Brief Communication | Published:

Periodic breathing in patients with NALCN mutations

Journal of Human Geneticsvolume 63pages10931096 (2018) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  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.

  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.

  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.

  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.

  5. 5.

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

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

Download references

Author information


  1. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    • Danielle K. Bourque
    •  & David A. Dyment
  2. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada

    • David A. Dyment
    • , Ian MacLusky
    • , Kristin D. Kernohan
    •  & Hugh J. McMillan
  3. Division of Respirology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    • Ian MacLusky
  4. Division of Neurology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    • Hugh J. McMillan


  1. Search for Danielle K. Bourque in:

  2. Search for David A. Dyment in:

  3. Search for Ian MacLusky in:

  4. Search for Kristin D. Kernohan in:

  5. Search for Hugh J. McMillan in:


  1. Care4Rare Canada Consortium

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Corresponding author

    Correspondence to Hugh J. McMillan.

    About this article

    Publication history






    Further reading

    • Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

      • Nuria C. Bramswig
      • , Aida M. Bertoli-Avella
      • , Beate Albrecht
      • , Aida I. Al Aqeel
      • , Amal Alhashem
      • , Nouriya Al-Sannaa
      • , Maissa Bah
      • , Katharina Bröhl
      • , Christel Depienne
      • , Nathalie Dorison
      • , Diane Doummar
      • , Nadja Ehmke
      • , Hasnaa M. Elbendary
      • , Svetlana Gorokhova
      • , Delphine Héron
      • , Denise Horn
      • , Kiely James
      • , Boris Keren
      • , Alma Kuechler
      • , Samira Ismail
      • , Mahmoud Y. Issa
      • , Isabelle Marey
      • , Michèle Mayer
      • , Jennifer McEvoy-Venneri
      • , Andre Megarbane
      • , Cyril Mignot
      • , Sarar Mohamed
      • , Caroline Nava
      • , Nicole Philip
      • , Cecile Ravix
      • , Arndt Rolfs
      • , Abdelrahim Abdrabou Sadek
      • , Lara Segebrecht
      • , Valentina Stanley
      • , Camille Trautman
      • , Stephanie Valence
      • , Laurent Villard
      • , Thomas Wieland
      • , Hartmut Engels
      • , Tim M. Strom
      • , Maha S. Zaki
      • , Joseph G. Gleeson
      • , Hermann-Josef Lüdecke
      • , Peter Bauer
      •  & Dagmar Wieczorek

      Human Genetics (2018)