col4a1 syndrome life expectancy col4a1 syndrome life expectancy

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. We describe, here, the phenotype of a likely pathologic variant (p.Gly743Val) in exon 30 of the COL4A1 gene, responsible for an oculo-cerebral phenotype characterized by severe hypermetropia and highly penetrant porencephaly in absence of other systemic complications. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. 55 Kenosia Avenue We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. Washington, DC 20036 Novel COL4A1 mutation in a fetus with early prenatal onset of - Nature Individuals with COL4A1 or COL4A2 mutations can also develop formation of clefts or slits in the two halves of the brain (schizencephaly) in which cerebral hemispheres are missing and replaced with sacs filled with cerebrospinal fluid (hydranencephaly), abnormal folds in the brain surface (polymicrogyria) or abnormalities in the normal laying of the neuronal cells in the brain (cortical lamination defects). Various muscles can be affected and muscle strength can become weakened. Therapies are based on the specific symptoms in each individual. (2010) 14:1827. Lenses corrected for hypermetropia. came with risks and was the hardest decision we had ever faced, yet we felt 100 Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. doi: 10.1111/j.1469-8749.2011.04198.x, 26. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Copyright 2023 by Gould Syndrome Foundation -. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. Neurol. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. [Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC): a new basement membrane-disease associated with mutations of the COL4A1 gene]. J Med Genet. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant thus, Gould Syndrome is considered Autosomal Dominant. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. He smiled, caught it, and asked Zeeva if he could throw it back. doi: 10.1056/NEJMoa053727, 7. Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. He would separate the two halves of her brain by COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Bookshelf Jeanne M, Gould DB. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. 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. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. 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. (2020). January 31, 2019 Contact a health care provider if you have questions about your health. Quincy, MA 02169 The COL4A2 test was negative. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. It is not uncommon for an unaffected parent to have a severely affected child. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual (called sporadic or de novo). Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Neurology. See our, Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome, URL of this page: https://medlineplus.gov/genetics/condition/hereditary-angiopathy-with-nephropathy-aneurysms-and-muscle-cramps-syndrome/. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. IV-3 was diagnosed with ventriculomegaly in utero. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. (2013) 73:4857. Ophthalmological features associated with COL4A1 mutations. September 2003. Genet Med. Painful muscle cramps can occur and can develop before three years of age. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. For example, an individual may carry genetic variants elsewhere in their genome that confers protection or susceptibly to the mutation and environmental experiences (trauma, anticoagulant use, physical exertion etc.) Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. What does it mean if a disorder seems to run in my family? COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. doi: 10.1212/01.WNL.0000123113.46672.68, 25. HANAC syndrome is caused by genetic changes in the COL4A1 gene. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES Figure 3. Keywords: COL4A1, Type IV collagen, familial porencephaly, ocular malformations, variable expressivity, Citation: Scoppettuolo P, Ligot N, Wermenbol V, Van Bogaert P and Naeije G (2020) p.Gly743Val Mutation in COL4A1 Is Responsible for Familial Porencephaly and Severe Hypermetropia. In the brain, intracerebral hemorrhage is the most frequent phenotype. 2012;21:R97-R110. Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Curr Opin Neurol. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. The COL4A1 and COL4A2 genes were screened in proband IV-6. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Muscle cramps can be spontaneous or triggered by exercise. Orphanet: HANAC syndrome Standardized (15) familiar pedigree is showed in Figure 1. Your support helps to ensure everyones free access to NORDs rare disease reports. A dashed arrow indicates secondary atrophy in the left cerebral peduncle. (2005) 308:116771. All individuals with this condition have arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eyes (arterial retinal tortuosity). Molecular Dynamics Investigation on the Effects of Protonation and Lysyl Hydroxylation on Sulfilimine Cross-links in Collagen IV. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. doi: 10.1001/archophthalmol.2010.42, 10. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Lanfranconi S, Markus HS. Rarely, affected individuals will have a condition called Raynaud phenomenon in which the blood vessels in the fingers and toes temporarily narrow, restricting blood flow to the fingertips and the ends of the toes. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). Eur J Med Genet. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. 10.1161/STROKEAHA.110.581918. cuts under the microscope. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. The retina is the light-sensitive membrane that lines the inside of the eyes. It affects mainly young adults, children and more typically neonates. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. The team may eventually include pediatric neurologists (diagnose and treat disorders of the brain, nerves and nervous system in children); ophthalmologists (who specialize in eye disorders) hematologists (who specialize in blood disorders); cardiologists (who specialize in heart disorders, nephrologists (who specialize in kidney disorders) and other healthcare professionals may need to systematically and comprehensively plan treatment. