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NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study

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Abstract

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4–20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3–6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations.

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Acknowledgements

The authors thank Nathalie Bonello-Palot (Marseille, France), Philippe Latour (Lyon, France), Anne-Sophie LIA (Limoges, France), and Marie-Claire Malinge (Angers, France) for their collaboration.

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Authors and Affiliations

  1. Neurology Department, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, 78 rue du Général Leclerc, 94276, Kremlin-Bicêtre Cedex, France

    Andoni Echaniz-Laguna

  2. French National Reference Center for Rare Neuropathies (NNERF), 94276, Le Kremlin-Bicêtre, France

    Andoni Echaniz-Laguna

  3. INSERM U1195, Paris-Saclay University, 94276, Le Kremlin-Bicêtre, France

    Andoni Echaniz-Laguna

  4. Pediatrics Department, Besançon University Hospital, Besançon, France

    Cecilia Altuzarra

  5. Genetics Department, APHP, Robert Debré Hospital, Paris, France

    Alain Verloes

  6. Pediatrics Department, Garches University Hospital, Garches, France

    Marta Gomez Garcia De La Banda, Susana Quijano-Roy & Raluca Anca Tudorache

  7. Pediatric Neurology Clinic, Obregia Hospital, Bucharest, Romania

    Raluca Anca Tudorache

  8. Astana Medical University, Nur-sultan, Kazakhstan

    Altynshash Jaxybayeva

  9. Kazakh-Turkish International University, Turkestan, Kazakhstan

    Bakhytkul Myrzaliyeva

  10. Neurology Department, Children’s Hospital, Almaty, Kazakhstan

    Bakhytkul Myrzaliyeva

  11. Neurology Department, Mustapha University Hospital, Alger, Algeria

    Meriem Tazir

  12. Neurology Department, Limoges University Hospital, Limoges, France

    Jean-Michel Vallat

  13. Department of Molecular Genetics Pharmacogenomics and Hormonology, APHP, CHU de Bicêtre, 94276, Le Kremlin-Bicêtre, France

    Bruno Francou

  14. Institut de Myologie, Paris, France

    Jon Andoni Urtizberea

Authors
  1. Andoni Echaniz-Laguna
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  2. Cecilia Altuzarra
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  3. Alain Verloes
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  4. Marta Gomez Garcia De La Banda
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  6. Raluca Anca Tudorache
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  7. Altynshash Jaxybayeva
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  8. Bakhytkul Myrzaliyeva
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  9. Meriem Tazir
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  10. Jean-Michel Vallat
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Contributions

AEL, CDA, AV, MGGDLB, SQR, RAT, AJ, BM, MT, JMV, BF, and JAU designed research, performed research, and participated in data-collection. AEL and JAU wrote the manuscript. CDA, AV, MGGDLB, SQR, RAT, AJ, BM, MT, JMV, and BF revised the manuscript for intellectual content.

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Correspondence to Andoni Echaniz-Laguna.

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Echaniz-Laguna, A., Altuzarra, C., Verloes, A. et al. NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study. Neurogenetics 22, 333–341 (2021). https://doi.org/10.1007/s10048-021-00668-z

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  • DOI: https://doi.org/10.1007/s10048-021-00668-z

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