NALCN CHANNELOPATHY. WHEN TO SUSPECT THE DIAGNOSIS.
ARE NALCN CONDITIONS RARE?
CLIFAHDD and IHPRF are ULTRA-RARE severe neurodevelopmental syndromes linked to mutations in the
NALCN gene and UNC80 gene, a key regulator of neuronal and endocrine involved in essential physiological processes
(e.g., locomotion, breathing, sleep, pain & digestion). Mutations causing disease severely impact on
the protein function and to date, no treatment are available.
NALCN CONDITIONS are very debilitating rare disorders that impose a life-long economical and social burden to families of affected children. Although rare disorders are recognized as a public health priority, there is no current treatment available to cure or alter disease progression. In addition, a systematic study of diagnostic criteria for this symptoms has not been undertaken.
We are an ultra-rare condition. CLIFAHDD: 45 patients with de novo mutations; IHPRF1: 40 patients from 24 families reported to date; iIHPRF2: 32 patients from 21 families).
NALCN CONDITIONS IMPACT
WHAT DO CLIFAHDD AND IHPRF1&2 (NALCN/UNC80 genes)HAVE IN COMMUN?
The sodium leak channel NALCN is part of a large ion channel complex, consisting of multiple proteins including UNC80 and UNC79. (NALCN, UNC80 and UNC79 work together. If one of them does not work, the others will be affected as well. NALCN forms a channel complex, interacting directly with UNC80, and indirectly with UNC79).
RESEARCH ON THE NALCN CHANNELOSOME IS NECESSARY AND WILL PAVE THE WAY TO THE IDENTIFICATION OF NOVEL THERAPEUTICS TO IMPROVE THE QUALITY OF LIFE FOR PATIENTS WITH CLIFAHDD AND IHPRF 1&2.
ABOUT NALCN (Sodium Leak Channel)
In Humans, NALCN, regulates resting membrane potential and neuronal excitability and it has been implicated in different neurological diseases. This NALCN channelosome plays a vital role in the communication between neurons in the brain.
The gene encoding NALCN is located on chromosome 13q32.3-33.1 and monoallelic (de novo) and biallelic (recessive) variants lead to different clinical phenotypes with some overlapping features. Heterozygous NALCN variant led to CLIFAHDD and predicted to be gain-of-function (congenital contractures of the limbs and face, muscular hypotonia and global developmental delay) while biallelic NALCN variant lead to IHPRF1 and predicted to be loss-of-function (Infantile hypotonia, psychocomotor retardation and characteristic facies).
The gene encoding UNC80 is located on chromosome 2q34 and biallic (recessive) UNC80 variants are associated with IHPRF2 and predicted to be loss-of-function (Infantile hypotonia, psychomotor retardation, and characteristic facies).
- In a Gain of Function variant, the channel is open and stay for a long time. As a result, there are too much neuronal excitability.
- In a Loss of Function variant, the opposite occurs. There is improper channel opening resulting in a decreased neuronal excitability.
A change in the NALCN/UNC80 gene alter the function of the channel.
- Recessive pathogenic variants of NALCN and UNC80: IHPRF type 1 and IHPRF type 2. Loss of function.
- Dominant pathogenic variants of NALCN: Clifahdd Syndrome. patients with de novo mutations). Gain of function.
Bouasse M, Impheng H, Servant Z, Lory P, Monteil A. Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties. Sci Rep. 2019;9(1):11791. Published 2019 Aug 13. doi:10.1038/s41598-019-48071-x
Dominant: A genetic trait is considered dominant if it is expressed in a person who has only one copy of that gene. (In genetic terms, a dominant trait is one that is phenotypically expressed in heterozygotes).
Recessive: dominant trait is opposed to a recessive trait which is expressed only when two copies of the gene are present. (In genetic terms, a recessive trait is one that is phenotypically expressed only in homozygotes).
De Novo: Genetic changes that are described as de NOVO (NEW) MUTATIONS can be either hereditary or somatic. In some cases, the mutation occurs in a person’s egg or sperm cell but is not present in any of the person’s other cells. In other cases, the mutation occurs in the fertilized egg shortly after the egg and sperm cells unite. (It is often impossible to tell exactly when a de novo mutation happened.) As the fertilized egg divides, each resulting cell in the growing embryo will have the mutation. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell in the body but the parents do not, and there is no family history of the disorder.
PATIENTS WITH NALCN/UNC80 MUTATIONS EXHIBIT COMMON SYMPTOMS.
NALCN/UNC80-related disorders, CLIFAHDD and IHPRF1 & 2 syndromes, cause a large panel of symptoms that include severe encephalopathy associated with speech impairment, intellectual disability, dysautonomia and hypotonía, combined with non-neurological symptoms such as facial dysmorphism, cardiac arrhythmia, endocrine dysfunction and gastrointestinal symptoms.
Mutations in NALCN/UNC80 cause a number of neurological phenotypes that need to be better studied. However studies have indicated clinical overlap.
CLIFAHDD/IHPRF patients exhibit common symptoms of variable severity :
*Note that not everyone with a NALCN condition (NALCN/UNC80) develop all the symptoms. Patients exhibit symptoms of variable severity.
