Neurology

Diagnostic Tests & Understanding Your Reports

At a Glance

ADAR-related HSP evaluation combines genetic testing with clinical findings. Brain MRI and an interferon-signature blood test can provide supporting clues, but neither test alone confirms or excludes the condition, and report terms such as VUS require specialist interpretation.

Navigating the diagnostic process for a rare condition like ADAR-related HSP often involves a complex puzzle of genetic sequencing, clinical assessment, brain imaging, and specialized blood tests. This page is designed to help you decode the reports you receive and understand the “checkpoints” your medical team uses to reach a definitive diagnosis. Importantly, not every test listed here is automatically needed for every patient; selection depends heavily on your clinical phenotype.

The Genetic Blueprint: Panels vs. WES

Because the symptoms of ADAR-related HSP can overlap with many other conditions, doctors use molecular testing to find the exact cause.

Multigene Panels: This is often the first step. A lab looks at a specific “list” of genes known to cause spasticity or Aicardi-Goutières Syndrome (AGS) ^[1]. Panels are efficient and can identify changes in the ADAR1 gene alongside other similar genes like TREX1 or RNASEH2B ^[2]^[3].
Whole-Exome Sequencing (WES): If a panel is negative, doctors may use WES to look at all the protein-coding regions in your DNA. This is particularly helpful for atypical cases or when a second, unrelated genetic condition is suspected ^[4].

The Biomarker: The Interferon Signature

A feature of ADAR-related disease is an overactive immune system. To measure this, doctors may order a blood test called an interferon-stimulated gene (ISG) signature, sometimes called an “interferon score” ^[5].

In one research context, a study of 34 patients with ADAR1 mutations showed elevated scores in 50 out of 52 blood samples ^[5]. However, this test is an assay-specific adjunct rather than a stand-alone confirmation. A high score is not specific to ADAR1 (it can occur with infections or other interferonopathies), and a normal result does not completely exclude the disease. There is no universally standardized cutoff, and it serves as supportive clinical information ^[6]^[7].

Reading the MRI Report

Magnetic Resonance Imaging (MRI) of the brain is used to look for physical clues. While no single finding “proves” it is ADAR-related, several patterns are common depending on the phenotype. (Note that CT is often more sensitive than MRI for calcification, while MRI is better for structural findings):

White Matter Abnormalities: Changes in the “wiring” of the brain (leukodystrophy) are frequent in some phenotypes ^[3].
Intracranial Calcifications: These are small mineral deposits, often found in the basal ganglia (the part of the brain that controls movement), principally discussed in AGS6 presentations ^[8]^[3].
Striatal Necrosis: In some children with biallelic mutations, the MRI may show damage to a specific area called the striatum, which can be linked to sudden changes in movement or muscle tone ^[9].
Brain Atrophy: A general shrinking or thinning of certain brain areas over time ^[3].

Differential Diagnosis: Ruling Out Mimics

Depending on the clinical phenotype, family history, and strength of the molecular result, your doctor may evaluate treatable mimics in parallel. These include:

X-linked Adrenoleukodystrophy (X-ALD): Evaluated via a blood test for very-long-chain fatty acids (VLCFA) ^[10]^[11].
Homocysteine Disorders: Evaluated by checking blood levels of homocysteine and methionine ^[12].
Metabolic/Mitochondrial Diseases: Screened through tests like urine organic acids ^[13]^[14].

Understanding the Technical Terms

You may encounter these five terms on your reports:

Pathogenic: The genetic change is confirmed to cause the disease. Only pathogenic or likely pathogenic variants should guide predictive testing in family members.
VUS (Variant of Uncertain Significance): A “gray area” result where a change was found, but there isn’t enough research yet to know if it causes symptoms ^[15]. A VUS should not be used to confirm disease, change treatment, or test unaffected relatives.
Heterozygous: You have one copy of the mutated gene ^[5].
Biallelic: You have two copies of the mutated gene ^[16].
Penetrance: This refers to how likely it is that someone with the mutation will actually show symptoms ^[17]. For example, “incomplete penetrance” means someone can have the gene change but remain healthy. ^[18].

