An unexplored sodium channel and its implication in rare and not so rare diseases

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Angel Aledo Serrano, Antonio Gil-Nagel Rein

Neurology Service, Hospital Ruber Internacional. MADRID

Researchers from a French-Spanish consortium, together with the Fundación Libellas, are trying to find pathophysiological mechanisms, phenotype, and precision medicine treatments targeting a voltage-independent sodium channel, the NALCN, for patients with neurological and psychiatric diseases.

The implication of genetic mutations in ion channels as a cause of disease has been a frequent tonic for many years. And it is that the pathologies of the ionic channels, also called channelopathies, have been related to clinical syndromes as different as epilepsy, migraine, movement disorders or even cardiac arrhythmias. And the list keeps growing.

Ion channels are essential, not only for the generation of action potentials but also for the establishment of resting membrane potentials. However, these two functions have been related to pathology in a very disparate way. Thus, while hundreds of mutations in the genes encoding voltage-gated ion channels – responsible for the generation of action potentials – have been discovered as causes of disease, the functions of voltage-independent “leak” channels are less established in human diseases.

 So what are voltage-independent ion channels for?

For years it was thought that the NALCN ( sodium leak channel ) had little or no involvement in pathology. This voltage-independent sodium channel is expressed primarily in the brain, spinal cord, heart, and endocrine glands, but also in the uterus and intestine. NALCN contributes to the tonic current and plays a critical role in your neuronal excitability. In fact, there are currently multiple pieces of evidence that support its physiological importance. First, the knockout NALCN is lethal the day after birth in mice due to disruption of the respiratory rhythm. Second, changes in the expression and/or function of NALCN have been implicated in other physiological processes, such as motor function, pain sensitivity, and circadian rhythm in animals. Finally, we already know that mutations in NALCN cause rare neurodevelopmental diseases.

The Fundación Libellas is the only international foundation dedicated to supporting families affected by NALCN-related syndromes and research into this ion channel.

This is where Isabel, her family, and the Fundación Libellas come into play. Isabel is a 13-year-old girl who suffers from a neurodevelopmental disorder associated with respiratory problems and other comorbidities that, like so many others, received a genetic diagnosis late, at 9 years of age. She was the first diagnosed with a syndrome related to NALCN in Spain, specifically with CLIFHADD (an acronym for congenital contractures of the limbs and face with hypotonia and developmental delay ), due to a de novo mutation in this channel with a gain of function. And is that, currently, both CLIFHADD (36 patients in the world, 2 of them in Spain) and its recessive variant due to loss of function IHPRF1 (acronym infantile hypotonia, with psychomotor retardation and characteristic facies type 1, with 35 patients from 22 families, none in Spain), are considered ultra-rare diseases. However, its actual prevalence is not known, since NALCN is not included in the majority of genetic panels performed in patients with intellectual disabilities, autism, or epilepsy, and the majority of these patients have not yet accessed genetic studies that could detect pathogenic variants in NALCN, such as the exome or the trio exome.

Isabel’s case is also paradigmatic, since it has encouraged her family, and especially her mother, Isabel Pastor, to create in 2019 the first international foundation that tries to promote the investigation of dysfunctions in cellular excitability, with special emphasis in the ion channel NALCN, as well as its associated syndromes. In addition, it offers care and help to patients and their families, currently having 6 IHPRF1 and 30 CLIFHADD families.

Characteristic phenotypic traits of diseases produced by a gain of function (CLIFAHDD) or loss of function (IHRF) in NALCN. Image: Fundación Libellas

From the efforts of this foundation, a research consortium has emerged between the Neuronal Plasticity laboratory of the Prince Felipe Research Center of Valencia (Dra. Del Pino), the ion channels laboratory of the Montpellier Institute of Functional Genomics (Dr. Monteil) and the Neurodevelopmental Epilepsy and Encephalopathies Program of the Hospital Ruber Internacional de Madrid (Dr. Gil-Nagel and Dr. Aledo-Serrano) to study the neurobiological basis of IHPRF1 and CLIFHADD in animal models and deep phenotyping in patients, as well as Therapeutic potential for IHPFR1 and CLIFHADD drugs with effectiveness in preliminary clinical studies.

Although useful precision medicine treatments are being found in some sodium channelopathies, such as Dravet syndrome or SCN2A encephalopathy, currently there are no proven effective therapies for CLIFHADD or IHPRF1.

The treatments directed at NALCN could be of interest, not only for people with these rare diseases, but also for patients with schizophrenia, autism, pain, or even respiratory or endocrinological disorders, since this ion channel seems to play a key role in all of them.

Artículo científico: 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 Aug 13;9(1):11791. Doi:

Source:  NALCN – UNC80. Advances in the investigation of CLIFAHDD and IHPRF Syndrome.