(2010) 75:7479. This can manifest as porencephaly if the vessels rupture in utero, hemorrhagic stroke postnatally or in adults, or even small cerebral microbleeds that might go unnoticed except on MRI. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. COL4A1/A2-related disorders are dominant genetic disorders. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Neurology. The site is secure. Other patients have been reported with cysts on the liver, irregular heartbeats (supraventricular arrhythmia), and Raynaud phenomenon, which is in which the fingers or toes become numb or have a prickly sensation in response to cold due to narrowing of blood vessels. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. COL4A1 brain small-vessel disease is an autosomal dominant condition resulting from a mutation to the COL4A1 gene, located on the long arm of chromosome 13, that normally encodes for the alpha-1 chain of type IV collagen 1-6. Epub 2016 Apr 24. In affected individuals, stroke is 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. Developmental defects to the front of the eye, which also includes the ocular drainage structures between the iris and cornea, can lead to increased pressure in the eye (elevated intraocular pressure, or IOP). doi: 10.1038/gim.2014.210, 3. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. Dev Med Child Neurol. 2008 May;192(5):971-84; discussion 984-6. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. (2009) 73:187382. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. ClinVar; [VCV000389182.3]. Our review highlights that COL4A1 mutations can present for the first time in adult life with features of cerebral SVD, including subcortical hemorrhage and ischemic stroke, . Thirdly, bioinformatic tools and ACMG (20) classify p.Gly743Val as likely pathogenic due to the combination of the following criteria: (i) the p.Gly743Val variant is located in a mutational hotspot/or critical and well-established functional domain, (ii) the p.Gly743Val variant is absent from controls in the Exome Sequencing Project as reported by GeneDx (30), (iii) the p.Gly743Val variant is a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease, (iv) the variant p.Gly743Val has been previously reported, without phenotypic description in one other report [GeneDx Accession: SCV000531635.4 Submitted: (January 29, 2019)] and from one likely pathogenic [Undiagnosed Diseases Network, NIH Accession: SCV000926981.1 Submitted: (February 21, 2019)], and (v) which multiple lines of computational evidence support a deleterious effect on the gene product (see the Bioinfromatic Interpretation of Results). She, then, developed seizures which were controlled by valproic acid. Therapies are based on the specific symptoms in each individual. At the age of 12, IV-3 underwent cerebral palsy quality of life (CPQoL) questionnaires in which they expressed a satisfactory quality of life and a good relationship with other children. Meuwissen MEC, Halley DJJ, Smit LS, Lequin MH, Cobben JM, De Coo R, et al. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 128:4839. What are the different ways a genetic condition can be inherited? In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. It affects mainly young adults, children and more typically neonates. Clipboard, Search History, and several other advanced features are temporarily unavailable. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. PS: wrote thi paper and performed the review of the literature under the supervision of GN. However, in people with HANAC syndrome, these aneurysms typically do not burst. Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Science. Phone: 202-588-5700. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. 1779 Massachusetts Avenue Accessibility 1900 Crown Colony Drive Therefore, it is important to note that there is a very broad spectrum of clinical presentations with different organs affected to different degrees between patients. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. came with risks and was the hardest decision we had ever faced, yet we felt 100 TTY: (866) 411-1010 Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. The outcomes are highly variable ranging from brain hemorrhage before birth (in utero) leading to cavities in the brain (porencephaly) to mild age-related brain abnormalities that can only be observed on a specialized x-ray called magnetic resonance imaging (MRI). Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, COL4A1 is an essential component for basal membrane stability and exon mutations of COL4A1 gene mutations are responsible for a broad spectrum of systemic manifestations characterized by small vessel involvement of variable severity, including neurological ( 1) [porencephaly ( 2 - 4 ), hemorrhage ( 2, 5 - 7) and aneurysms ( 8 )], ophthalmological His bedside manner was incredible. (2011) 42:13. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The main symptom is single or repeated bleeding inside the skull (intracranial hemorrhaging) that can occur without cause (spontaneously), after trauma, or when taking drugs that slow blood clotting (anticoagulants). (18) and Staals et al. A diagnosis can be confirmed through molecular genetic testing. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Changing lives of those with rare disease. Muscle cramps can be spontaneous or triggered by exercise. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Contact a health care provider if you have questions about your health. Quincy, MA 02169 Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. seizure activity. Disclaimer. There are no standardized treatment protocols or guidelines for affected individuals. People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). In most cases, an affected person has one parent with the condition. Washington, DC 20036 Axenfeld-Rieger anomaly and cataract can cause impaired vision. Phone: 203-263-9938 Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. An official website of the United States government. doi: 10.1212/WNL.0b013e3181c3fd12, 9. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Treatment A dashed arrow indicates secondary atrophy in the left cerebral peduncle. (2014) 83:122834. Neurology. About half of people with this condition also have leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI). He smiled, caught it, and asked Zeeva if he could throw it back. Nat Methods. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. the basement membranes surrounding the body's blood vessels, National Organization for Rare Disorders (NORD), BRAIN SMALL VESSEL DISEASE 1 WITH OR WITHOUT OCULAR ANOMALIES. A variety of additional signs and symptoms have been reported in individuals with COL4A1/A2-related disorders including childhood-onset epilepsy, hemolytic anemia (a condition characterized by low levels of circulating red blood cells due to their premature destruction leading to fatigue, weakness, lightheadedness, dizziness, irritability, headaches, and pale skin color), mitral valve prolapse (flaps of the valve located between the upper and lower left heart chambers bulge or collapse during contraction allowing leakage of blood back into the left atrium). (2010) 14:1827. (2015) 84:91826. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Years published: 2019. eCollection 2022. Prenatal clinical manifestations in individuals with COL4A1/2 variants. The .gov means its official. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. 1. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. (E,F) IV-3Brain MRI showed left frontotemporal dilatation and diffusion tensor imaging (DTI) sequences demonstrated no left corticospinal tract (cranio-caudal fibers, indigo, with arrows). Would you like email updates of new search results? Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. 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, and dystonia, a group of neurological disorders characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions. Danbury, CT 06810 Bone. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. Epub 2010 Jun 17. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Bull Acad Natl Med. Neurol. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. In people with HANAC syndrome, angiopathy affects several parts of the body. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. NORD is not a medical provider or health care facility and thus can neither diagnose any disease or disorder nor endorse or recommend any specific medical treatments. We describe here the phenotype of a likely pathogenic gene variant, p.Gly743Val, which is responsible for a missense mutation in the COL4A1 gene exon 30 in a three generation family with severe hypermetropia and highly penetrant porencephaly in the absence of systemic manifestations. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). When we didnt feel we had any options left for treatment, ACS Omega. Any muscle may be affected, and cramps usually last from a few seconds to a few minutes, although in some cases they can last for several hours. I dont think we will ever be able to truly articulate our appreciation for Dr. Madsen and Boston Childrens for all that they did for Zeeva and our family. Plaisier E, Ronco P. COL4A1-Related Disorders. How are genetic conditions treated or managed? This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Stroke. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Ultrasound in utero from IV-6 (A). Please note that NORD provides this information for the benefit of the rare disease community. 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 NORDs mission. This page is currently unavailable. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma such as contact sports, and the use of anti-clotting (anticoagulant) medications, should be avoided. Suite 500 The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). Various muscles can be affected and muscle strength can become weakened. The information on this site should not be used as a substitute for professional medical care or advice.

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