What is behind it, how it manifests itself, what research progress has been made…

IHPRF1 and 2 are severe autosomal recessive neurological disorders that are probably caused by a loss of function in the NALCN channel or the associated UNC80 protein. Those affected who suffer from “Infantile hypotonia with psychomotor retardation and characteristic facies-1 and 2” (IHPRF 1 – 615419 and IHPRF 2 – 616801) show severe global developmental delay with poor or absent speech and absent or limited ability to walk. Some patients can have seizures, but these can be controlled.

In IHPRF-1 there is reduced electrical activity, with insufficient sodium entry into cells. IHPRF-2 occurs when there is a loss of function in the UNC80 gene, which is required for NALCN function. UNC80 mutations affect the stability of the NALCN channel. However, it is still unclear how exactly the UNC80 subunit and other accessory proteins modulate NALCN function, although it is known that this modulation is critical for channel activity. This understanding may also be important for future drug therapies.

The main features of the syndrome are:

• Hypotonia: Hypotonia refers to reduced muscle tone, which can lead to poor muscle strength and control. Infants with IHPRF1 often have flabby muscles, making it difficult for them to hold their heads up, sit, stand, or walk.
• Psychomotor retardation: Children typically experience delays in reaching developmental milestones such as rolling over, sitting, crawling, and walking. Mental and cognitive development is also usually delayed.
• Distinctive face: “Face” refers to an individual’s facial features. Children may have distinctive facial features, although these features may vary. These features may include a broad forehead, deep-set eyes, a flat bridge of the nose, a wide and open mouth, and full cheeks.
• Epilepsy: Epileptic seizures are common. These seizures can be of different types, including generalized tonic-clonic seizures (formerly known as grand mal seizures) and absence seizures.
• Regression: Some children may experience a loss of previously acquired developmental skills, a phenomenon known as developmental regression. This can be particularly distressing for families as they witness their child’s skills and abilities decline over time.
• Intellectual disability: Children typically have varying degrees of intellectual disability, which can range from mild to severe.

What treatment options are available?

There are currently no specific medications for this type of rare disease. Therefore, treatment focuses on two things: relieving symptoms and improving the patient’s quality of life. These include:

• Supportive care: Comprehensive care tailored to the patient’s individual needs to improve overall quality of life.
• Physical and occupational therapy: Therapies to improve motor skills, muscle strength and coordination. Physical and occupational therapy help to minimize physical limitations and promote mobility.
• Treatment of seizures: For patients who experience seizure-like episodes, antiepileptic medications are used to reduce the frequency and severity of seizures. The selection and adjustment of medication is individualized based on the specific seizure type and the patient’s response to treatment.
• Treatment of comorbidities: In addition to symptomatic therapy, other medical measures may be needed to treat other health problems associated with the disease, such as sleep disorders, breathing problems or endocrine dysregulation.

What is research currently working on?

The research is focused on better understanding the underlying molecular mechanisms. Key aspects of the research include:

• Molecular mechanisms: Investigating how mutations in the NALCN gene and associated proteins affect the function of the NALCN channel and what impact this has on neuronal activity and overall cell function.
• Structural studies: Using high-resolution cryo-electron microscopy (cryo-EM) to study in detail the structure of the NALCN channelosome and its interactions with other proteins. This helps to decipher exactly how the channel works and the role of its modulators.
• Therapeutic approaches: Developing and testing therapies that specifically target the specific dysfunctions of the NALCN channel. This includes both pharmacological approaches to modulate channel activity and potential gene therapies to correct the underlying genetic defects.

Advances in these areas of research offer hope for new and improved treatment options for patients suffering from NALCN- or UNC80-related disorders and help advance our understanding of the molecular basis of neurological and developmental disorders.