeting the most prevalent forms of inherited neuromuscular diseases, emphasizing approved treatments and those already undergoing human testing, offering insights into the state-of-the-art interventions.

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“…This has resulted in the exclusion of certain genes, such as MORC2, SORD and SPTLC1, which are relatively prevalent within axonal CMT cohorts. 5,35 Second, we only screened a selected subpopulation of consecutive axonal neuropathies referred for genetic testing. This may have introduced some selection bias.…”

Section: Discussionmentioning

confidence: 99%

“…First, we screened a relatively small number of genes compared to reports from other populations. This has resulted in the exclusion of certain genes, such as MORC2 , SORD and SPTLC1 , which are relatively prevalent within axonal CMT cohorts 5,35 . Second, we only screened a selected subpopulation of consecutive axonal neuropathies referred for genetic testing.…”

Section: Discussionmentioning

confidence: 99%

Mutational screening of Greek patients with axonal Charcot‐Marie‐Tooth disease using targeted next‐generation sequencing: Clinical and molecular spectrum delineation

Kontogeorgiou,

Kartanou,

Rentzos

et al. 2023

J Peripheral Nervous Sys

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Background and aimsAxonal forms of Charcot–Marie–Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.MethodsSixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and an NGS custom‐made gene panel covering 24 commonly mutated genes in axonal CMT.ResultsOverall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/ likely pathogenic and 6 were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1.InterpretationA wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favorably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.This article is protected by copyright. All rights reserved.

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Neurological update: hereditary neuropathies

Cited by 9 publications

References 28 publications

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Early onset hereditary neuronopathies: an update on non-5qmotor neuron diseases

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

Mutational screening of Greek patients with axonal Charcot‐Marie‐Tooth disease using targeted next‐generation sequencing: Clinical and molecular spectrum delineation

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