Publications by authors named "Shawna Feely"

Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80%-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous.

View Article and Find Full Text PDF

Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.

View Article and Find Full Text PDF

Background: Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets.

View Article and Find Full Text PDF
Article Synopsis
  • The study aimed to evaluate the responsiveness of calf intramuscular fat accumulation in various forms of Charcot-Marie-Tooth disease (CMT) using quantitative MRI, alongside other clinical measures.
  • Researchers assessed groups of patients with CMTX1, CMT1B, and CMT2A over a year, finding elevated muscle fat fractions correlated with clinical assessments and significant annual increases in fat accumulation.
  • The findings suggest that measuring calf muscle fat using MRI is a reliable outcome measure for future CMT clinical trials, as it reflects disease progression across multiple common CMT variants.
View Article and Find Full Text PDF
Article Synopsis
  • Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are rare disorders affecting sensory and autonomic neurons, making them hard to study due to limited data.
  • A large international study identified 80 new pathogenic variants in 73 families across known CIP/HSAN-related genes, expanding knowledge on these diseases.
  • Advanced methodologies like in silico predictions and metabolic tests improved variant classification, crucial for guiding future gene-specific treatments in clinical trials.
View Article and Find Full Text PDF

Dominant mutations in () a known cause of hereditary sensory autonomic neuropathy type 1 (HSAN1), are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression. We present a case of associated JALS followed for 30 years. She was initially evaluated at age 22 years for upper extremity weakness.

View Article and Find Full Text PDF
Article Synopsis
  • - Charcot-Marie-Tooth disease (CMTX1) is an X-linked genetic disorder affecting nerve function, primarily impacting males more severely, and is often caused by variants in the GJB1 gene, with many of these variants being classified as variants of uncertain significance (VUS).
  • - A large study involving 387 patients across 295 families assessed the pathogenicity of GJB1 variants, finding that 82.4% had pathogenic or likely pathogenic (P/LP) variants, and noted no significant baseline differences in symptoms between patients with P/LP variants and VUS.
  • - The research tracked disease progression over 8 years using the CMT Examination Score (CMTES) and identified that specific variants
View Article and Find Full Text PDF

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary CoQ10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder.

View Article and Find Full Text PDF

Objective: To evaluate the parent-proxy version of the pediatric Charcot Marie Tooth specific quality of life (pCMT-QOL) outcome instrument for children aged 7 or younger with CMT. We have previously developed and validated the direct-report pCMT-QOL for children aged 8-18 years and a parent proxy version of the instrument for children 8-18 years old. There is currently no CMT-QOL outcome measure for children aged 0-7 years old.

View Article and Find Full Text PDF

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes.

View Article and Find Full Text PDF

Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL) in children. We have previously developed and validated the English and Italian versions of the pediatric CMT-specific QOL outcome measure (pCMT-QOL) for children aged 8 to 18. There is currently no parent-proxy CMT QOL outcome measure for use in clinical trials, which could provide complementary information in these children and adolescents.

View Article and Find Full Text PDF

Objective: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium.

Methods: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy.

View Article and Find Full Text PDF

Objective: To determine whether microRNAs (miRs) are elevated in the plasma of individuals with the inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A), miR profiling was employed to compare control and CMT1A plasma.

Methods: We performed a screen of CMT1A and control plasma samples to identify miRs that are elevated in CMT1A using next-generation sequencing, followed by validation of selected miRs by quantitative PCR, and correlation with protein biomarkers and clinical data: Rasch-modified CMT Examination and Neuropathy Scores, ulnar compound muscle action potentials, and motor nerve conduction velocities.

Results: After an initial pilot screen, a broader screen confirmed elevated levels of several muscle-associated miRNAs (miR1, -133a, -133b, and -206, known as myomiRs) along with a set of miRs that are highly expressed in Schwann cells of peripheral nerve.

View Article and Find Full Text PDF

Mutations in Myelin Protein Zero (MPZ) cause CMT1B, the second leading cause of CMT1. Many of the >200 mutations cause neuropathy through a toxic gain of function by the mutant protein such as ER retention, activation of the Unfolded Protein Response (UPR) or disruption of myelin compaction. While there is extensive literature on the loss of function consequences of MPZ in heterozygous Mpz +/- null mice, there is little known of the consequences of MPZ haploinsufficiency in humans.

View Article and Find Full Text PDF

The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys.

View Article and Find Full Text PDF

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking.

View Article and Find Full Text PDF

Objective: Charcot-Marie-Tooth disease (CMT) reduces health-related quality of life (QOL), especially in children. Defining QOL in pediatric CMT can help physicians monitor disease burden clinically and in trials. We identified items pertaining to QOL in children with CMT and conducted validation studies to develop a pediatric CMT-specific QOL outcome measure (pCMT-QOL).

View Article and Find Full Text PDF
Article Synopsis
  • Scientists found that changes in the SORD gene are the most common cause of a type of nerve problem that runs in families.
  • They discovered that people with these changes have too much sorbitol and not enough SORD protein, which can lead to issues with their nerves.
  • They also found that giving certain medications can help reduce sorbitol levels and improve nerve and movement problems in patients and in fruit flies used for research.
View Article and Find Full Text PDF

Objective: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).

Methods: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores.

View Article and Find Full Text PDF

Objective: Development of biomarkers for Charcot-Marie-Tooth (CMT) disease is critical for implementing effective clinical trials. The most common form of CMT, type 1A, is caused by a genomic duplication surrounding the PMP22 gene. A recent report (Neurology 2018;90:e518-3524) showed elevation of neurofilament light (NfL) in plasma of CMT1A disease patients, which correlated with disease severity.

View Article and Find Full Text PDF

Mutations in TRPV4 are linked to a group of clinically distinct, but also overlapping axonal neuropathies, including Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. The incidence of TRPV4-linked cases ranges from 0 to 7% in overall axonal neuropathy cohorts from European countries and Australia. However, the data from other areas remain largely unknown.

View Article and Find Full Text PDF

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.

View Article and Find Full Text PDF