Association Between Body Mass Index and Disability in Children With Charcot-Marie-Tooth Disease

Objective:This study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT).Methods:We conducted a cross-sectional analysis of 477 patients with CMT aged 3-20 years from the Inherited Neuropathy Consortium, and 316 age-and-sex matched healthy children from the 1000 Norms Project. BMI was categorised according to the International Obesity Task Force (IOTF) criteria, and BMI categorisation was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were: severely underweight (BMI<17kg/m2); underweight (BMI≥17 to <18.5kg/m2); healthy weight (BMI≥18.5 to <25kg/m2); overweight (BMI ≥25 to <30kg/m2); obese (BMI ≥30kg/m2). Scores on the 0-44 point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI.Results:There was a higher proportion of children with CMT categorised as severely underweight (5.7%vs0.3%), underweight (10.3%vs5.1%), and obese (7.3%vs3.8%) (p<0.05). Fewer children with CMT were categorised as healthy weight (61.8%vs74.4%) (p<0.05), and the proportion of overweight (14.9%vs16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were: severely underweight (27±9), underweight (20±8), healthy weight (17±9), overweight (17±9) obese (22 ±10). Compared to healthy weight children with CMT, being severely underweight was associated with being more disabled (p<0.001), as was being obese (p=0.015).Conclusion:The proportion of underweight and obese children with CMT is higher compared to age-and sex-matched healthy children. Children with CMT who are underweight or obese are associated with greater disability than compared children with CMT of healthy weight.

Targeted PMP22 TATA-box editing by CRISPR/Cas9 reduces demyelinating neuropathy of Charcot-Marie-Tooth disease type 1A in mice

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A.

Charcot-Marie-Tooth: From Molecules to Therapy

Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

Treatment-induced remission of medulloblastoma using a chemotherapeutic regimen devoid of vincristine in a child with Charcot–Marie–Tooth disease

Charcot–Marie–Tooth (cmt) disease is the most common form of inherited neuropathy. Core features include peripheral neuropathy and secondary axonal degeneration, with a noted distal predominance of limb-muscle wasting, weakness, and sensory loss. Given the significant prevalence of cmt, superimposed neoplastic disease can be encountered within this patient population. Malignancies that are treated with vincristine (a microtubule-targeting agent), even at low doses as part of standard treatment, pose a significant challenge for patients with cmt. Here, we present the case of a child with cmt who was successfully treated for medulloblastoma without vincristine, a standard drug used for treatment of that disease, to avoid the risk of severe debilitating neuropathy. This report is the first of a patient successfully treated for medulloblastoma without vincristine.