• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • Resources
  • References
  • Programs & Resources
  • Complete Report
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Brain Small Vessel Disease 1 With or Without Ocular Anomalies

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Last updated: 10/23/2024
Years published: 2010, 2013, 2016, 2019, 2023, 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Jeffrey A. Kuller, MD, Professor of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Duke University Medical Center, for assistance in the preparation of this report.


Disease Overview

Brain small vessel disease 1 with or without ocular anomalies (BSVD1) is a rare genetic disorder in which fluid-filled cysts and cavities develop on the surface of the brain. Affected people are more likely to have damage in their small blood vessels, including those in the brain. The signs and symptoms that may present reflect the location and severity of the vascular defect and, thus, vary greatly from person to person. Signs and symptoms can include weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, cognitive impairment (ranging from mild to severe) and migraines.
BSVD1 is caused by changes (disease-causing variants) in the COL4A1 gene. Inheritance is  autosomal dominant pattern, meaning only one copy of the altered gene is enough to cause the condition. Treatment is focused on managing the specific symptoms that each affected person has.
BSVD1 is considered as part of the spectrum of COL4A1-related disorders or part of a condition known as COL4A1/A2-related disorders that include diseases that can be caused by variants in the COL4A1 and/or in the COL4A2 genes and which may include:
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Synonyms

  • Gould syndrome 1
  • hemiplegia, infantile, with porencephaly
  • brain small vessel disease with hemorrhage
  • retinal arteriolar tortuosity, infantile hemiparesis and leukoencephalopathy, AD
  • brain small vessel disease with Axenfeld-Rieger anomaly
  • porencephaly, type 1, autosomal dominant, formerly; ADPTIP, formerly
  • porencephaly 1, formerly; poren1, formerly
  • porencephaly, type 1, formerly; TIP, formerly
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Signs & Symptoms

The age of onset, specific symptoms, disease progression and severity of BSVD1 vary greatly from one person to another, even among members of the same family.

In some children, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Other affected people may not develop any symptoms until well into adulthood. Affected individuals should talk to their physicians and medical team about their specific medical history and associated symptoms.

Symptoms that may occur in individuals with BDSV1 include:

  • Weakness of the facial muscles (facial paresis) resulting from damage to the facial nerve
    Eye and vision problems such as:

    • Visual field defects
    • Blurred vision due to an imperfection in the curvature of the cornea or lens of the eye (astigmatism)
    • Crossed eyes (strabismus)
    • Nearsightedness (myopia)
    • Clouding of the lens of the eye (cataract)
    • Increased pressure inside the eye (glaucoma)
    • Axenfeld-Rieger anomalies (underdevelopment (hypoplasia) and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye)
    • Arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity) which may cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss
  • Vascular problems such as weakening of the blood vessels in the brain which may result in:
    • Stroke (often the first symptom), typically occurring in mid-adulthood and usually caused by bleeding in the brain (hemorrhagic stroke) rather than a lack of blood flow in the brain (ischemic stroke), although either type can occur
  • Neurologic problems including:
    • Leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI)
    • Seizures
    • Migraine headaches accompanied by visual sensations known as auras
    • Paralysis of one side of the body (hemiparesis or hemiplegia)
    • Varying degrees of intellectual disability
    • Dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions
    • Poor or absent speech development
    • Involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements
    • Hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the brain causes pressure on the tissues of the brain, resulting in a variety of symptoms
    • Development of fluid-filled cavities or cysts on the brain (porencephaly) that can delay and impair growth and development
  • Hemolytic anemia, a disorder in which red blood cells are destroyed (hemolysis) faster than they can be made

Some affected individuals may have additional symptoms sometimes associated with variants in the COL4A1 gene. For more information, see the COL4A1-related disorders in the Disorders with Similar Symptoms section below.

 

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Causes

BSVD1 is caused by variants in the COL4A1 gene. The COL4A1 gene contains instructions for creating a protein known as collage type IV. Collagen type IV is essential for the proper strength and function of the vascular basement membrane, which is the thin membrane that lines blood vessels. Variants in the COL4A1 gene can result in deficient levels or defective function of collagen type IV, which, in turn, results in structural weakening of the vascular basement membrane predisposing blood vessels to damage or rupture. Because the blood vessels are structurally weakened, environmental factors such as trauma (including birth trauma in infants with a COL4A1 variant) are much more likely to cause rupture or damage to the vessels. Damaged blood vessels within the skull result in bleeding on the brain or lack of blood flow (ischemia) to the brain and, subsequently, damage to brain tissue. The cavities or cysts that characterize porencephaly form at the sites of brain tissue damage.

Inheritance is autosomal dominant. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Most individuals with BDSV1 have a parent with a disease-causing variant in the COL4A1 gene. In an unknown number of cases, the COL4A1 variant occurs randomly for no apparent reason (de novo) and is not inherited from a parent.

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Affected populations

BDSV1 affects males and females in equal numbers. The incidence of the disorder in the general population is unknown. This condition may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency.

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Diagnosis

A diagnosis of BDSV1 may be suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as advanced imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues.

A diagnosis can be confirmed by molecular genetic testing, in which a person’s DNA is tested for variants in the COL4A1 gene. Molecular genetic testing for this disorder is available on a clinical basis.

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Standard Therapies

The treatment for BDSV1 is geared toward the specific symptoms that are present in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke.

Early intervention is important in ensuring that children with BDSV1 reach their highest potential. Services that may be beneficial for some affected individuals include medical, social and/or vocational services such as special remedial education.

Smoking, which increases the risk of stroke, physical activities that can cause head trauma and the use of anti-clotting (anticoagulant) medications should be avoided.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., seizures).

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References

JOURNAL ARTICLES
Vahedi K, Kubis N, Boukobza M, et al. COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage. Stroke. 2007;38:1461-1464.

Van der Knaap MS, Smit LME, Barkhof F, et al. Neonatal porencephaly and adult stroke related to mutations in collagen IV A1. Ann Neurol. 2006;59:504-511.

Breedveld G, de Coo IF, Lequin MH, et al. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet. 2006;43:490-495.

Gould DB, Phalan FC, van Mil SE, et al. Role of COLA41 in small-vessel disease and hemorrhagic stroke. N Eng J Med. 2006;354:1489-1496.

Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005;308:1167-1171.

INTERNET
Plaisier E, Ronco P. COL4A1-Related Disorders. 2009 Jun 25 [Updated 2016 Jul 7]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed Nov 30, 2022.

National Institute of Neurological Disorders and Stroke. Porencephaly Information Page. Last reviewed July 25, 2022. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Porencephaly-Information-Page Accessed Nov 30, 2022.

van Bogaert P. Porencephaly. Orphanet. June 2019. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=99810 Accessed Nov 30, 2022.

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Programs & Resources

RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


National Organization for Rare Disorders