Symptoms and Disease Progression in ADAR-Related HSP

The symptoms of ADAR-related Hereditary Spastic Paraplegia (HSP) can vary significantly from one person to another, even among members of the same family who share the same genetic variant ^[1][2]. Because this condition affects both the nervous system and the immune system, you may observe a combination of movement challenges and physical changes in the skin. Understanding what to look for can help you track these symptoms and have more detailed conversations with your care team.

Neurological and Movement Symptoms

While symmetric lower-limb spasticity is typical of the HSP phenotype, the broader ADAR1 spectrum can include other manifestations depending on the exact variant.

• Symmetric Lower Limb Spasticity: This is a persistent stiffness or tightness in the leg muscles that occurs on both sides of the body ^[3]. It may make the legs feel heavy or difficult to move, leading to a “stiff” or “scissoring” way of walking.
• Dystonia: About 39% of patients in one large study of ADAR1-related disorders experienced dystonia ^[4]. This is a movement disorder where muscles contract involuntarily, causing repetitive movements or twisting postures. It can sometimes be mistaken for simple clumsiness or muscle spasms.
• Motor Delays and Encephalopathy: In children, this may first appear as a delay in reaching milestones like crawling or walking ^[3]. In more complex cases, particularly those within the Aicardi-Goutières Syndrome (AGS6) spectrum, a child might experience early encephalopathy, seizures, feeding problems, or regression (the loss of a motor skill they had previously mastered) ^[5][6].

Skin Changes: The DSH Pattern

A unique feature of ADAR1 mutations is the effect they can have on skin pigmentation. This is often referred to as Dyschromatosis Symmetrica Hereditaria (DSH) ^[7].

• Mixed Macules: You may notice a pattern of small, flat spots (macules) on the backs of the hands and the tops of the feet ^[1].
• Color Variation: These spots are typically a mixture of hyperpigmented (darker than the surrounding skin) and hypopigmented (lighter than the surrounding skin) ^[8].
• Facial Features: In some cases, small, freckle-like spots may also appear on the face ^[1].

While these specific DSH pigment changes do not cause pain or itching, other inflammatory skin findings (such as chilblains) can occur in the AGS spectrum and can be quite uncomfortable ^[9].

Variability and Progression

One of the most challenging aspects of this diagnosis is its “extreme variability.” No two patients follow the exact same path.

• Progression vs. Stability: For some, the condition is relatively stable or progresses very slowly over many years. However, in a broad study of ADAR1-related cases, approximately 43% followed a more progressive course, where symptoms worsened over time ^[4]. This figure includes more severe phenotypes and cannot be used to predict an individual’s course.
• Incomplete Penetrance: This is a medical term meaning that someone can carry the genetic mutation but show very mild symptoms or no symptoms at all ^[2]. This explains why a parent might be “unaffected” even though they passed the gene to a child who shows symptoms.
• Family Differences: Even with the same mutation, one family member might only have skin spots (DSH), while another has severe walking difficulties (HSP) ^[1].

Why Misdiagnosis is Common

Because ADAR-related HSP is rare and its symptoms overlap with many other conditions, it can initially resemble other disorders.

• Cerebral Palsy (CP): Many patients are first told they have spastic or dystonic cerebral palsy ^[10]. The key difference is that CP is a clinical syndrome caused by a non-progressive disturbance in the developing brain, which has many causes. Genetic disorders like ADAR-HSP can mimic CP, coexist with it, or evolve secondarily ^[6].
• Leukodystrophies: Because imaging may show changes in the brain’s “white matter,” the condition can be confused with other leukodystrophies (diseases that damage the protective covering of nerve fibers) ^[11].
• Other HSPs: There are over 80 different genetic types of HSP. A compatible phenotype plus a pathogenic or likely pathogenic result on genetic testing is required for confirmation. (A Variant of Uncertain Significance does not confirm the diagnosis).

Recognizing these symptoms as part of a single genetic spectrum is the first step toward getting the right support and monitoring for your specific needs.