Common questions in this guide

What genetic tests are used to evaluate ADAR-related HSP?

A multigene panel is often the first test because it checks ADAR1 and other genes that can cause similar spasticity or Aicardi-Goutières syndrome features. If the panel is negative, the presentation is atypical, or another condition is suspected, whole-exome sequencing may be considered.

What does an interferon-signature or interferon-score blood test show?

This test measures activity of interferon-stimulated genes and can support the evaluation of ADAR-related disease. A high score is not specific to ADAR1, there is no universally standardized cutoff, and a normal score does not completely rule out the condition.

What might a brain MRI show in ADAR-related HSP?

Depending on the clinical presentation, MRI may show white matter abnormalities, brain atrophy, calcifications in the basal ganglia, or injury to the striatum called striatal necrosis. These findings are not individually diagnostic, and CT may detect calcification better than MRI.

What does VUS mean on an ADAR1 genetic report?

A variant of uncertain significance, or VUS, is a DNA change that researchers do not yet know causes disease. It should not be used by itself to confirm ADAR-related HSP, change treatment, or guide testing of unaffected relatives; ask whether the laboratory will reassess it as evidence develops.

What is the difference between heterozygous and biallelic results?

Heterozygous means that one copy of the ADAR1 gene has the reported change, while biallelic means that changes are present in both copies. The significance depends on the exact changes and clinical context, so a genetics professional should interpret the result.

Which other conditions may need to be ruled out?

Depending on symptoms, family history, and the genetic result, clinicians may check for treatable look-alikes. Examples include X-linked adrenoleukodystrophy using very-long-chain fatty acids, homocysteine disorders using homocysteine and methionine levels, and metabolic or mitochondrial disease using tests such as urine organic acids.

Get notified when new evidence is published on ADAR-related hereditary spastic paraplegia.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.

Key takeaways

Multigene panels often provide the first genetic evaluation, while whole-exome sequencing may be considered after a negative panel or for atypical cases.
An interferon-stimulated gene signature can support evaluation but is not specific to ADAR1, has no universal cutoff, and a normal result does not exclude the condition.
Brain MRI may show white matter abnormalities, basal ganglia calcification, striatal necrosis, or brain atrophy, while CT may be more sensitive for calcification.
A variant of uncertain significance should not be used alone to confirm disease, change treatment, or guide testing of unaffected relatives.
Depending on the clinical picture, treatable mimics such as X-linked adrenoleukodystrophy, homocysteine disorders, and metabolic or mitochondrial diseases may be screened for.

References (18)