*Mutations in NALCN/UNC80 cause a number of neurological phenotypes (observable characteristics or traits). Channel functions and its relationship to phenotype need to be better studied. Given the rarity of this condition, long-term natural history studies are limited. If you want to participate in a Deep phenotype study write to firstname.lastname@example.org This study aims to understand the clinical features of patients with NALCN/UNC80 dysfunctions. This step is crucial to identify research needs for the development of future therapies. You can get more information at https://fundacionlibellas.org/phenotype-study/
Below are the most common symptoms:
–Global developmental delay. Intellectual disability that is caused by NALCN/UNC80 can rage from mild to severe. Children can have difficulty with language and motor development. Most children are not able to walk and they do not develop speech. Inherited and spontaneous mutations in the NALCN CONDITIONS cause devastating symptoms including hypotonia, developmental delay, inability to sit, stand or walk, severe intellectual disability, lack of speech developement, epilepsy and seizures and premature death in children
-Hypotonia. Weak muscle tone. s the medical term for decreased muscle tone. Newborn babies and young children with severe hypotonia are often described as being “floppy”.
-Breathing abnormalities. Episodes of disrupted respiratory rhythms, central and obstructive sleep apneas with recurrent hypoxia may be presented. Apneas and hypoapneas. Central apneas during sleep. Chronic respiratory dysfunctions should be anticipated and treated aggressively in infants with confirmed NALCN mutations, as they may adversely affect the neurodevelopmental outcome. It is recommended sleep studies (POLYSOMNOGRAPHY TEST) for all patients with NALCN/UNC80 gene mutations.
-In addition, CLIFAHDD Syndrome may exhibit distal arthogryposis. DA are a group of disorders that mainly involve the distal parts of the limbs. Arthrogryposis, describes congenital joint contracture in two or more areas of the body.Contractures in CLIFAHDD patients can be mild enough in some cases to have been overlooked, particularly in older children and young adults.
Some Patients also have:
– Epileptic Seizures
-Ataxia and episodic ataxia. Episodic ataxia consists of episodes of unsteadiness of movement and poor balance, vertigo (dizziness), nausea and headache. Children with episodic ataxia may typically walk without any problem but suddenly struggle to keep their balance. These attacks can by triggered by physical stress, fevers, exercise, warm wheather among others.
-Cerebellar dystrophy (MRI). This affects muscle coordination and balance. Symptoms include uncoordinated movement of the arms and legs, wide-based uncoordinated walk, back and forth tremor in the trunk of the body among others.
-Eyes disorders IHPRF1.
-Alteration in pain sensitivity
-Endocrine dysfunction. The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells. FASEB J. 2021, demonstrate that the sodium leak channel NALCN as well as its ancillary subunits are endogenously expressed in GH3 cells at least at the mRNA level. Results suggest that symptoms observed in patients with both the IHPRF1 and the CLIFAHDD syndromes that are complex may arise not only from an alteration of neuronal excitability, but also from endocrine defects
-Early death in severe mutations..
NALCN BREATHING ABNORMALITIES. ANESTHESIA SENSITIVITY. REFERENCES.
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 Apr 20;129(2):371-83. doi: 10.1016/j.cell.2007.02.041. PMID: 17448995.
The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 2007;129:371–383., , , et al.
H Hong, R Kretzmer, R Kato, S D Ward, 1156 A Pediatric Case of UNC80 Mutation and Abnormal Respiratory Control Treated with Positive Airway Pressure Therapy, Sleep, Volume 41, Issue suppl_1, April 2018, Pages A426–A427, https://doi.org/10.1093/sleep/zsy063.1155
Impheng H, Lemmers C, Bouasse M, Legros C, Pakaprot N, Guérineau NC, Lory P, Monteil A. The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells. FASEB J. 2021 May;35(5):e21400.doi:10.1096/fj.202000841RR. PMID: 33793981.
Karimi AH, Karimi MR, Farnia P, Parvini F, Foroutan M. A Homozygous Truncating Mutation in NALCN Causing IHPRF1: Detailed Clinical Manifestations and a Review of Literature. Appl Clin Genet. 2020 Aug 27;13:151-157. doi: 10.2147/TACG.S261781. PMID: 32943903; PMCID: PMC7459142.
Chong, J. X., McMillin, M. J., Shively, K. M., Beck, A. E., Marvin, C. T., Armenteros, J. R., Buckingham, K. J., Nkinsi, N. T., Boyle, E. A., Berry, M. N., Bocian, M., Foulds, N., Uzielli, M. L. G., Haldeman-Englert, C., Hennekam, R. C. M., Kaplan, P., Kline, A. D., Mercer, C. L., Nowaczyk, M. J. M., … Bamshad, M. J. (2015). De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. American journal of human genetics, 96(3), 462-473. https://doi.org/10.1016/j.ajhg.2015.01.003
Wie J, Bharthur A, Wolfgang M, Narayanan V, Ramsey K; C4RCD Research Group, Aranda K, Zhang Q, Zhou Y, Ren D. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Nat Commun. 2020 Jul 3;11(1):3351. doi: 10.1038/s41467-020-17105-8. PMID: 32620897; PMCID: PMC7335163.