Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants

Abstract

Background Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review.

Methods We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients.

Results The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype.

Conclusion We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and/or hypertrichosis may represent peculiar diagnostic clues.

Keywords

ataxia - cerebellum - sodium - WES - arthrogryposis - hypertrichosis

Institutional Review Board

Submission of the manuscript has been approved by our institution (approval number RAP-2024-0004).

Informed Consent

The patient's parents have signed the written informed consent for genetic analyses and participation in study research.

Data Availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Publication History

Received: 07 August 2024

Accepted: 21 January 2025

Article published online:
06 February 2025

• References

• 1 Kschonsak M, Chua HC, Noland CL. et al. Structure of the human sodium leak channel NALCN. Nature 2020; 587 (7833): 313-318
• 2 Khaliq ZM, Bean BP. Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J Neurosci 2010; 30 (21) 7401-7413
• 3 Shi Y, Abe C, Holloway BB. et al. Nalcn is a “leak” sodium channel that regulates excitability of brainstem chemosensory neurons and breathing. J Neurosci 2016; 36 (31) 8174-8187
• 4 Xie L, Gao S, Alcaire SM. et al. NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion. Neuron 2013; 77 (06) 1069-1082
• 5 Flourakis M, Kula-Eversole E, Hutchison AL. et al. A conserved bicycle model for circadian clock control of membrane excitability. Cell 2015; 162 (04) 836-848
• 6 Philippart F, Khaliq ZM. G_i/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. eLife 2018; 7: e40984
• 7 Lu B, Zhang Q, Wang H, Wang Y, Nakayama M, Ren D. Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 2010; 68 (03) 488-499
• 8 Zhou L, Liu H, Zhao Q, Wu J, Yan Z. Architecture of the human NALCN channelosome. Cell Discov 2022; 8 (01) 33
• 9 Kang Y, Chen L. Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex. Nat Commun 2022; 13 (01) 2639
• 10 Chua HC, Wulf M, Weidling C, Rasmussen LP, Pless SA. The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium. Sci Adv 2020; 6 (17) eaaz3154
• 11 Al-Sayed MD, Al-Zaidan H, Albakheet A. et al. Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. Am J Hum Genet 2013; 93 (04) 721-726
• 12 Gal M, Magen D, Zahran Y. et al. A novel homozygous splice site mutation in NALCN identified in siblings with cachexia, strabismus, severe intellectual disability, epilepsy and abnormal respiratory rhythm. Eur J Med Genet 2016; 59 (04) 204-209
• 13 Takenouchi T, Inaba M, Uehara T, Takahashi T, Kosaki K, Mizuno S. Biallelic mutations in NALCN: expanding the genotypic and phenotypic spectra of IHPRF1. Am J Med Genet A 2018; 176 (02) 431-437
• 14 Chong JX, McMillin MJ, Shively KM. et al; University of Washington Center for Mendelian Genomics. De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet 2015; 96 (03) 462-473
• 15 Fukai R, Saitsu H, Okamoto N. et al. De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia. J Hum Genet 2016; 61 (05) 451-455
• 16 Aoyagi K, Rossignol E, Hamdan FF. et al. A gain-of-function mutation in NALCN in a child with intellectual disability, ataxia, and arthrogryposis. Hum Mutat 2015; 36 (08) 753-757
• 17 Karakaya M, Heller R, Kunde V. et al. Novel mutations in the nonselective sodium leak channel (NALCN) lead to distal arthrogryposis with increased muscle tone. Neuropediatrics 2016; 47 (04) 273-277
• 18 Lozic B, Johansson S, Lovric Kojundzic S. et al. Novel NALCN variant: altered respiratory and circadian rhythm, anesthetic sensitivity. Ann Clin Transl Neurol 2016; 3 (11) 876-883
• 19 Sivaraman I, Friedman NR, Prayson RA. Muscle biopsy findings in a child with NALCN gene mutation. J Clin Neurosci 2016; 34: 222-223
• 20 Vivero M, Cho MT, Begtrup A. et al. Additional de novo missense genetic variants in NALCN associated with CLIFAHDD syndrome. Clin Genet 2017; 91 (06) 929-931
• 21 Bend EG, Si Y, Stevenson DA. et al. NALCN channelopathies: distinguishing gain-of-function and loss-of-function mutations. Neurology 2016; 87 (11) 1131-1139
• 22 Wang Y, Koh K, Ichinose Y, Yasumura M, Ohtsuka T, Takiyama Y. A de novo mutation in the NALCN gene in an adult patient with cerebellar ataxia associated with intellectual disability and arthrogryposis. Clin Genet 2016; 90 (06) 556-557
• 23 Chen Y, Xia X, Zhang Y, Gao L, He C, Cao J. Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review. Front Pediatr 2024; 12: 1370790
• 24 Liao Z, Liu Y, Wang Y, Lu Q, Peng Y, Liu Q. Case Report: A de novo variant in NALCN associated with CLIFAHDD syndrome in a Chinese infant. Front Pediatr 2022; 10: 927392
• 25 Bramswig NC, Bertoli-Avella AM, Albrecht B. et al. Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Hum Genet 2018; 137 (09) 753-768
• 26 Kumaki T, Enomoto Y, Aida N, Goto T, Kurosawa K. Progression of cerebral and cerebellar atrophy in congenital contractures of limbs and face, hypotonia, and developmental delay. Pediatr Int 2022; 64 (01) e14734
• 27 Singh P, Agrawal N, Maurya RK, Moirangthem A. Novel variant c.1838A>G, p.(Gln613Arg) in NALCNcauses camptodactyly and cognitive delay. Clin Dysmorphol 2022; 31 (04) 206-210
• 28 Winczewska-Wiktor A, Hirschfeld AS, Badura-Stronka M. et al. Central apneas due to the CLIFAHDD syndrome successfully treated with pyridostigmine. Int J Environ Res Public Health 2022; 19 (02) 775
• 29 Indelicato E, Nachbauer W, Fauth C. et al. SYNE1-ataxia: novel genotypic and phenotypic findings. Parkinsonism Relat Disord 2019; 62: 210-214
• 30 Baumann M, Steichen-Gersdorf E, Krabichler B. et al. Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation. Eur J Hum Genet 2017; 25 (02) 262-266