REGISTRO DOI: 10.5281/zenodo.10850389
Daniel Antunes Pereira1; Camila Ferraz Machado2; Anick Martins de Andrade3; Roberta Lúcia de Souza Teixeira4; Daila Oliveira da Rocha5; Rafaela Ohana e Silva Cristina6; Igor da Rosa Coelho7; Esther Duarte de Oliveira8; Isadora Ferreira Pacheco Ribeiro9; Haylander Novaes de Santa Rita10; Caio Filipe Tartaglia Amorim11; Yulli Wienen12;
Analu Araújo Sobral13
ABSTRACT
The complexity of Charcot-Marie-Tooth disease (CMT) highlights the importance of genetic analysis for an accurate diagnosis and understanding of the various clinical manifestations of the disease. Identifying the pathogenic variant in the MME gene reinforces the crucial role of genetics in determining the disease profile and developing targeted therapies. Although the current treatment of CMT is predominantly symptomatic, advances in gene therapy and pharmacology offer hope for future more effective and specific therapeutic approaches. The MBAC patient, 56 years old, with a significant medical history, presents progressive mobility difficulties, numbness in her feet, and muscle weakness. Physical examination revealed characteristics of CMT, confirmed by genetic analysis that identified a pathogenic variant in the MME gene. This case report highlights the complexity of Charcot-Marie-Tooth disease (CMT), highlighting the importance of genetic analysis for an accurate understanding of the different clinical manifestations of the disease.
- Keywords: Charcot-Marie-Tooth, gene therapy, neuropathy, hereditary motor and sensory neuropathy
INTRODUCTION
As research into inherited neuropathies advances, a clearer understanding of their diverse manifestations and underlying genetic mechanisms is emerging. These conditions can present either as part of multisystem disorders or as primary genetic neuropathies, each with distinct phenotypic classifications. At one end of the spectrum are disorders such as hereditary motor neuropathies (HMN), characterized by minimal sensory involvement, and hereditary sensory neuropathies (HSN), which exhibit significant sensory impairment, potentially leading to skin ulcers or autonomic dysfunction(SMITH, 2020).
One of the well-known entities in this field is Charcot-Marie-Tooth disease (CMT), which represents a genetically heterogeneous group of primary genetic neuropathies. Typically, CMT encompasses sensory and motor involvement, falling within the broader hereditary sensory and motor neuropathy (HSMN) category. However, CMT can manifest itself in various forms, including purely motor or sensory forms, reflecting the complexity of its genetic basis(MORENA; GUPTA; HOYLE, 2019; SMAN et al., 2015; SMITH, 2020).
The global prevalence of CMT underscores its importance as the most common inherited disorder affecting peripheral nerves, with estimates varying between populations. Variability in prevalence rates may arise from differences in assessment methods or founder effects. Furthermore, the genetic landscape of CMT is marked by diverse inheritance patterns and electrophysiological classes, adding layers of complexity to its diagnosis and management(MCCRAY; SCHERER, 2021; MORENA; GUPTA; HOYLE, 2019).
Advances in genetic testing have revolutionized the diagnosis of CMT, with targeted testing and next-generation sequencing (NGS) panel testing expanding diagnostic yield. However, a subset of patients remains genetically unresolved, highlighting the continued need for collaboration between clinicians and molecular biologists to elucidate the remaining genetic basis of CMT(AUER-GRUMBACH et al., 2016; JAMIRI et al., 2022).
Despite significant advances in understanding the genetic basis of CMT, effective pharmacological treatments remain elusive. Current management strategies focus primarily on supportive care, with interventions such as ankle and foot orthoses (AFOs) and physical rehabilitation playing critical roles in improving mobility and mitigating musculoskeletal complications. Furthermore, exercise regimens tailored to individual capabilities offer promising prospects for increasing muscular strength and endurance while alleviating symptoms of fatigue and pain(MCCRAY; SCHERER, 2021; PIPIS et al., 2020).
