NALCN encodes a sodium non-selective leak channel critical for neuronal excitability 1. Mutations affecting NALCN have been known to cause neurodevelopmental impairment, but their clinical spectrum remains incompletely defined. By reporting a de novo and previously unreported NALCN (NM₀52867. 4) c. 3521 G > T p. (Arg1174Ile) missense variant associated with arthrogryposis and neonatal respiratory failure, we aim to contribute to a better understanding of the phenotypic and genotypic spectrum of this rare disease. A female newborn presented to the emergency department at 15 days of life with a severe episode of cyanosis following bottle feeding. Her clinical history was marked by delivery at 37 + 4 weeks via caesarean prior labor, due to fetal heart rate abnormalities and breech presentation. She experienced transient neonatal respiratory distress, requiring high-flow nasal cannula for 9 h. Bilateral distal joint contractures with ulnar finger deviation, stiffness of the third finger and a reducible left foot varus deformity were noted. Retrospective view of early ultrasounds revealed fetal clenched fists positioned near the jaw. Polyhydramnios was detected late in pregnancy. There was no reported medication or toxic exposure, maternal serologies were negative and the parents were non-consanguineous. A malformation assessment, including echocardiography, abdominopelvic ultrasound, and spinal MRI, yielded normal results. During hospitalization, she experienced repeated cyanotic episodes, apnea and severe respiratory distress with intermittent stridor. Despite high-flow oxygen and an initial trial of caffeine, respiratory support had to be escalated to non-invasive ventilation due to worsening fatigue. Additional evaluations, including toxicology screening, biological workup, multiplex nasal PCR, chest X-ray, electroencephalogram and brain MRI, were normal. Laryngoscopy revealed a malacic epiglottis prolapsing over the laryngeal inlet during inspiration, necessitating epiglottopexy and posterior supraglottoplasty. At 1 month, suture dehiscence occurred, leading to respiratory deterioration and requiring a second surgical intervention with remodeling of posterior supraglottic plan and epiglottoplasty. A second suture dehiscence occurred and she finally underwent a third intervention using reconstructive transoral laser microsurgery (R-TLM) targeting the vallecula. Despite surgery and CPAP ventilation, apnea persisted and was attributed to severe pharyngolaryngomalacia. Stability was achieved at 2 months of age with CPAP 7 cm H₂O during sleep. A sleep oximetry and pCO2 transcutaneous recording were performed under CPAP, showing an average SpO2 of 97% (min 78%–max 100%), 3. 4% of time with SpO2 under 90% and an average pCO2 of 37. 0 mmHg (min 30. 5 mmHg–max 45. 0 mmHg). A polysomnography was planned, though not urgently, given favorable clinical improvement. Excessive drooling, pharyngeal and bronchial congestion were managed with SCOPOLAMINE, and she received AZITHROMYCINE for its anti-inflammatory properties following aspiration pneumonia episodes. Initial tube feeding support was required for swallowing disorders, however she gradually increased oral intake, including breastfeeding. Notably, third-trimester polyhydramnios may have reflected prenatal sucking impairment. On neurodevelopmental level, despite a mild delay likely influenced by prolonged hospitalization, motor skills improved with infant demonstrating visual tracking, sound responses, effective sucking, symmetric limb movements and rolling. Finally, she was discharged home with CPAP during sleep, home pulse oximetry and continued physiotherapy, speech and occupational therapy. Genetic analysis was performed by next-generation sequencing (Illumina) using a congenital myopathies/hypotonia gene panel. The analysis identified a novel NALCN (NM₀52867. 4) c. 3521 G > T p. (Arg1174Ile) missense variant at the heterozygous state, absent from the latest version of populational Genome Aggregation database (Gnomad v. 4. 