Genotype-Phenotype Landscape of NALCN and UNC80-Related Disorders
Issued Date
2025-04-08
Resource Type
eISSN
1526632X
Scopus ID
2-s2.0-86000674524
Pubmed ID
40048676
Journal Title
Neurology
Volume
104
Issue
7
Rights Holder(s)
SCOPUS
Bibliographic Citation
Neurology Vol.104 No.7 (2025) , e213429
Suggested Citation
Parra-Díaz P., Monteil A., Calame D., Hadouiri N., Soliani L., Spinelli E., Caron E.J., Dieterich K., Kritzer A., Riley K., Serratosa Fernández J.M., Tanner J.A., Tevissen H., Thauvin C., Vera-Medialdea R., Waltz S.M., Beltrán-Corbellini Á., García Morales I., Sánchez-Miranda Román I., Toledano R., Valls-Carbó A., Gil-Nagel A. Genotype-Phenotype Landscape of NALCN and UNC80-Related Disorders. Neurology Vol.104 No.7 (2025) , e213429. doi:10.1212/WNL.0000000000213429 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/106754
Title
Genotype-Phenotype Landscape of NALCN and UNC80-Related Disorders
Author(s)
Parra-Díaz P.
Monteil A.
Calame D.
Hadouiri N.
Soliani L.
Spinelli E.
Caron E.J.
Dieterich K.
Kritzer A.
Riley K.
Serratosa Fernández J.M.
Tanner J.A.
Tevissen H.
Thauvin C.
Vera-Medialdea R.
Waltz S.M.
Beltrán-Corbellini Á.
García Morales I.
Sánchez-Miranda Román I.
Toledano R.
Valls-Carbó A.
Gil-Nagel A.
Monteil A.
Calame D.
Hadouiri N.
Soliani L.
Spinelli E.
Caron E.J.
Dieterich K.
Kritzer A.
Riley K.
Serratosa Fernández J.M.
Tanner J.A.
Tevissen H.
Thauvin C.
Vera-Medialdea R.
Waltz S.M.
Beltrán-Corbellini Á.
García Morales I.
Sánchez-Miranda Román I.
Toledano R.
Valls-Carbó A.
Gil-Nagel A.
Author's Affiliation
Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique
Siriraj Hospital
Duke University Hospital
Université de Montpellier
Université Bourgogne Franche-Comté
Istituto delle Scienze Neurologiche di Bologna
Université Grenoble Alpes
Hospital Clínico San Carlos
Université de Bourgogne
Centre Hospitalier Universitaire Dijon Bourgogne
Boston Children's Hospital
Hospital Ruber Internacional
Hospital Universitario Ramón y Cajal
Hospital Universitario Fundación Jiménez Díaz
The University of Texas Health Science Center at San Antonio
Hospital Regional Universitario Carlos Haya
Western University
Texas Children's Hospital
Centre Hospitalier de Valence
Hôpital d'Enfants CHU Dijon
Baylor College of Medicine
University of Tennessee Health Science Center
Center for Neuropediatrics
Fundación Iniciativa para las Neurociencias (FINCE)
Siriraj Hospital
Duke University Hospital
Université de Montpellier
Université Bourgogne Franche-Comté
Istituto delle Scienze Neurologiche di Bologna
Université Grenoble Alpes
Hospital Clínico San Carlos
Université de Bourgogne
Centre Hospitalier Universitaire Dijon Bourgogne
Boston Children's Hospital
Hospital Ruber Internacional
Hospital Universitario Ramón y Cajal
Hospital Universitario Fundación Jiménez Díaz
The University of Texas Health Science Center at San Antonio
Hospital Regional Universitario Carlos Haya
Western University
Texas Children's Hospital
Centre Hospitalier de Valence
Hôpital d'Enfants CHU Dijon
Baylor College of Medicine
University of Tennessee Health Science Center
Center for Neuropediatrics
Fundación Iniciativa para las Neurociencias (FINCE)
Corresponding Author(s)
Other Contributor(s)
Abstract
BACKGROUND AND OBJECTIVES: The NALCN channelosome regulates the resting membrane potential through sodium leak currents, influencing cellular excitability. Genetic variants in NALCN and UNC80, a subunit of the NALCN channelosome, cause ultra-rare and severe neurodevelopmental disorders. Autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome is associated with gain-of-function (GOF) variants in NALCN. Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) 1 syndrome is associated with biallelic variants in NALCN and IHPRF 2 syndrome with biallelic variants in UNC80, both resulting in a loss-of-function (LOF). This study aims to expand the phenotypes associated with these syndromes, exploring potential genotype-phenotype associations. METHODS: This is a cross-sectional study including patients with pathogenic or likely pathogenic variants in NALCN and UNC80. Phenotypes were evaluated through a structured interview, questionnaires, and review of medical records. Associations between variants, clinical features, and syndromes were analyzed. RESULTS: Fifty-one patients were included (34 with CLIFAHDD, 9 with IHPRF 1, 8 with IHPRF 2; 3 months-27 years; 37.3% female). All exhibited neurodevelopmental delay, more severe in patients with LOF variants (p = 0.019). Neurodevelopmental regression was observed in 29.4% of patients with CLIFAHDD syndrome, associated with the onset of ataxia (70%). Patients with CLIFAHDD had more severe respiratory symptoms at birth (11.7% orotracheal intubation). Distal arthrogryposis (76.5%), episodic ataxia (41.2% of ambulatory patients), and paroxysmal dystonia (11.7%) were exclusively diagnosed in patients with CLIFAHDD. Patients with LOF variants presented more frequently with failure to thrive (88.2%, p = 0.001), central sleep apnea (CSA, 64.7%, p < 0.001), and epilepsy (70.6%, p < 0.001). Epilepsy was associated with more severe cognitive delays (p = 0.016) and was refractory in 58.8% of patients. Earlier seizure onset was associated with refractory epilepsy (p = 0.014). Patients with CLIFAHDD and premature death, epilepsy, or paroxysmal dystonia carried variants within NALCN pore domains. DISCUSSION: This study provides an in-depth clinical characterization of NALCN-related and UNC80-related disorders. Distal arthrogryposis, episodic ataxia, and paroxysmal dystonia were diagnosed in patients with CLIFAHDD while failure to thrive, CSA, and epilepsy were associated with LOF variants. We suggest potential genotype-phenotype associations, formulating hypotheses for validation in future studies with larger cohorts.