The last few decades have witnessed remarkable scientific progress in elucidating the pathophysiology of CMT, paving the way for innovative therapeutic strategies. Emerging approaches, including RNA, DNA, and CRISPR/Cas9 technologies, can potentially develop targeted treatments to address the underlying molecular abnormalities in CMT(BELORIBI-DJEFAFLIA; ATTARIAN, 2023; SMAN et al., 2015; SMITH, 2020).
The pathways affected by genes that, when mutated, result in axonal neuropathy stand out. Most causative genes in CMT (type 2) encode proteins expressed widely beyond peripheral neurons. However, manifestations in other organ systems and the central nervous system are almost always absent, suggesting specific vulnerabilities of peripheral neurons to molecular insults. There are also examples of multisystem hereditary diseases with peripheral neuropathy as a manifestation. Mitochondria, transported by axons, are crucial for cellular function, and their dynamics are essential for neuronal health. MFN2, GDAP1, and OPA1 are crucial genes in mitochondrial dynamics, and mutations in them are associated with hereditary neuropathies(AUER-GRUMBACH et al., 2016; BELORIBI-DJEFAFLIA; ATTARIAN, 2023; MORENA; GUPTA; HOYLE, 2019). MFN2, for example, is associated with the most common form of CMT2, with manifestations ranging from severe to mild. Mutations in GDAP1 and OPA1 are also linked to mitochondrial disorders and peripheral neuropathies. Furthermore, mutations that impair mitochondrial energy production or mitochondrial DNA stability cause multisystem diseases, in which peripheral neuropathy is one of the manifestations. These diseases may have additional features, such as visual disturbances, gastrointestinal disorders, and central neurological disorders. These insights highlight the importance of mitochondrial dynamics in neuronal health and the pathogenesis of inherited neuropathies(AUER-GRUMBACH et al., 2016; MATHIS et al., 2016; SCHERER; KLEOPA, 2012).
One study demonstrated that heterozygous mutations in MME predispose individuals to late-onset axonal neuropathies. Identifying 11 different mutations in MME: 7 were loss-of-function alleles (nonsense, frameshift, splice site), and 4 were missense variants. Family studies have shown that MME variants typically segregate with the disease according to an autosomal dominant model with age-dependent or occasionally incomplete penetrance, as previously documented in other hereditary neuropathies. The mutations identified in MME were unique to the cases or were contained in internal and public databases with allele frequencies lower than 0.02%, except for the c.1040A>G (p.Tyr347Cys) mutation, which is more prevalent. Observed overrepresentation of each MME variant among individuals with late-onset hereditary neuropathies compared to any control data set. Furthermore, gene-based burden analysis demonstrated a significant association of MME loss-of-function variants with late-onset neuropathies compared to control subjects(JAMIRI et al., 2022; MATHIS et al., 2016).
CASE REPORT
MBAC, 56 years old, teacher, has a significant medical history, including systemic arterial hypertension (SAH), diabetes mellitus (DM) and an unspecified psychiatric condition. She reports mobility difficulties in 2020, characterized by a lack of speed when walking and unexplained episodes of stumbling. Since then, her condition has gradually progressed, reaching a critical point the following year. Additionally, she mentions feeling unbalanced when walking, mainly when she cannot focus her visual attention or is distracted. The patient also reports numbness in the feet, extending to the leg’s middle third.
In 2021, after an accident with a buggy, she suffered a spinal injury. On physical examination, it is observed that the patient has pes cavus, hammer toes, peroneal atrophy, and a deformity known as “inverted champagne bottle syndrome.” Her gait demonstrates characteristics of sensory ataxia. Deep reflexes are reduced, with patellar hyporeflexia and bilateral Achilles areflexia. Deep sensitivity shows normal conscious proprioception and hypoesthesia in the distal third of the leg, while superficial sensitivity reveals tactile, thermal, and painful hypoesthesia in the same region. Regarding muscular strength, there is weakness in the wrist extensors, finger flexors, dorsal and palmar interosseous muscles, as well as in several muscle groups of the lower limbs, with emphasis on the anterior tibial, peroneal (long and short), gastrocnemius, soleus muscles. And posterior tibialis (Figure 1). The patient cannot walk on toes or heels and has severe scoliosis as a compensatory mechanism.