1) and predicted deleterious by multiple bioinformatic softwares. Segregation study by Sanger sequencing (ABI3500XL, Thermofisher) revealed a de novo occurrence, as illustrated in Figure 1. According to American College of Medical Genetics criteria, this variant should be classified as likely pathogenic (class 4). We suggest it can be responsible for joint limitations and respiratory failure, but further cases are needed to determine if specific oro-pharyngeal features observed are directly linked to this genotype. NALCN encodes a non-selective, voltage insensitive sodium leak channel, primarily expressed in brain and spinal cord neurons, modulating neuronal excitability 1. Over time, the number of reported patients with NALCN genetic variations has increased, presenting with a variety of phenotypes depending on the affected region of the gene and variant. De novo heterozygous gain-of-function variants are associated with congenital contractures of limbs and face, hypotonia, and global developmental delay (CLIFAHDD syndrome). Homozygous and compound heterozygous loss-of-function variants are associated with severe infantile hypotonia, psychomotor retardation, and characteristic facies (IHPRF) 2. NALCN is implicated in generating rhythmic firing of pacemaker neurons responsible for breathing. Therefore, pathogenic NALCN sequence variants might present respiratory dysregulation. Maselli et al. reported biallelic (loss-of-function) variants in NALCN to be associated with high apnea-hypopnea indices, occasional periodic breathing and oxygen desaturations 3. Abnormal respiratory patterns in the neonatal period have also been documented in patients with CLIFAHDD, with suggested more severe respiratory symptoms at birth. Treatment options range from supplemental oxygen and non-invasive ventilation to orotracheal intubation 4, 5. It is notable that our patient underwent three surgical interventions for airway abnormalities as well as CPAP support, yet apnea persisted until 2 months of age. This may reflect the possible involvement of a central respiratory dysregulation or dysautonomia, which have been previously reported in CLIFAHDD 4. Polysomnography would have been useful to better distinguish between these potential mechanisms. The coordination of sucking-swallowing and breathing during neonatal feeding is known to depend on the integrity of the neuronal network located in the brainstem. It is possible that NALCN plays a role in the establishment of this embryonic neural network, explaining our patient's sucking and swallowing deficiency and pharyngolaryngomalacia. This novel NALCN c. 3521 G > T p. (Arg1174Ile) variant lies within the DIII-DIV intracellular loop of NALCN. Although not part of the pore itself, this region has been identified as a hotspot for pathogenic variants reported in CLIFAHDD syndrome with respiratory involvement 2, 5. Given the broad neurological spectrum of NALCN-related disorders, no clear neurodevelopmental prognosis can be made, and it will be necessary to monitor closely the developmental progress. From a genetic counselling perspective, it can offer some reassurance, as a recurrence risk in a future pregnancy should be considered as slightly higher than in the general population (around 1%) due to the possibility of germline mosaicism. This case expands the genotypic spectrum of NALCN-related disorders. Further studies are warranted to elucidate genotype-phenotype correlations and tailor more individually NALCN-related conditions. Coralie Eyraud: conceptualization, investigation, writing – original draft, writing – review and editing, resources, data curation. Julie Cassibba: conceptualization, methodology, writing – review and editing, supervision. Eglantine Hullo: writing – review and editing. Anne Coffre: writing – review and editing. Ihab Atallah: writing – review and editing. Guillaume Mortamet: writing – review and editing. Veronique Abadie: writing – review and editing. John Rendu: writing – review and editing. Anthony Maino: methodology, writing – review and editing, data curation. Klaus Dieterich: supervision, methodology, writing – review and editing. The authors received no specific funding for this work. No ethics agreement is required for a case-report in accordance with French regulations. As case report, the study received an exemption from ethics approval by Grenoble University Hospital Clinical research and Innovation Delegation. The study was conducted in accordance with recognized ethical standards including the Declaration of Helsinki. Written informed consent was obtained from the patient's legal guardian before data collection and publication and is available upon request. All patient identifiers have been removed to ensure confidentiality. The authors declare no conflicts of interest. The data are not publicly available due to privacy/ethical restrictions but are available from the corresponding author upon reasonable request.
Eyraud et al. (Sun,) studied this question.