Type 2B Charcot-Marie-Tooth disease

Also Known As:

Charcot-Marie-Tooth disease, Type 2B; CMT 2B; CMT2B; Charcot-Marie-Tooth Disease, Autosomal Dominant, Type 2B; Charcot-Marie-Tooth Neuropathy, Type 2B; Charcot-Marie-Tooth disease, axonal, Type 2B; Charcot-Marie-Tooth disease, neuronal, Type 2B; HMSN IIB; HMSN2B; Hereditary Motor And Sensory Neuropathy IIB; Hereditary motor and sensory neuropathy 2 B (HMSN 2 B); Peripheral sensory neuropathy, autosomal dominant (PSN)

Networked: 26 relevant articles (0 outcomes, 0 trials/studies)

Disease Context: Research Results

Related Diseases

1.	Infections
2.	Peripheral Nervous System Diseases (PNS Diseases)
3.	Muscle Weakness
4.	Foot Ulcer
5.	Muscular Atrophy (Muscle Atrophy)

Experts

1.	Bucci, Cecilia: 11 articles (01/2022 - 02/2008)
2.	Romano, Roberta: 4 articles (01/2022 - 01/2020)
3.	Progida, Cinzia: 4 articles (02/2013 - 02/2008)
4.	De Luca, Maria: 3 articles (01/2021 - 12/2012)
5.	Manganelli, Fiore: 3 articles (01/2021 - 01/2018)
6.	Nolano, Maria: 3 articles (01/2021 - 01/2018)
7.	Santoro, Lucio: 3 articles (01/2021 - 01/2018)
8.	Cogli, Laura: 3 articles (02/2013 - 10/2009)
9.	Guerra, Flora: 2 articles (01/2022 - 12/2020)
10.	Pareyson, Davide: 2 articles (01/2022 - 01/2020)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Type 2B Charcot-Marie-Tooth disease:

1.	GTP Phosphohydrolases (GTPases)IBA 02/04/2017 - "CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. " 01/20/2016 - "Five missense mutations in the gene encoding Rab7 GTPase have been identified as causative in human CMT2b disease. " 09/16/2023 - "In Charcot-Marie-Tooth 2B disease (CMT2B), familial missense mutations in Rab7 cause alterations in GTPase cycling and trafficking, leading to an ulcero-mutilating peripheral neuropathy. " 01/01/2018 - "Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. " 01/11/2013 - "Four missense mutations in the late endosomal Rab7 GTPase (L129F, K157N, N161T, and V162M) cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth type 2B (CMT2B) disease. "
2.	Monomeric GTP-Binding ProteinsIBA 05/01/2014 - "Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. " 01/25/2014 - "To date, only four mutations of the RAB7 gene, which encodes the small GTPase, have been associated with CMT2B. " 04/24/2013 - "Genetic analysis of human CMT2B patients has revealed four missense point mutations in Rab7, a small GTPase that regulates late endosomal/lysosomal pathways, but the exact pathological mechanism remains poorly understood. " 12/01/2012 - "Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. " 11/01/2010 - "Four missense mutations of Rab7, a small GTPase of the Rab family involved in intracellular vesicular trafficking, are associated with the CMT2B phenotype. "
3.	Proteins (Proteins, Gene)FDA Link 01/01/2022 - "With the aim to analyze the autophagy process and lysosomal activity in CMT2B fibroblasts carrying the p.K126R RAB7 novel mutation and to investigate further the causes of the different phenotype, we have performed Western blot, immunofluorescence and cytometric analyses monitoring autophagic markers and endocytic proteins. " 12/10/2013 - "Live imaging reveals that CMT2B proteins are inefficiently recruited to endosomes, but do not impair endosomal maturation. " 10/01/2009 - "Indeed, how these mutations in the rab7 gene affect specifically peripheral neurons leading to an axonal pathology in CMT2B is not clear, and it is a particularly puzzling and challenging issue in view of the fact that Rab7 is a ubiquitous protein. " 07/25/2008 - "Therefore, activated forms of Rab7 protein cause the CMT2B disease." 01/01/2021 - "We found higher expression of late endocytic proteins in CMT2B cells compared to control cells, as well as higher activity of cathepsins and higher receptor degradation activity. "
4.	Mutant Proteins (Protein, Mutant)IBA 12/10/2013 - "All CMT2B mutant proteins retain 10-50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. " 12/01/2012 - "These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. " 12/09/2010 - "The nerve growth factor receptor TrkA interacted similarly with Rab7 wild-type and CMT2B mutant proteins, but the mutant proteins significantly enhanced TrkA phosphorylation in response to brief NGF stimulation. "
5.	Nerve Growth Factor (NGF)IBA 04/24/2013 - "We propose that Rab7 mutants induce premature degradation of retrograde NGF-TrkA trophic signaling, which may potentially contribute to the CMT2B disease." 04/24/2013 - "We also show that CMT2B Rab7 mutants markedly impaired NGF-induced Erk1/2 activation and differentiation in PC12M cells. " 04/24/2013 - "In PC12M cells, the CMT2B Rab7 mutants drastically reduced the level of surface TrkA and NGF binding, presumably by premature degradation of TrkA. " 12/09/2010 - "Here, we analyze the effects Rab7 CMT2B mutants on nerve growth factor (NGF) dependent intracellular signaling in PC12 cells. " 09/16/2023 - "The prevailing hypothesis to account for CMT2B pathologies is that CMT2B-associated Rab7 alleles alter endocytic trafficking of the neurotrophin NGF and its receptor TrkA and, thereby, disrupt normal trophic signaling in the peripheral nervous system, but other Rab7-dependent pathways are also impacted. "
6.	Guanosine Triphosphate (GTP)IBA 10/01/2010 - "The active behavior of these CMT2B-associated mutants is in line with their previously demonstrated increased GTP loading, thus confirming that active Rab7 mutants are responsible for CMT2B. " 07/25/2008 - "Altogether these data indicate that Rab7 K157N, similarly to the other three mutated proteins causative of CMT2B, is predominantly in the GTP-bound form and behaves as an active mutant. " 03/01/2003 - "We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. "
7.	PeripherinsIBA 02/01/2013 - "Since peripherin plays a role not only in neurite outgrowth during development but also in axonal regeneration after injury, these data suggest that the altered interaction between disease-causing RAB7A mutants and peripherin could play an important role in CMT2B neuropathy." 01/01/2020 - "The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. "
8.	ErbB Receptors (EGF Receptor)IBA 01/11/2013 - "Three different cell lines expressing Rab7 CMT2B mutants and stimulated with EGF exhibited delayed trafficking of EGF to LAMP1-positive late endosomes and lysosomes and slowed EGF receptor (EGFR) degradation. "
9.	Fatty Acid Synthases (Fatty Acid Synthase)IBA 12/01/2020 - "Moreover, in CMT2B cells a higher expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), key enzymes of de novo fatty acid synthesis, with a concomitantly increased [1-14C]acetate incorporation into fatty acids, was observed. "
10.	Dual Specificity Phosphatase 1IBA 12/09/2010 - "Nuclear shuttling of phospho Erk1/2, which is required to induce MAPK phosphatase expression and down regulate signaling, was greatly reduced by the Rab7 CMT2B mutants and explains the previously reported inhibition in PC12 neurite outgrowth. "

Therapies and Procedures

1.	Surgical Amputation (Amputations) 01/01/1997 - "Six patients with HMSN IIB had distal trophic ulcerations in the feet, leading to eventual toe amputations in four cases. " 12/01/2012 - "CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. " 07/25/2008 - "CMT2B peripheral axonal neuropathies are characterized by severe sensory loss, often complicated by infections, arthropathy, and amputations. " 02/13/2008 - "In particular, CMT type 2B (CMT2B) neuropathies are characterized by severe sensory loss, often complicated by infections, arthropathy, and amputations. " 11/28/2000 - "Marked sensory disturbances and the high frequency of foot ulcers, infections, and amputations in our patients seem to be typical for CMT2B. "
2.	Therapeutics 10/01/2010 - "Thus, our data suggest that lowering the activity of Rab7 in neurons could be a targeted therapy for CMT2B."