Electroneuromyography demonstrates a suggestive picture of sensory-motor polyneuropathy with axonal and distal predominance, predominantly in the lower limbs.
Furthermore, genetic analysis revealed a pathogenic variant in the MME gene associated with the autosomal recessive Charcot-Marie-Tooth Disease, specifically the C2020-T variant (p.Arg68).
Figure 1 – Pes Cavus, elevation of the longitudinal plantar arch of the foot.
DISCUSSION
This report, with a significant medical history including systemic arterial hypertension, diabetes mellitus, and an unspecified psychiatric condition, illustrates the clinical and genetic nuances of CMT.
The clinical presentation includes progressive mobility difficulties, characterized by a slow gait, frequent stumbling, and a feeling of imbalance, especially during visual distractions. Additionally, she reports numbness in her feet and legs, suggesting sensory impairment. Physical examination reveals typical features of CMT, such as pes cavus, peroneal atrophy, and foot deformities. Neurological evaluation demonstrates muscle weakness, diminished reflexes, and reduced sensation in the lower extremities, consistent with peripheral sensory and motor neuropathy.
Electrophysiological studies and genetic analysis confirmed the diagnosis of MTC in MBAC. The analysis revealed a pathogenic variant in the MME gene associated with the autosomal recessive form of the disease. This discovery highlights the importance of genetic analysis in accurately identifying mutations causing hereditary diseases, facilitating early diagnosis, and guiding personalized treatment options(PISCIOTTA; SAVERI; PAREYSON, 2021).
In the context of CMT, treatment options aim to alleviate symptoms, slow disease progression, and improve patients’ quality of life. However, the therapeutic approach for MBAC and other patients with MTC must consider the complexity of the disease, including its variable clinical presentation and underlying genetic heterogeneity(PISCIOTTA; PAREYSON, 2023; PISCIOTTA; SAVERI; PAREYSON, 2021).
To conventional therapies such as physical therapy and symptom-relieving medications, recent advances in gene therapy and pharmacology offer hope for developing more effective and targeted treatments for CMT. For example, identifying specific mutations, such as the one found in the MME gene of MBAC, could pave the way for targeted gene therapies that aim to correct or compensate for underlying genetic defects(CHOI et al., 2015).
In addition to gene therapies, several pharmacological approaches are being investigated to treat CMT. For example, PXT3003, a mixture of baclofen, naltrexone, and sorbitol, was developed to modulate PMP22 gene expression and promote effective myelination. Initial clinical studies have shown promising results, although challenges related to dosing and safety have been noted. Other pharmacological strategies in development include using P2X7 receptor antagonists to modulate cellular stress and promote myelination and using compounds such as curcumin to mitigate endoplasmic reticulum stress and promote cell survival(OKAMOTO; TAKASHIMA, 2023; PISCIOTTA; SAVERI; PAREYSON, 2021; SCHERER; KLEOPA, 2012).
Physical therapy, rehabilitation, pharmaceutical methods, and gene therapies are crucial in managing CMT, as they enhance patients’ functional abilities, muscle strength, and range of motion. Continued research in these areas is critical to identifying effective interventions complementing other treatment forms(PISCIOTTA; PAREYSON, 2023).
However, it is important to recognize the challenges associated with developing effective therapies for CMT, including efficiently delivering therapeutic agents to target cells, minimizing adverse side effects, and ensuring equitable access to innovative treatments.
Continued advances in genetic and therapeutic research offer hope for significant improvements in the treatment of CMT and the quality of life of affected patients.
