Skip to content
How It Works
Explore
Ask a Question Resources Pricing
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 15 peer-reviewed journal articles Updated
Neurology

How PADMAL is Diagnosed: MRI and Genetics

At a Glance

PADMAL is suspected when MRI shows clustered small holes in the pons—the “raisin bread” sign—and confirmed by a disease-causing COL4A1 change. Testing must include the 3′-UTR region, and routine checks for other stroke causes may still be needed.

Diagnosing PADMAL requires connecting a highly specific pattern on a brain MRI with a confirmed genetic change in the COL4A1 gene [1][2].

However, diagnosing PADMAL does not mean your doctors can skip standard stroke evaluations. A person with a genetic small vessel disease can still have atrial fibrillation, atherosclerosis, or another concurrent, treatable cause of stroke [3][4]. Therefore, your diagnosis will run parallel to routine vascular checks.

The MRI “Signature”

While many small vessel diseases affect the entire brain, PADMAL often has a “bottom-up” appearance, starting heavily in the brainstem [5][6].

The Raisin Bread Sign

Doctors often look for what is called the raisin bread sign [6]. On an MRI, the pons (the middle part of your brainstem) normally looks solid and uniform. In PADMAL, the pons becomes dotted with multiple small, oval-shaped lacunes—tiny holes left behind by microscopic strokes [5][7]. These clustered spots resemble raisins scattered through a loaf of bread [6].

  • Early Detection: This sign is strongly suggestive of PADMAL and can often be seen on an MRI years before a person has their first symptom [5][6].
  • Progression: Over time, similar spots and “white matter hyperintensities” (areas of scarring) can appear in the supratentorial region—the upper parts of the brain including the thalamus and deep white matter [8][9].

Formal Genetic Diagnosis

While an MRI can suggest PADMAL, a genetic test is required for a definitive diagnosis [2]. This usually involves Whole Exome Sequencing (WES) or a targeted “Small Vessel Disease Panel.”

It is important to know that standard genetic tests can sometimes miss PADMAL [2]. Most genetic tests focus on the “coding regions” (the parts of the gene that build proteins). However, the PADMAL mutation is located in the 3’-UTR, a “non-coding” regulatory region at the very end of the gene [1][7]. A negative standard panel does not exclude PADMAL unless the laboratory confirms that the relevant 3’-UTR region was explicitly assessed [2].

Additionally, the lab must classify the finding. A “pathogenic” or “likely pathogenic” variant confirms the disease, whereas a “variant of uncertain significance” (VUS) means the lab found a change but doesn’t yet know if it causes disease; a VUS should not be used to test healthy family members [2].

The Differential Diagnosis

During the diagnostic process, your neurology team must distinguish PADMAL from other conditions that cause “early-onset” small vessel disease [3].

Condition Primary Gene Key Features
PADMAL COL4A1 (3’-UTR) “Raisin bread” spots centered in the pons; predominantly ischemic, though microbleeds occur [6][5].
CADASIL NOTCH3 Most common genetic form; often shows damage in the anterior temporal poles and may include migraines [10][11].
CARASIL / HTRA1 HTRA1 Biallelic variants cause classic CARASIL (balding, severe back pain); heterozygous variants cause an autosomal-dominant small-vessel phenotype without those specific signs [12][13].
Sporadic SVD Multifactorial Associated with aging, hypertension, and other vascular risks; usually seen in older patients, but can overlap with genetic findings [14][3].

Understanding exactly which genetic condition you have allows your doctors to tailor your counseling, anticipate specific systemic issues (like eye or kidney changes, which vary by mutation), and carefully weigh the risks and benefits of stroke prevention medications [2][15].

Common questions in this guide

What does the raisin bread sign mean on a PADMAL MRI?
The raisin bread sign is a cluster of small, oval lacunes in the pons on a brain MRI. These tiny cavities reflect prior microscopic strokes and can strongly suggest PADMAL, sometimes before symptoms appear.
Can an MRI diagnose PADMAL by itself?
No. MRI can strongly suggest PADMAL, but a definitive diagnosis requires a genetic finding in COL4A1 that the laboratory classifies as pathogenic or likely pathogenic.
Can a standard genetic panel miss PADMAL?
Yes, a standard panel can miss PADMAL if it mainly examines protein-coding regions. The relevant PADMAL change is in the 3′-UTR, so the laboratory should confirm that this regulatory region was included.
What does a variant of uncertain significance mean for PADMAL?
A variant of uncertain significance is a genetic change whose effect on disease is not yet known. It does not establish PADMAL and should not be used by itself to test healthy relatives.
Why do I still need routine stroke tests after a PADMAL diagnosis?
PADMAL can coexist with atrial fibrillation, atherosclerosis, or another treatable cause of stroke. Doctors may still recommend evaluations such as heart monitoring and vascular imaging.
How is PADMAL distinguished from CADASIL or HTRA1-related disease?
PADMAL is associated with a COL4A1 change and a pons-centered raisin bread pattern. CADASIL is linked to NOTCH3 and often affects the anterior temporal poles, while HTRA1-related disease can have different inheritance patterns and features.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my MRI show the 'raisin bread' pattern of oval spots in the pons, and are there signs of 'supratentorial' involvement yet?
  2. 2.Did my genetic testing specifically include the 3'-UTR region of the COL4A1 gene, or was it a standard panel that might have missed the regulatory areas?
  3. 3.Are there findings on my imaging—such as temporal pole changes—that suggest we should also consider NOTCH3 or HTRA1 mutations?
  4. 4.Is my variant considered 'pathogenic', 'likely pathogenic', or a 'variant of uncertain significance'?
  5. 5.Given my imaging and genetics, what common stroke tests (like heart monitors or ultrasounds) are still necessary to rule out overlapping conditions?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (15)
  1. 1

