Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases

Martin, Paige; Hicks, Amy N; Holbrook, Sarah E.; Cox, Gregory A.

doi:10.1016/j.brainres.2019.146532

Cited by 10 publications

(7 citation statements)

References 270 publications

(324 reference statements)

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“…A recently characterized subtype, CMT6C, was identified in two families from our cohort, associated with homozygous mutations in PDXK (under publication; Dr. Delague). Additionally, CMT patients in this study were observed with mutations in BAG3, DNAJB2, MTMR4, and VRK1 (under publication; Dr. Delague); CMT genotype-phenotype correlations with variants in BAG3 and DNAJB2 genes were recently described [63,64]. Our cohort also included CMT4B3 patients presenting with unique syndromic features.…”

Section: Charcot-marie-tooth Diseasementioning

confidence: 96%

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

Mégarbané

Bizzari

Deepthi

et al. 2022

JND

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Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999–2019) was reviewed. Results: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4%of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3%of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17%of patients). The latter disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5%of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. Conclusions: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

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Section: Charcot-marie-tooth Diseasementioning

confidence: 96%

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

Mégarbané

Bizzari

Deepthi

et al. 2022

JND

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“…A number of inherited variants and de novo mutations have been identified in human KIF1A from clinical studies. These mutations have been linked to neurodevelopmental and neurodegenerative disorders including spastic paraplegias, encephalopathies, intellectual disability, autism, and sensory neuropathies (3,(10)(11)(12)(13)(14)(15). For KIF1A-associated neurological disorder (KAND), the mutations span the entirety of the KIF1A protein sequence; the majority are located within the kinesin motor domain (aa 1-369) and…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms

Budaitis

Jariwala

Rao

et al. 2020

Preprint

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The kinesin-3 motor KIF1A functions in neurons where its fast and superprocessive motility is thought to be critical for long-distance transport. However, little is known about the force-generating properties of kinesin-3 motors. Using optical tweezers, we demonstrate that KIF1A and its C. elegans homolog UNC-104 undergo force-dependent detachments at ~3 pN and then rapidly reattach to the microtubule to resume motion, resulting in a sawtooth pattern of clustered force generation events that is unique among the kinesin superfamily. Whereas UNC-104 motors stall before detaching, KIF1A motors do not. To examine the mechanism of KIF1A force generation, we introduced mutations linked to human neurodevelopmental disorders, V8M and Y89D, based on their location in structural elements required for force generation in kinesin-1. Molecular dynamics simulations predict that the V8M and Y89D mutations impair docking of the N-terminal (β9) or C-terminal (β10) portions of the neck linker, respectively, to the KIF1A motor domain. Indeed, both mutations dramatically impair force generation of KIF1A but not the motor's ability to rapidly reattach to the microtubule track. Homodimeric and heterodimeric mutant motors also display decreased velocities, run lengths, and landing rates and homodimeric Y89D motors exhibit a higher frequency of non-productive, diffusive events along the microtubule. In cells, cargo transport by the mutant motors is delayed. Our work demonstrates the importance of the neck linker in the force generation of kinesin-3 motors and advances our understanding of how mutations in the kinesin motor domain can manifest in disease.

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“…Indeed, we have described two novel compound heterozygous missense mutations in the VRK1 gene, in two siblings, from a non-consanguineous Lebanese family, affected with a distal hereditary motor neuropathy (dHMN), associated with upper motor neuron signs (El-Bazzal et al, 2019). Diseases due to mutations in VRK1 , that we regrouped under the name of “ VRK1-related motor neuron diseases”, illustrate very well the clinical overlap which exists between CMT/dHMN and diseases affecting upper and/or lower motor neuron diseases, such as hereditary spastic paraplegias, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy (Hanemann & Ludolph, 2002; Irobi et al, 2006; Martin, Hicks, Holbrook, & Cox, 2020; Rossor, Polke, Houlden, & Reilly, 2013; Timmerman, Clowes, & Reid, 2013).…”

Section: Introductionmentioning

confidence: 85%

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Hamzé,

Humbert,

Rihan

et al. 2024

Preprint

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Hereditary Motor and Sensory Neuropathy (HMSN), or Charcot-Marie-Tooth disease (CMT), are the most common group of Inherited peripheral neuropathies (IPN), characterized by a strong clinical and genetic heterogeneity. Among them, distal Hereditary Motor Neuropathy (dHMN), also known as neuronopathy, is a subgroup, where only motor nerves are affected. This subgroup is also genetically heterogeneous, with 25 genes described to date, of which VRK1, that we have recently described as responsible for dHMN, associated to upper motor neuron signs. There are now more than thirty mutations in VRK1, which cause a range of neurological diseases affecting motor neurons (mainly lower, but also upper) or their axons in the peripheral nervous system, that we design as VRK1-related motor neuron diseases.In two previous studies, we have demonstrated that dHMN due to VRK1 mutations lead to reduced levels of VRK1 in the nucleus, and that this depletion alters the dynamics of coilin, a phosphorylation target of VRK1. hiPSC-derived Motor Neurons (hiPSC-MN) from these patients, display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching, altered Action Potential (AP) waveform and decreased Axonal Initial Segment (AIS) length.In this study, we have further studied the link between the loss of VRK1 function and the defects observed in hiPSC-MNs, by realizing bulk mRNA-Seq sequencing in this in vitro model of the disease. Our results evidenced altered NRG1/ERBB4 signaling, leading to cholesterol metabolism dysregulation and deregulation of genes encoding the glutamate receptors AMPAR and NMDAR, which role in the Axonal Initial Segment and abnormal AP initiation in hiPSC-MNs remains to be investigated.

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Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases

Cited by 10 publications

References 270 publications

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

Pathogenic Mutations in the Kinesin-3 Motor KIF1A Diminish Force Generation and Movement Through Allosteric Mechanisms

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

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