CONCLUSION
The case vividly illustrates the complexity of Charcot-Marie-Tooth disease (CMT), highlighting the importance of genetic analysis for an accurate diagnosis and understanding of the variable clinical manifestations of the disease. Identifying the pathogenic variant in the MME gene highlights the crucial role of genetics in determining the disease profile and developing targeted therapies. Although current treatment of CMT is primarily symptomatic, advances in gene therapy and pharmacology offer hope for future more effective and targeted therapeutic approaches. However, addressing the challenges associated with developing and implementing these therapies is critical, including access, safety, and long-term efficacy issues. Ultimately, an integrated and collaborative approach involving clinicians, geneticists, and researchers is essential to improve the diagnosis, treatment, and quality of life of patients with CMT.
REFERENCES
AUER-GRUMBACH, M. et al. Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies. American journal of human genetics, v. 99, n. 3, p. 607–623, 1 set. 2016.
BELORIBI-DJEFAFLIA, S.; ATTARIAN, S. Treatment of Charcot-Marie-Tooth neuropathies. Revue neurologique, v. 179, n. 1–2, p. 35–48, 1 jan. 2023.
CHOI, B. O. et al. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. Clinical genetics, v. 87, n. 6, p. 594–598, 1 jun. 2015.
JAMIRI, Z. et al. A nonsense mutation in MME gene associates with autosomal recessive late-onset Charcot-Marie-Tooth disease. Molecular genetics & genomic medicine, v. 10, n. 5, 1 maio 2022.
MATHIS, S. et al. Reasons Charcot-Marie-Tooth disease due to mutations in the MME gene should not be named AR-CMT2T. Annals of neurology, v. 80, n. 3, p. 477, 1 set. 2016.
MCCRAY, B. A.; SCHERER, S. S. Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, v. 18, n. 4, p. 2269–2285, 1 out. 2021.
MORENA, J.; GUPTA, A.; HOYLE, J. C. Charcot-Marie-Tooth: From Molecules to Therapy. International journal of molecular sciences, v. 20, n. 14, 2 jul. 2019.
OKAMOTO, Y.; TAKASHIMA, H. The Current State of Charcot-Marie-Tooth Disease Treatment. Genes, v. 14, n. 7, 1 jul. 2023.
PIPIS, M. et al. Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study. Brain : a journal of neurology, v. 143, n. 12, p. 3589–3602, 1 dez. 2020.
PISCIOTTA, C.; PAREYSON, D. Gene therapy and other novel treatment approaches for Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD, v. 33, n. 8, p. 627–635, 1 ago. 2023.
PISCIOTTA, C.; SAVERI, P.; PAREYSON, D. Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives. Brain sciences, v. 11, n. 11, 1 nov. 2021.
SCHERER, S. S.; KLEOPA, K. A. X-linked Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS, v. 17 Suppl 3, n. 0 3, p. 9–13, 2012.
SMAN, A. D. et al. Systematic review of exercise for Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS, v. 20, n. 4, p. 347–362, 1 dez. 2015.
SMITH, A. G. Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies. Continuum (Minneapolis, Minn.), v. 26, n. 5, p. 1224–1256, 1 out. 2020.
1 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: danielantunespi@gmail.com
2 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: edcamilaferraz@gmail.com
3 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: anickmartins@gmail.com
4 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: robertalteixeira@gmail.com
5 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: rochadaila66@gmail.com
6 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: rafaelaohana2016@outlook.com
7 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: igorrcoelhotab@gmail.com
8 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: estherduarte.oliceira@gmail.com
9 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: isa.fpacheco@gmail.com
10 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: Haylander.novaes@gmail.com
11 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: caio.tartaglia2018@gmail.com
12 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: yulliwienen@gmail.com
13 Discente do Curso Superior de Medicina da Universidade Iguaçu Campus Nova Iguaçu e-mail: luu.sobral@hotmail.com