Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center

Data de publicació: 01/09/2021 Data Ahead of Print: 01/07/2021

Autors de IIS La Fe

• Herminia Argente Escrig

  Autor

• Marina Frasquet Carrera

  Autor

• Juan Francisco Vázquez Costa

  Autor

• Elvira Millet Sancho

  Autor

• Inmaculada Pitarch Castellano

  Autor

• Miguel Tómas Vila

  Autor

• Carmen Espinos Armero

  Autor

• Vincenzo Lupo

  Autor

• 

  Teresa Sevilla Mantecón

  Autor

Grups d'Investigació

• Investigación Traslacional en Genética

  

  Leader

  Francisco Martínez Castellano

• Patología Neuromuscular y Ataxias

  

  Investigador Principal

  Teresa Sevilla Mantecón

• Unidad mixta de investigación en enfermedades raras (CIPF)

  

  Leader

  José María Millán Salvador

Abstract

Background Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs). Methods Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS). Results From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (+/- 3.7) over 1 year (p < 0.0005, n = 62) and a 2-year rate of 3.6 (+/- 4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 +/- 3.6, p < 0.05) and 2 years (4.2 +/- 4.3, p < 0.0005). Conclusions This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials.

Keywords

• CHARCOT-MARIE-TOOTH; NATURAL-HISTORY; HEREDITARY NEUROPATHIES; DISEASE FREQUENCY; GENETIC SUBTYPES; MUTATIONS; ARYLSULFATASE; VALIDATION; GUIDELINES; PHENOTYPE