Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Periodic breathing in patients with NALCN mutations

Abstract

Biallelic mutations in NALCN are responsible for infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1). Common features of this condition include severe neonatal-onset hypotonia and profound global developmental delay. Given the rarity of this condition, long-term natural history studies are limited. Here, we present a 9-year-old male with a homozygous nonsense mutation in NALCN (c.3910C>T, p.Arg1304X) leading to profound intellectual disability, seizures, feeding difficulties, and significant periodic breathing. Breathing irregularity was also reported in three previous patients; similar to our patient, those children demonstrated periodic breathing that was characterized by alternating apneic periods with deep, rapid breathing. As the phenotype associated with NALCN mutations continues to be delineated, attention should be given to abnormal respiratory patterns, which may be an important distinguishing feature of this condition.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1

References

  1. 1.

    Koroglu C, Seven M, Tolun A. Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism. J Med Genet. 2013;50:515–20.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Al-Sayed MD, Al-Zaidan H, Albakheet A, Hakami H, Kenana R, Al-Yafee Y, et al. Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay. Am J Hum Genet. 2013;93:721–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Gal M, Magen D, Zahran Y, Ravid S, Eran A, Khayat M, 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;59:204–9.

    Article  PubMed  Google Scholar 

  4. 4.

    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;176:431–7.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Seven M, Ozkilic A, Yuksel A. Dysmorphic face in two siblings with infantile neuroaxonal dystrophy. Genet Couns. 2002;13:465–73.

    PubMed  CAS  Google Scholar 

  6. 6.

    Tetreault M, Fahiminiya S, Antonicka H, Mitchell GA, Geraghty MT, Lines M, et al. Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet. 2015;134:981–91.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Hamilton A, Tétreault M, Dyment DA, Zou R, Kernohan K, Geraghty MT, et al. Concordance between whole-exome sequencing and clinical Sanger sequencing: implications for patient care. Mol Genet Genomic Med. 2016;4:504–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    Beaulieu CL, Majewski J, Schwartzentruber J, Samuels ME, Fernandez BA, Bernier FP, et al. FORGE Canada consortium: outcomes of a 2-year national rare-disease gene-discovery project. Am J Hum Genet. 2014;94:809–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Lu B, Su Y, Das S, Liu J, Xia J, Ren D. The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell. 2007;129:371–83.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Cochet-Bissuel M, Lory P, Monteil A. The sodium leak channel, NALCN, in health and disease. Front Cell Neurosci. 2014;8:1–17.

  11. 11.

    Bend EG, Si Y, Stevenson DA, Bayrak-Toydemir P, Newcomb TM, Jorgensen EM, et al. NALCN channelopathies: distinguishing gain-of-function and loss-of-function mutations. Neurology. 2016;0:1131–9.

    Article  CAS  Google Scholar 

  12. 12.

    Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, et al. 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;96:462–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Aoyagi K, Rossignol E, Hamdan FF, Mulcahy B, Xie L, Nagamatsu S, et al. A gain-of-function mutation in NALCN in a child with intellectual disability, ataxia, and arthrogryposis. Hum Mutat. 2015;36:753–7.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    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;68:488–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Shamseldin HE, Faqeih E, Alasmari A, Zaki MS, Gleeson JG, Alkuraya FS. Mutations in UNC80, encoding part of the UNC79-UNC80-NALCN channel complex, cause autosomal-recessive severe infantile encephalopathy. Am J Hum Genet. 2016;98:210–5.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Stray-Pedersen A, Cobben J-M, Prescott TE, Lee S, Cang C, Aranda K, et al. Biallelic mutations in UNC80 cause persistent hypotonia, encephalopathy, growth retardation, and severe intellectual disability. Am J Hum Genet. 2016;98:202–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Hugh J. McMillan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bourque, D.K., Dyment, D.A., MacLusky, I. et al. Periodic breathing in patients with NALCN mutations. J Hum Genet 63, 1093–1096 (2018). https://doi.org/10.1038/s10038-018-0484-1

Download citation

Further reading

Search

Quick links