Journal of Human Genetics

https://doi.org/10.1038/s10038-018-0484-1

BRIEF COMMUNICATION

Periodic breathing in patients with NALCN mutations

Danielle K. Bourque 1 David A. Dyment1,2 Ian MacLusky2,3 Kristin D. Kernohan2
● ● ● ●

Care4Rare Canada Consortium2 · Hugh J. McMillan2,4

Received: 26 March 2018 / Revised: 30 May 2018 / Accepted: 30 May 2018

© The Author(s) under exclusive licence to The Japan Society of Human Genetics 2018

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
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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.

Introduction Clinical report

Biallelic mutations in NALCN are responsible for infantile The proband is the first child of a consanguineous healthy
hypotonia with psychomotor retardation and characteristic couple of Turkish descent. The pregnancy was complicated
facies 1 (IHPRF1, OMIM #615419) [1, 2]. IHPRF1 is an by severe oligohydramnios and decreased fetal movements.
extremely rare condition [1–5]. The common features of He was delivered at 33 weeks gestational age. Birth weight
this condition include severe neonatal-onset hypotonia and was 1848 g (27th centile) and head circumference was 30
profound global developmental delay. Other features cm (10–50th) (Table 1). APGARs were 4 at 1 min and 7 and
include a lack of speech, severe feeding difficulties, con- 5 min. He was intubated at 10 min of life for respiratory
stipation, respiratory abnormalities, and seizures. Given the distress syndrome. He was weaned off ventilation at 7 days
rarity of this condition, long-term natural history studies are of life. Abdominal ultrasound showed bilateral cryptorch-
limited. We present a 9-year-old male with a homozygous idism and inguinal hernias. Head ultrasound was normal.
nonsense mutation in NALCN leading to profound intel- His neurologic examination was unremarkable and he was
lectual disability, seizures, feeding difficulties, and a unique discharged home at 3 weeks of life.
periodic breathing pattern. At 10 weeks corrected age, he was admitted to hospital
for investigation of periodic rapid breathing. Examination at
that time revealed a normally grown infant with hypotonia.
He was unable to visually fixate or follow objects. He
showed dysconjugate eye movements and horizontal nys-
* Hugh J. McMillan tagmus. Deep tendon reflexes were brisk with pathologic
[email protected]
clonus at the ankle. His magnetic resonance imaging (MRI)
1
Department of Genetics, Children’s Hospital of Eastern Ontario, brain, electromyography, electrocardiogram, echocardio-
Ottawa, ON, Canada gram, and chest X-ray were unremarkable.
2
Children’s Hospital of Eastern Ontario Research Institute, By 1 year of age, profound global developmental delay
University of Ottawa, Ottawa, ON, Canada was apparent. At 16 months, he required a gastrostomy tube
3
Division of Respirology, Children’s Hospital of Eastern Ontario, for failure to thrive. At 18 months, periodic breathing was
Ottawa, ON, Canada again noted, which prompted a sleep study. The breathing
4
Division of Neurology, Children’s Hospital of Eastern Ontario, pattern was similar in awake and asleep states with three to
Ottawa, ON, Canada four rapid deep breaths followed by central apneas (mean
Table 1 Clinical and genetic characteristics of individuals with NALCN mutations
Series Current Koroglu et al. Al-Sayed et al. [2] Gal et al. [3] Takenouchi et al. [4] Total
[1]
Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Mutation c.3910C>T, c.1924C>T, c.1489delT, c.3860G>T, p.3390G>A, c.1267- c.2022_23delAT,