1
Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.
Méreaux JL, Banneau G, Papin M, et al.
Brain : a journal of neurology 2022; (145(3)):1029-1037 doi:10.1093/brain/awab386.
PMID: 34983064
2
Developmental Outcomes of Aicardi Goutières Syndrome.
Adang L, Gavazzi F, De Simone M, et al.
Journal of child neurology 2020; (35(1)):7-16 doi:10.1177/0883073819870944.
PMID: 31559893
3
Analysis of clinical characteristics of children with Aicardi-Goutieres syndrome in China.
Wang W, Wang W, He TY, et al.
World journal of pediatrics : WJP 2022; (18(7)):490-497 doi:10.1007/s12519-022-00545-1.
PMID: 35551623
4
Coexisting ADAR and TSHB Mutations in an Infant With Retinal Detachment and Transient Cardiomyopathy.
Draidi T, Khalil M, Kabaha A, et al.
Case reports in endocrinology 2026; (2026()):5534847 doi:10.1155/crie/5534847.
PMID: 42256321
5
Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease.
Rice GI, Kitabayashi N, Barth M, et al.
Neuropediatrics 2017; (48(3)):166-184 doi:10.1055/s-0037-1601449.
PMID: 28561207
6
Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.
Armangue T, Orsini JJ, Takanohashi A, et al.
Molecular genetics and metabolism 2017; (122(3)):134-139 doi:10.1016/j.ymgme.2017.07.006.
PMID: 28739201
7
Case Report: The JAK-Inhibitor Ruxolitinib Use in Aicardi-Goutieres Syndrome Due to ADAR1 Mutation.
Cattalini M, Galli J, Zunica F, et al.
Frontiers in pediatrics 2021; (9()):725868 doi:10.3389/fped.2021.725868.
PMID: 34778129
8
Case Report: Aicardi-Goutières Syndrome Type 6 and Dyschromatosis Symmetrica Hereditaria With Congenital Heart Disease and Mitral Valve Calcification - Phenotypic Variants Caused by Adenosine Deaminase Acting on the RNA 1 Gene Homozygous Mutations.
Liu L, Zhang L, Huang P, et al.
Frontiers in pediatrics 2022; (10()):852903 doi:10.3389/fped.2022.852903.
PMID: 35832578
9
Adar-associated Aicardi Goutières syndrome in a child with bilateral striatal necrosis and recurrent episodes of transaminitis.
van Toorn R, van Niekerk M, Moosa S, et al.
BMJ case reports 2023; (16(3)) doi:10.1136/bcr-2022-252436.
PMID: 36914176
10
Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy.
Rattay TW, Rautenberg M, Söhn AS, et al.
Scientific reports 2020; (10(1)):15093 doi:10.1038/s41598-020-71248-8.
PMID: 32934269
11
X-linked adrenoleukodystrophy as an etiological cause of progressive spastic paraplegia: A case report.
Chang MC, Yang S
The Journal of international medical research 2026; (54(3)):3000605261431607 doi:10.1177/03000605261431607.
PMID: 41871978
12
Clinical, Biochemical, Radiological, and Genetic Profile of Patients with Homocysteine Remethylation Pathway Defect and Spastic Paraplegia.
Padmanabha H, Mahale R, Christopher R, et al.
Annals of Indian Academy of Neurology 2021; (24(6)):908-916 doi:10.4103/aian.AIAN_223_21.
PMID: 35359558
13
Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.
Teive HAG, Camargo CHF, Pereira ER, et al.
Neurogenetics 2022; (23(3)):167-177 doi:10.1007/s10048-022-00688-3.
PMID: 35397036
14
Inherited metabolic diseases mimicking hereditary spastic paraplegia: a cohort of ten Egyptian patients.
Khalifa OA, Youssef TM, Mahmoud RG
Frontiers in genetics 2026; (17()):1963118 doi:10.3389/fgene.2026.1963118.
PMID: 42991214
15
Case Report: Heterozygous ADAR c.3019G>A pathogenic variant associated with variable neurological symptoms and incomplete penetrance in a four-generational family.
Bauer AK, Marquardt I, Sundermann B, et al.
Frontiers in immunology 2025; (16()):1453496 doi:10.3389/fimmu.2025.1453496.
PMID: 40755772
16
Co-occurrence of Aicardi-Goutières syndrome type 6 and dyschromatosis symmetrica hereditaria due to compound heterozygous pathogenic variants in ADAR1: a case series from India.
Sathishkumar D, Muthusamy K, Gupta A, et al.
Clinical and experimental dermatology 2021; (46(4)):704-709 doi:10.1111/ced.14531.
PMID: 33289110
17
Multi-dimensional Insight into the Coexistence of Pathogenic Genes for ADAR1 and TSC2: Careful Consideration is Essential for Interpretation of ADAR1 Variants.
Liu X, Lei M, Xue Y, et al.
Biochemical genetics 2024; (62(3)):1811-1826 doi:10.1007/s10528-023-10488-5.
PMID: 37740860
18
Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy.
Jones HF, Stoll M, Ho G, et al.
Brain & development 2022; (44(2)):153-160 doi:10.1016/j.braindev.2021.10.001.
PMID: 34702576

This page is for informational purposes only and does not constitute medical advice. A neurologist or genetics specialist should interpret your genetic, MRI, and blood-test results in the context of your symptoms.