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

Echaniz-Laguna A. Altuzarra C. Verloes A. De La Banda M.G.G. Quijano-Roy S. Tudorache R.A. Jaxybayeva A. Myrzaliyeva B. Tazir M. Vallat J.-M. Francou B. Urtizberea J.A.
October 2021 Springer Science and Business Media Deutschland GmbH

Neurogenetics
2021 #22 Issue 4 333 - 341 pp.

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.

CIPA , Congenital insensitivity to pain with anhidrosis , NTRK1

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Neurology Department, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, 78 rue du Général Leclerc, Kremlin-Bicêtre Cedex, 94276, France
French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin-Bicêtre, 94276, France
INSERM U1195, Paris-Saclay University, Le Kremlin-Bicêtre, 94276, France
Pediatrics Department, Besançon University Hospital, Besançon, France
Genetics Department, APHP, Robert Debré Hospital, Paris, France
Pediatrics Department, Garches University Hospital, Garches, France
Pediatric Neurology Clinic, Obregia Hospital, Bucharest, Romania
Astana Medical University, Nur-sultan, Kazakhstan
Kazakh-Turkish International University, Turkestan, Kazakhstan
Neurology Department, Children’s Hospital, Almaty, Kazakhstan
Neurology Department, Mustapha University Hospital, Alger, Algeria
Neurology Department, Limoges University Hospital, Limoges, France
Department of Molecular Genetics Pharmacogenomics and Hormonology, APHP, CHU de Bicêtre, Le Kremlin-Bicêtre, 94276, France
Institut de Myologie, Paris, France

Neurology Department
French National Reference Center for Rare Neuropathies (NNERF)
INSERM U1195
Pediatrics Department
Genetics Department
Pediatrics Department
Pediatric Neurology Clinic
Astana Medical University
Kazakh-Turkish International University
Neurology Department
Neurology Department
Neurology Department
Department of Molecular Genetics Pharmacogenomics and Hormonology
Institut de Myologie

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