Aicardi–Goutières syndrome

Overview

Aicardi–Goutières syndrome (AGS) is a rare, genetic neuroinflammatory disorder that primarily affects the brain, immune system, and skin. It typically presents in infancy or early childhood and is often misdiagnosed as congenital viral infection due to overlapping features like brain calcifications and elevated white blood cell counts in cerebrospinal fluid. AGS causes progressive neurological impairment, developmental delays, and systemic inflammation, and in some cases, it begins even before birth (in utero). It was first described by Jean Aicardi and Françoise Goutières in the 1980s.

Causes

Aicardi–Goutières syndrome is caused by mutations in any of several genes involved in the body’s nucleic acid metabolism and immune regulation. The most commonly affected genes include:

• TREX1

• RNASEH2A, RNASEH2B, RNASEH2C

• SAMHD1

• ADAR1

• IFIH1

These gene mutations lead to the accumulation of nucleic acids (DNA or RNA) that are mistaken by the body as viral material, triggering a chronic immune response, especially through the overproduction of interferon alpha. This immune overactivation causes inflammation and damage to brain tissue and other organs.

Symptoms

The symptoms of AGS vary in severity and age of onset, but commonly include:

Neurological Symptoms:

• Developmental regression or delay

• Microcephaly (small head size)

• Spasticity (stiff or tight muscles)

• Seizures

• Feeding difficulties

• Intellectual disability

Immunological and Systemic Features:

• Elevated interferon levels in cerebrospinal fluid

• Chronic sterile inflammation in the brain and other tissues

• Encephalopathy and brain atrophy

Skin and Physical Features:

• Chilblain-like skin lesions on fingers, toes, or ears (especially in cold weather)

• Facial features such as prominent forehead and small jaw in some subtypes

Diagnosis

Diagnosis of Aicardi–Goutières syndrome requires a combination of clinical findings, imaging, and genetic testing. Diagnostic steps include:

• Neuroimaging (MRI or CT): Shows intracranial calcifications, white matter abnormalities, and brain atrophy

• Lumbar puncture (CSF analysis): Elevated interferon alpha and lymphocytosis (increase in white blood cells)

• Genetic testing: To confirm mutations in AGS-related genes

• Blood tests: Elevated inflammatory markers, liver enzymes, and autoimmune profiles in some cases

It is crucial to differentiate AGS from congenital infections (e.g., TORCH infections), which may show similar brain abnormalities and systemic symptoms.

Treatment

There is no known cure for Aicardi–Goutières syndrome, and treatment focuses on managing symptoms and reducing immune system overactivity. Current approaches include:

Supportive Care:

• Physical, occupational, and speech therapy for developmental support

• Seizure management with antiepileptic drugs

• Nutritional support, including feeding tubes if needed

Targeted Therapies (Experimental/Research-based):

• JAK inhibitors (e.g., baricitinib, ruxolitinib): Under investigation to reduce interferon signaling

• Anti-inflammatory and immunosuppressive drugs: Used cautiously to control systemic inflammation

Genetic Counseling:

• Recommended for families, especially in consanguineous or inherited cases

Prognosis

The prognosis of Aicardi–Goutières syndrome varies significantly based on the severity and type of gene mutation. Some children experience profound and progressive neurological decline, while others may stabilize with mild to moderate disability. Life expectancy can be shortened in severe cases, but milder forms may allow survival into adolescence or adulthood.

Early intervention, symptom management, and supportive care can improve quality of life, but the condition is lifelong. Ongoing research into interferon-targeted therapies offers hope for better outcomes in the future.