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IRF2BPL

IRF2BPL



Overview

Interferon regulatory factor 2 binding protein-like–related disorder (IRF2BPL–related disorder) is a very rare genetic condition. IRF2BPL refers to a gene that helps the brain and nervous system work properly.  

Symptoms typically begin in childhood. Symptoms can start as early as the first 6 months of life. They can include: 

Extra movements that can appear shaky, wiggly, dance-like, twisting, or stiff 

Trouble controlling movements 

Seizures 

Loss or failure to attain developmental skills  

This is a rare disorder. Experts are still learning about all the different symptoms that may be associated with it.

A mutation is a change in a gene that causes it to not work properly. Mutations in the IRF2BPL gene can affect the brain and nervous system. The function of IRF2BPL is not yet known. Experts believe IRF2BPL is important for developing and maintaining healthy brain cells.  

Symptoms usually begin in early childhood and can get worse over time. This disorder is a lifelong condition.

SYMPTOMS

Common Symptoms

Developmental Regression: Loss of previously acquired skills (walking, talking).

Motor Issues: Ataxia (balance issues), dystonia (involuntary movements/twisting), spasticity, tremors, poor coordination.

Seizures: Various types, including infantile spasms, focal seizures.

Cognitive/Behavioral: Intellectual disability, autism spectrum disorder, anxiety, depression.

Feeding/GI: Difficulty swallowing (dysphagia), gastrointestinal dysmotility.

Brain Imaging: Cerebellar atrophy, corpus callosum abnormalities. 

Spectrum of Severity

Severe (NEDAMSS): Early onset, severe regression, profound disability, loss of walking/speech.

Milder/Late-Onset: Can present in adulthood with progressive imbalance, chorea, cognitive decline, less regression, or preserved ambulation. 

Onset & Progression

Onset is highly variable (infancy to adulthood).

Often progressive, with skill loss worsening over time, though some milder cases don't regress. 

Causes

Gene Mutation: A change (mutation) in the IRF2BPL gene (Interferon Regulatory Factor 2 Binding Protein Like).

De Novo: Most cases arise from a new mutation in the child, not inherited from parents.

Autosomal Dominant: Can be passed down, with a 50% chance of inheritance from an affected parent.

Types of Mutations: Nonsense, missense, and frameshift mutations have been identified, often truncating the protein. 

Complications

Neurological Regression: Many children experience a period of normal development followed by loss of motor skills (sitting, walking) and speech.

Epilepsy: Seizures are very common, including infantile spasms, myoclonic, absence, and tonic-clonic types, notes National Institutes of Health (NIH) | (.gov).

Movement Disorders: Ataxia (uncoordinated movement), dystonia (involuntary muscle contractions), tremor, and parkinsonism are frequent.

Feeding & Swallowing: Severe dysphagia (trouble swallowing) often necessitates feeding tubes, according to Orphanet and Child Neurology Foundation.

Brain Abnormalities: MRI scans show cerebellar atrophy, cortical/subcortical atrophy, and corpus callosum issues.

Psychiatric/Behavioral: Autism spectrum disorder (ASD), anxiety, and other behavioral issues are reported. 

Risk Factors

Genetic Mutation: The primary risk factor is the presence of a pathogenic IRF2BPL gene variant, which causes the protein to not function properly in the brain and nervous system.

Inheritance Pattern: The disorder is autosomal dominant, meaning a child of an affected individual has a 50% chance of inheriting the pathogenic variant.

Type and Location of Variant: The specific type and location of the mutation may influence the severity and age of onset of symptoms. Truncating (loss-of-function) variants often lead to the severe childhood-onset form, while some missense variants or N-terminal mutations might result in a milder, later-onset phenotype. 

Diagnosis

Clinical Presentation: Early normal development followed by loss of skills (motor, speech).

Neurological Symptoms: Seizures (epileptic encephalopathy), ataxia, dystonia, spasticity, autism, anxiety, and feeding issues.

Brain Imaging (MRI): Cortical/cerebellar atrophy, corpus callosum abnormalities.

Genetic Testing: Confirms diagnosis by identifying a pathogenic IRF2BPL mutation. 

Treatments

Therapies: Physical, Occupational, Speech, and Developmental therapies.

Medications: For seizures (e.g., sodium valproate, levetiracetam) and movement issues (e.g., baclofen for spasticity).

Nutritional Support: Feeding therapy or tubes (gastrostomy) for poor weight gain.

Specialist Care: Neurologists, orthopedists, ophthalmologists for specific issues like vision or bone health. 

 Therapy: A significant breakthrough occurred with the first child receiving an IRF2BPL gene replacement therapy in April 2025, showing promise for treating the underlying cause.

Drug Repurposing: Researchers are exploring existing drugs, like copper ATSM (CuATSM), which rescued neuronal function in lab studies and flies.

Gene Editing: Base editing and prime editing (CRISPR-based tools) are being developed as potential cures by correcting the genetic mutation.

Antisense Oligonucleotides (ASOs): These are also being investigated to target the mutated IRF2BPL mRNA. 

Type of Doctor Department : A clinical geneticist and a neurologist


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