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Autosomal Dominant Porencephaly Type I

NORD is very grateful to 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.

Synonyms of Autosomal Dominant Porencephaly Type I

  • No synonyms found.

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Autosomal dominant porencephaly type I is a rare genetic disorder in which fluid-filled cysts and cavities develop on the surface of the brain. Autosomal dominant porencephaly type I is caused by mutations of the COL4A1 gene. Affected individuals are predisposed to damage to small blood vessels, including the small vessels within the brain. The signs and symptoms of this disorder vary greatly from one individual to another, but may include weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, varying degrees of cognitive impairment, and migraines.

Mutations of the COL4A1 gene also cause at least two other disorders - brain small vessel disease with hemorrhage and HANAC (hereditary angiopathy with neuropathy, aneurysms, and muscle cramps) syndrome. Researchers now know that these three disorders represent a spectrum or continuum of disease with overlapping features.

Symptoms

The age of onset, specific symptoms, disease progression and severity of autosomal dominant porencephaly type I vary greatly from one individual to another, even among members of the same family. The term porencephaly refers to the formation of fluid-filled cysts or cavities on the surface of the brain. The size and exact locations of such cysts and cavities contribute to the clinical variability of this disorder. In some cases, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Still other individuals may not develop any symptoms (asymptomatic) until well into adulthood. Affected individuals should talk to their physicians and medical team about their specific case and associated symptoms.

Symptoms that may occur in individuals with autosomal dominant type I porencephaly include migraines, weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, stroke, varying degrees of mental retardation, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions.

Additional features that may be associated with autosomal dominant porencephaly type I include poor or absent speech development, facial paralysis (paresis), involuntary muscle spasms (spasticity) that result in slow, stiff, rigid movements, visual field defects, and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms.

Some individuals with autosomal dominant porencephaly type I may have additional symptoms sometimes associated with mutations of the COL4A1 gene. For more information, see the COL4A1-related disorders in the Related Disorders section below.

Causes

This genetic form of porencephaly is caused by mutations of the COL4A1 gene. This genetic mutation is inherited as an autosomal dominant trait. Most individuals with autosomal dominant porencephaly type I have a parent with a COL4A1 mutation. In an unknown number of cases, the COL4A1 mutation occurs randomly for no apparent reason (de novo mutation).

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that the COL4A1 gene is located on the long arm (q) of chromosome 13 (13q34). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 13q34" refers to band 34 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

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. Mutations of the COL4A1 gene 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 mutation) 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.

Affected Populations

Autosomal dominant porencephaly type I affects males and females in equal numbers. The incidence of the disorder in the general population is unknown. Autosomal dominant porencephaly type I may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of this disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of autosomal dominant porencephaly type I. Comparisons may be useful for a differential diagnosis.

COL4A1-related disorders are a group of rare disorders characterized by damage to small blood vessels, including those in the brain. The age of onset, disease progression, specific symptoms, and disease severity varies greatly from one person to another. In addition to autosomal dominant porencephaly type I, two other disorders that are caused by COL4A1 mutations include brain small vessel disease with hemorrhage and HANAC (hereditary angiopathy with neuropathy, aneurysms, and muscle cramps) syndrome. Symptoms may include paralysis on one side of the body (hemiparesis or hemiplegia), migraines, stroke, and cognitive impairment. HANAC syndrome is associated with systemic disease and can involve the kidneys, muscles and small blood vessels of the eyes. In some individuals, including adults who previously had no symptoms, the first symptom of a COL4A1 mutation is intracerebral hemorrhaging or bleeding in the brain caused by rupturing of blood vessels within the head. Affected individuals may also experience stroke-like symptoms. COL4A1-related disorders are inherited as autosomal dominant traits.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare genetic disorder characterized by damage to small- and medium-sized blood vessels, especially those in the brain. CADASIL potentially causes a wide variety of symptoms including migraines, strokes, cognitive impairment, speech problems, vision abnormalities and changes in personality and behavior. CADASIL eventually progresses to cause dementia. Affected individuals may be at a higher risk than the general population of developing a heart attack. The symptoms, age of onset, and disease progression vary greatly from individual to another. CADASIL is caused by mutations of the NOTCH3 gene located on chromosome 19. (For more information on this disorder, choose "CADASIL" as your search term in the Rare Disease Database.)

Sporadic porencephaly is a rare disorder affecting the central nervous system. In porencephaly, cysts or cavities form on the surface of the brain. These cysts or cavities may become filled with cerebrospinal fluid, a colorless fluid that normally surrounds the brain and spinal cord to provide protection and nourishment. The severity and associated symptoms of porencephaly vary dramatically from one person to another based upon the size and exact locations of the fluid-filled cavities or cysts. Some infants develop serious complications shortly after birth; others individuals may have mild symptoms that may go undetected. (For more information on this disorder, choose "sporadic porencephaly" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of autosomal dominant porencephaly type I is 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 particular organs and bodily tissues.

A diagnosis can be confirmed by molecular genetic testing, in which a person’s DNA is examined for the gene mutation that causes autosomal dominant porencephaly type I. Molecular genetic testing for this disorder is available on a clinical basis.

Treatment
The treatment of autosomal dominant porencephaly type I 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. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma and the use of anti-clotting (anticoagulant) medications should also be avoided.

Early intervention is important in ensuring that children with autosomal dominant porencephaly type I 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.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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

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

Organizations related to Autosomal Dominant Porencephaly Type I

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

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. Updated:March 8, 2011. COL4A1-Related Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org Accessed:January 29, 2013.

National Institute of Neurological Disorders and Stroke. Porencephaly Information Page.May 6, 2010. Available at: http://www.ninds.nih.gov/disorders/porencephaly/porencephaly.htm Accessed:January 29, 2013.

National Institute of Neurological Disorders and Stroke. Cephalic Disorders Fact Sheet. March 16, 2012. Available at: http://www.ninds.nih.gov/disorders/cephalic_disorders/detail_cephalic_disorders.htm Accessed:January 29, 2013.

Van Regemorter N, van Bogaert P. Familial Porencephaly. Orphanet encyclopedia, April 2006. Available at: http://www.orpha.net/data/patho/Pro/en/PorencephalyFamilial-FRenPro2654.pdf Accessed:January 29, 2013.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/02/07 00:00:00 GMT+0

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