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Get to Know Fundación Libellas

Updated: Apr 25, 2021


NALCN is involved in ultra-rare and severe genetic diseases that begins in infancy. The sodium leak channel NALCN is a highly conserved crucial player of cell excitability. Electrical activity of excitable cells, such as neurons and endocrine cells, involves a coordinated and tightly regulated action of a panel of specialized proteins including ion channels, transporters, exchangers, and receptors for hormones and neurotransmitters. Any alteration in the function of one component of this “Excitosome” induces a pathological state that may be not only severe, but also lethal in human.

The sodium (Na+)-leak channel NALCN was isolated in 1999 and later studies revealed that it conducts a background sodium influx and critically regulates the electrical activity of neurons. Indeed, disruption of NALCN expression in different types of neurons from several species led to a 15mV hyperpolarization of the resting membrane potential and a decrease of their firing rate.

Both recessive and dominant pathogenic variants of human NALCN and its Unc80 ancillary subunit (e.g. an important partner for NALCN function) were recently described in several clinical and genetic studies. Recessive pathogenic variants of NALCN and Unc80 are linked to a syndrome referred to as infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) type 1 (OMIM #615419; 39 patients from 24 families) and type 2 (OMIM #616801; 32 patients from 21 families), respectively.

Dominant pathogenic variants of NALCN are responsible for a syndrome referred to as congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD; OMIM #616266, 38 patients with de novo mutations).

It was recently demonstrated the gain- and loss-of-function effects of mutations causing the CLIFAHDD and IHPRF1 syndrome respectively.

Possible implications of NALCN in other diseases: Schizophrenia, Bipolar disorders, Epilepsy, Attention-deficit/Hyperactive disorder; Autism; 13q Syndrome, Alzheimer, Alcoholism, Cancer, etc

NALCN Clinical Features

NALCN mutations are responsible for the CLIFHADD and IHPRF1 syndromes and UNC80 mutations are responsible for the IHPRF2 syndrome.

- CLIFHADD and IHPRF syndromes are considered as ultra-rare genetic diseases that affect a small number of patients who are spread all over the world (> 150 patients identified to date).

NALCN is mainly expressed in brain, spinal cord, heart and endocrine glands but also in the uterus and intestine. As a whole, functional studies revealed that NALCN is a crucial player of cell excitability and is involved in several fundamental physiological processes such as respiratory rhythm, circadian rhythm, locomotor behavior, pain sensitivity, sleep, gastrointestinal motility, systemic osmoregulation and parturition.

Respiratory patterns may be an important distinguishing feature of NALCN mutation. It is characterized by alternating apneic periods with deep, and rapid breathing. Chronic respiratory dysfunctions should be anticipated and treated in infants with confirmed NALCN mutation as they may adversely affect neurodevelopmental outcome.

Both IHPRF and CLIFAHDD patients exhibit complex clinical traits of variable severity that may cause premature death in some cases. IHPRF and CLIFAHDD patients exhibit common symptoms such as hypotonia, facial dysmorphisms, global developmental delay, chronic constipation, and respiratory defects. In addition, patients with the CLIFAHDD syndrome exhibit distal arthrogryposis.

Other features that may be present:

Some children suffer from Epileptic seizures, sweating, excessive drooling, growth retardation, ataxia, Bruxism and Cerebellar atrophy.

Clinical features of NALCN continue to be identified, clarified and understood, throug early research of this newly discovered genetic mutation.

Unfortunately, there is no available treatment for patients to date and it is necessary to develop novel therapeutics.

Get to Know Fundación Libellas

Fundación Libellas is an international nonprofit patient advocacy organization dedicated to improving the lives of children affected by NALCN ion channel-related diseases, through research, family support programs and education. Even though the country of establishment of the foundation is Spain, we are creating an international network of patients, researchers and physicians who work together. The foundation was established on November 4, 2019, and entered into the “Registro de Fundaciones de competencia Estatal” (Registry of foundations) on 24 January 2020 with nº of registry 2279. CIF G88523006.

Our mission:

• To provide support and funding for research focused on NALCN-related diseases.

• To promote advocacy for families and patients with diseases related to the NALCN ion channel mutations

• To be a link between patients, physicians and researchers.

I am especially proud of ...

We are a new foundation, 150 updated patients. We are proud to be a member of an international network of patients, physicians and researchers working together to transform the lives of those living with severe neurodevelopmental disorders induced by NALCN mutations. Up to date, there are no treatments available to patients. Children with diseases related to the NALCN ion channels (CLIFAHDD and IHPRF1&2) do not have effective treatment options, so we are proud to work to change this and provide opportunities for collaboration in these orphan syndromes.

Excited to REN because...

Many genetic disorders and epileptic encephalopathies have so many similarities. Participating with all these organizations will allow us an opportunity to collaborate with others who also strive for more advocacy and research opportunities. Collectively, we can network, share our knowledge to raise all of our goals. Thus, all together, there are more opportunities for small patient organizations to move further faster collaboratively studying of our gene disorders. We look forward to exchanging ideas and collaborate with REN and REN members.

My journey and motivation...

My motivation is Isabel, my little daughter. After more than eight years, an answer came in Isabel’s complex medical puzzle. An exome had finally identified the NALCN gene mutation. We are here because we were given no standard of care and no treatment option after the diagnosed were made. Our syndrome was so rare that we thought we were alone. But we were not. We found a support group of parents finding a researcher in that group who gave us support and hope for a cure. Working together is an important role to improve and obtain treatments for our community. Foster Research is our hope for a cure for NALCN children.

By Isabel Pastor Alfonso. Founder and President of Fundación Libellas

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