p.Arg1304X p.Gln642Glu p.Tyr497Thrfs*21 p.Trp1287Leu IVS29-1G>A 2A>G p.Cys675Leufs*23
Type Nonsense Missense Frameshift Missense Splicing Splicing Frameshift
Age (yr), gender 9 M 21 F 18 M 7M 7M 4M 17 F 16 F 9F 1.7 Ma 8F 5 Fa 4F 11 M
Birth weight 1848 g 2200 g 2350 g 2600 g 4000 g 2500 g 2800 g 3000 g 2800 g 3090 g 3000 g 3200 g 2188 g 2216 g
−0.7 SD −2.3 −2 SD −1.2 −2.1 SD
SD SD
Failure to thrive Yes Yes Yes No Yes Yes No No No Yes Yes Yes Yes No 9/14, 64%
Microcephaly No Yes Yes No No No N/a No No Yes Yes Yes No No 5/13, 38%
Severe ID Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 14/14, 100%
Speech delay Yes, none Yes, Yes, Yes, none Yes, none Yes, none Yes, delay Yes, delay Yes, delay Yes, none Yes, Yes, N/a N/a 12/12, 100%
none none none none
Hypotonia Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 14/14,100%
Vision Yes, St, Ny Yes, Yes, Yes, Eso Yes, Anis No No No Yes, St Yes, St Yes, Yes, Yes, Yes, Eso 11/14, 79%
abnormality St, Ny, Ny, Oa St, Ny St, Op Eso
Oa
Hearing loss No SNHL SNHL No No No No No No N/a N/a N/a N/a N/a 2/9, 22%
Seizures Yes Yes Yes No No No Yes Yes Yes No Yes Yes No No 8/14, 57%
Seizure onset 3 yr 13 yr 8 yr 7 yr 7 yr 3 yr 4 yr 4 yr
Breathing Yes No No No No No No No No Yes Yes Yes No Yes 5/14, 29%
irregularity
Constipation Yes N/a N/a Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 12/12, 100%
Cryptorchidism Yes — Yes Yes Yes Yes — — — N/a — — — N/a 5/5, 100%
M male, F female, yr years old, N/a not available, St strabismus, Ny nystagmus, Oa optic atrophy (progressive), Eso esotropia, Anis anisometropia, Op ophthalmoplegia, SNHL sensorineural
hearing loss, ID intellectual disability
a
Deceased
D. K. Bourque et al.
Periodic breathing in patients with NALCN mutations

Fig. 1 Figure 1 shows the respiratory pattern present throughout sleep breaths followed by a 6–8 s apnea, with desaturations down to 85–90%
(sleep staging impossible based upon electroencephalogram, done by followed by return to baseline (95–97%). This pattern was present
direct observation). Top box shows two 30 s epochs (total 1 min throughout sleep. Transcutaneous CO2 remained stable throughout at
recording), bottom box shows 30 min of saturation monitoring from around 37 mmHg
2:50 to 3:20 am. During sleep, he showed persisting pattern of 2–4

duration of 7.5 s). The longest apneas were 11.6 s and the Exome sequencing was performed and analyzed as previously
lowest recorded oxygen saturation was 85.4%. Transcuta- described [6–8]. Average coverage was 125× with 97.8% of
neous CO2 recordings were normal. His central apnea/ Consensus Coding Sequence (CCDS) exons were covered
hypopnea index (AHI) was 320/h (normal <5/h) (Fig. 1). at >10×. All variants in known disease genes present in
Electroencephalogram (EEG) revealed diffuse slowing but OMIM and/or Orphanet were assessed. A homozygous
no electrographic seizures. A sleep study at 3 years old nonsense variant in NALCN (NM_001350748.1, c.3910C>T,
showed similar results (AHI 241/h). p.Arg1304X) was identified and validated by Sanger
At 3 years of age, he developed brief seizures char- sequencing. This variant has never been observed in affected
acterized by behavioral arrest, posturing of his limbs, fol- individuals in the literature, HGMD, or ClinVar. It has been
lowed by complete loss of tone. He has since developed observed in the heterozygous state in two presumed healthy
infrequent generalized tonic–clonic seizures that are well controls in gnomAD (Minor Allele Frequency (MAF) =
controlled on levetiracetam. 0.0008). There were no other variants in genes with any
At 9 years of age, he remains non-verbal, unable to sit or relevance to the patient’s phenotype.
ambulate independently, and unable to manipulate objects
with his hands. His most recent examination showed a
small, non-dysmorphic male (weight 24 kg, 11th centile; Discussion
head circumference 51.8 cm, 33rd centile) with axial
hypotonia and brisk deep tendon reflexes. He continues to The clinical features that are common to patients with
demonstrate profound periodic breathing awake and asleep. biallelic NALCN mutations are severe intellectual deficiency,
Microarray was significant for eight long (>10 Mb) speech delay, and hypotonia. Most patients do not develop
continuous stretches of homozygosity covering 138 Mb. expressive language (Table 1). Constipation and cryptorch-
Serum creatine kinase, lactate, and plasma amino acids were idism are also common. Seizures are present in just over half
normal. Quadriceps muscle biopsy was unrevealing. An of patients with a mean age of onset of 6.1 years old. Visual
intellectual disability panel of 169 genes did not identify a abnormalities have been reported in 79% patients.
pathogenic or likely pathogenic variant. Repeat MRI brain Breathing irregularity was a prominent feature in our
at 6 years old was unremarkable. patient and three previous patients [3]. Similar to our
Due to the lack of diagnosis, our patient was enrolled in the patient, these children demonstrated apneas or periodic
Care4Rare Canada research project. Research ethics board breathing that was characterized by alternating apneic per-
approval was obtained, as was free and informed consent. iods with deep, rapid breathing.
 D. K. Bourque et al.

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