NORD gratefully acknowledges 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.
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.
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.
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.
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.
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 th. . gene mutation that causes autosomal dominant porencephaly type I. Molecular genetic testing for this disorder is available on a clinical basis.
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.
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
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., seizures).
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.
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.
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