Study of NOTCH2NLC-(GGC)n expansion in Brazilian patients with Charcot-Marie-Tooth Axonal disease.

• Grant number: 24/08928-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Wilson Marques Junior
• Grantee: Anna Virgínia Bertelle Borges
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN) is a clinically and genetically heterogeneous group of diseases that affect the sensory and motor nerves of the peripheral nervous system (PNS). They can be classified according to motor nerve conduction velocities into CMT1 (demyelinating subtypes), CMT2 (axonal subtypes) and CMTi (intermediate subtypes), as well as by inheritance pattern (autosomal dominant, autosomal recessive, X-linked, or mitochondrial) and responsible gene. Genetic testing establishes a precise diagnosis and has a significant impact on both affected patients and their families. The introduction of sequencing technologies has enabled a major advancement in the discovery of new variants and genes related to HMSN (more than 120 genes), consequently leading to a significant increase in the number of patients receiving a molecular diagnosis. Despite these advances, most patients with axonal form (CMT2) (~60%) still lack a definitive molecular diagnosis, indicating that most genes or variants for this subtype remain to be discovered. Recently, the GGC repeat expansion in the NOTCH2NLC gene was identified as a pathogenic cause of neuronal intranuclear inclusion disease (NIID), a progressive neurodegenerative disorder characterized by the presence of eosinophilic hyaline intranuclear inclusions in the central/peripheral nervous system and visceral organs. Knowing that there is a clinical and pathological overlap between neuronal intranuclear inclusion disease (NIID) and hereditary motor-predominant neuropathies, we can infer that Brazilian patients with CMT2/dHMN may present this expansion. Therefore, the objective of the present study will be to investigate the NOTCH2NLC-(GGC) expansion in Brazilian patients with CMT2/dHMN without a definitive molecular diagnosis. Additionally, we intend to correlate the genotypic findings with the specific phenotypes of this cohort and propose a diagnostic scheme for investigating the NOTCH2NLC-(GGC) expansion.