Symptoms, Warning Signs, and Emergency Planning

Understanding the symptoms of AARS2-related leukoencephalopathy involves looking at three different areas: your thinking and mood, your physical movement, and your reproductive health. Because the condition is progressive, symptoms often appear gradually, but knowing what to look for can help you communicate more effectively with your medical team ^[1][2].

Cognitive and Psychiatric Symptoms

For many, the first signs are not physical but involve changes in how the brain processes information. Among reported cases, these “thinking” symptoms affect the vast majority of people with this condition ^[1].

• Cognitive Decline: About 86% of reported individuals experience cognitive changes ^[1]. This often looks like “executive dysfunction”—difficulty with planning, organizing, or multitasking—rather than simple memory loss. You might find it harder to manage finances or follow a complex recipe ^[1][3].
• Psychiatric Changes: Roughly 70% of reported people experience psychiatric or behavioral symptoms ^[1]. This can include depression, anxiety, social withdrawal, or a loss of “filter” (impulsivity). Sometimes these are the very first symptoms to appear, occasionally leading to a misdiagnosis of a primary psychiatric disorder before the genetic cause is found ^[2][3].

Motor and Physical Symptoms

As the disease affects the white matter in the brain, it disrupts the signals that tell your body how to move.

• Gait and Balance: About 80% of reported people develop a gait disturbance (changes in how they walk) ^[1]. This is often due to ataxia (clumsiness or lack of coordination) or spasticity (stiffness in the muscles) ^[4][5].
• Pyramidal and Extrapyramidal Signs: These medical terms describe different ways movement is disrupted. Pyramidal signs (seen in 82%) often involve muscle weakness or “hyperreflexia” (overactive reflexes). Extrapyramidal signs (seen in 45%) include involuntary movements like tremors or dystonia (unusual muscle twisting or posturing) ^[1][2].

Premature Ovarian Insufficiency

One of the most defining features of this condition is its effect on female reproductive health, occurring in approximately 82% of affected females among reported cases ^[1]. This is known as Premature Ovarian Insufficiency (POI). (Note that the neurological disease can also be present without ovarian manifestations, and in males).

• Symptoms: This may appear as primary amenorrhea (never starting a menstrual period) or as periods that become irregular and stop completely, often in a person’s 20s or 30s ^[1][6].
• Hormonal Impact: This is more than just a fertility issue; the loss of estrogen can lead to “early menopause” symptoms like hot flashes and increases the long-term risk for bone thinning (osteoporosis) and heart disease ^[7][3].

Emergency Action Plan and Warning Signs

While the typical course of AARS2-related disease is a slow, gradual progression over years, certain “red flag” symptoms require immediate medical evaluation. It is highly recommended that you keep a one-page written action plan with your baseline symptoms, emergency warning signs, and where to obtain urgent care.

When to Seek Emergency Care

Any sudden or marked worsening of symptoms requires urgent assessment. Seek emergency evaluation for:

• Sudden or severe altered mental status or inability to awaken.
• Sudden change in speech, strength, or vision.
• A new, prolonged, or different type of seizure.
• Severe headache, chest pain, or shortness of breath.
• Repeated serious falls or an inability to swallow.
• Signs of infection (fever with deterioration).
• Suicidal thoughts.

The “Silent” Seizure Risk

Seizures occur in about 10% of reported people with this condition ^[1]. While some seizures involve shaking (convulsions), others are much harder to spot.

• Nonconvulsive Status Epilepticus (NCSE): This has been documented in AARS2-related disease—a state where the brain has continuous seizure activity without visible shaking ^[3]. It can look like a sudden, severe “brain fog” or a significant change in personality that lasts for hours or days.
• Warning Signs: Sudden, marked reduction in speech (becoming nearly mute), impaired responsiveness (appearing “spaced out”), or bizarre behavioral changes.
• Action: If these symptoms appear, seek an emergency evaluation; emergency clinicians will decide whether an EEG (electroencephalogram) is needed ^[3].

Note: Gradual worsening (e.g. balance is slightly worse this month than last, or feeling generalized fatigue) is typically not an emergency and can be discussed at a routine visit, but sudden changes should never be ignored.