    Cervical Spinal Involvement in a Chinese Pedigree With Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy Caused by a 3' Untranslated Region Mutation of COL4A1 Gene.

    Zhao YY, Duan RN, Ji L, et al.

    Stroke 2019; (50(9)):2307-2313 doi:10.1161/STROKEAHA.119.024875.

    PMID: 31366314
  2. 2

    Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.

    Mancuso M, Arnold M, Bersano A, et al.

    European journal of neurology 2020; (27(6)):909-927 doi:10.1111/ene.14183.

    PMID: 32196841
  3. 3

    Monogenic causes of cerebral small vessel disease and stroke.

    Guey S, Chabriat H

    Handbook of clinical neurology 2024; (204()):273-287 doi:10.1016/B978-0-323-99209-1.00018-1.

    PMID: 39322384
  4. 4

    Free water determines diffusion alterations and clinical status in cerebral small vessel disease.

    Duering M, Finsterwalder S, Baykara E, et al.

    Alzheimer's & dementia : the journal of the Alzheimer's Association 2018; (14(6)):764-774 doi:10.1016/j.jalz.2017.12.007.

    PMID: 29406155
  5. 5

    Pontine autosomal dominant microangiopathy with leukoencephalopathy: Col4A1 gene variants in the original family and sporadic stroke.

    Roos J, Müller S, Giese A, et al.

    Journal of neurology 2023; (270(5)):2631-2639 doi:10.1007/s00415-023-11590-9.

    PMID: 36786861
  6. 6

    'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

    Kikumoto M, Kurashige T, Ohshita T, et al.

    Brain communications 2023; (5(6)):fcad281 doi:10.1093/braincomms/fcad281.

    PMID: 37953842
  7. 7

    Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.

    Verdura E, Hervé D, Bergametti F, et al.

    Annals of neurology 2016; (80(5)):741-753 doi:10.1002/ana.24782.

    PMID: 27666438
  8. 8

    A patient with pontine autosomal dominant microangiopathy and leukoencephalopathy caused by a de novo 3' untranslated region mutation of COL4A1 gene: case report and literature review.

    Xie F, Li S, Hu X, Li W

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2025; (46(6)):2833-2838 doi:10.1007/s10072-025-08025-w.

    PMID: 39976879
  9. 9

    A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy.

    Li Q, Wang C, Li W, et al.

    Translational stroke research 2022; (13(2)):238-244 doi:10.1007/s12975-021-00926-0.

    PMID: 34415564
  10. 10

    Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association.

    Meschia JF, Worrall BB, Elahi FM, et al.

    Stroke 2023; (54(10)):e452-e464 doi:10.1161/STR.0000000000000444.

    PMID: 37602377
  11. 11

    Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI.

    De Guio F, Vignaud A, Chabriat H, Jouvent E

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2018; (38(9)):1654-1663 doi:10.1177/0271678X17690164.

    PMID: 28128022
  12. 12

    "Chocolate Chip Sign" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease.

    Ando S, Saito R, Kitahara S, et al.

    Neurology. Genetics 2025; (11(2)):e200237 doi:10.1212/NXG.0000000000200237.

    PMID: 40017561
  13. 13

    Diagnostic performance of "pons chocolate chip sign" in heterozygous HTRA1-related cerebral small vessel disease.

    Guo Y, Peng Q, Yang Y, et al.

    BMC neurology 2025; (25(1)):360 doi:10.1186/s12883-025-04374-3.

    PMID: 40866829
  14. 14

    Clinical and neuroimaging review of monogenic cerebral small vessel disease from the prenatal to adolescent developmental stage.

    Enokizono M, Kurokawa R, Yagishita A, et al.

    Japanese journal of radiology 2024; (42(2)):109-125 doi:10.1007/s11604-023-01493-0.

    PMID: 37847489
  15. 15

    Recurrent Pontine Strokes in a Young Male.

    Grobe-Einsler M, Urbach H, Paus S

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2020; (29(12)):105386 doi:10.1016/j.jstrokecerebrovasdis.2020.105386.

    PMID: 33254373

This page is for informational purposes only and does not constitute medical advice. Your neurologist and genetics team should interpret your MRI and COL4A1 results and advise you about additional stroke evaluation.

Get notified when new evidence is published on Pontine autosomal dominant microangiopathy with leukoencephalopathy.

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