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. People with HANAC syndrome develop kidney disease (nephropathy). The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Front. The site is secure. Pediatricians are physicians who specialize in the childhood disorders and are often the first to detect patients with COL4A1/A2-related disorders. In most people, small vessel disease in the brain does not cause symptoms. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. What does it mean to have a COL4A1 gene mutation: The COL4A1 gene provides instructions for making one component of type IV collagen, which is a flexible protein important in the structure of many. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Epub 2022 Apr 14. Going from having seizures every day for six years to having no seizures is nothing short of a miracle. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). COL4A1 -Related Disorders - PubMed Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (2014) 11:3612. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1. 8600 Rockville Pike Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. 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). The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. In a retrospective study of 52 patients with COL4A1 mutations, stroke occurred in 17.3% of subjects and MRI showed white matter abnormalities (63.5%), subcortical microbleeds (52.9%), porencephaly (46%), enlarged spaces around blood vessels, (19.2%), and small infarctions (13.5%). Axenfeld-Rieger anomaly involves underdevelopment and eventual tearing of the colored part of the eye (iris) and a pupil that is not in the center of the eye. Ultrasound in utero from IV-6 (A). COL4A1 mutations as a monogenic cause of cerebral It is important to discuss these concepts with a genetic counselor and understand their implications. Type IV collagen networks play an important role in the basement membranes in virtually all tissues throughout the body, particularly the basement membranes surrounding the body's blood vessels (vasculature). However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Genet Med. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Matrix Biol. (2014) 34:757. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Six alpha chains of type IV. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Gould Syndrome Foundation (COL4a1/COL4A2) - NORD (National Organization The information on this site should not be used as a substitute for professional medical care or advice. What are the different ways a genetic condition can be inherited? 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. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Axenfeld-Rieger is a collection of abnormalities affecting the front of the eye including the iris (colored part of the eye) and cornea (abnormally small corneas called microcornea), which is the transparent membrane that covers the eyes. She, then, developed seizures which were controlled by valproic acid. The information on this site should not be used as a substitute for professional medical care or advice. Bull Acad Natl Med. PMC Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. J Perinatol. 2010 Aug;41(8):e513-8. Cesarean delivery for pregnancies with fetus at risk for a COL4A1-related disorder is recommended to prevent brain vascular injury attributable to birth trauma during delivery (6). Childhood presentation of COL4A1 mutations. (2017) 5758:2944. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Epub 2016 Apr 24. Front Aging Neurosci. The signs and symptoms can manifest at almost any age from before birth to old age. For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. doi: 10.1056/NEJMoa1707914, 6. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. 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. Dr. Madsen suggested Zeeva have an operation called a Neurology. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. 1900 Crown Colony Drive All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. In most cases, an affected person has one parent with the condition. Hum Mol Genet. doi: 10.1111/cge.12379, 13. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. doi: 10.1038/nmeth.2890, 22. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. Axenfeld-Rieger anomaly is associated with various other eye abnormalities, including underdevelopment and eventual tearing of the colored part of the eye (iris), and a pupil that is not in the center of the eye. Neurology. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). Focke JK, Veltkamp R, Bauer P, Kraemer M. J Neurol. What does it mean if a disorder seems to run in my family? Contact a health care provider if you have questions about your health. The pathogenic mechanisms of COL4A1 mutations are not fully elucidated and may vary according to the mutation type, the affected exon (mutations responsible for systemic HANAC syndrome cluster at exon 24 and 25), the position of the mutation within the triple-helix domain, and the mutation location. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Sue. Bethesda, MD 20894, Web Policies Fax: 203-263-9938, Washington, DC Office Breedveld G, De Coo IF, Lequin MH, Arts WFM, Heutink P, Gould DB, et al. Disease Overview. Children with the most severe brain malformations may have: Intellectual impairment Seizures Hydrocephalus Spasticity People who have a disorder of the corpus callosum typically have: Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. Early intervention is important in ensuring that children with reach their highest potential. NORD strives to open new assistance programs as funding allows. The first time he came to meet us, Zeeva threw a sock at him. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. https://www.ncbi.nlm.nih.gov/pubmed/20558831, Alamowitch S, Plaisier E, Favrole P, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. While there are other explanations, parental mosaicism should be considered. National Library of Medicine People with this condition may have a bulge in one or multiple blood vessels in the brain (intracranial aneurysms). It looks like nothing was found at this location. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. The COL4A1 gene mutations that cause COL4A1-related brain small-vessel disease result in the production of a protein that disrupts the structure of type IV collagen. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. 2018;91:e2078-e2088. 2010;41:e513-518. A diagnosis can be confirmed through molecular genetic testing. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. These disorders include autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukodystrophy (CARASIL), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Fabry disease, and a variety of leukodystrophies, rare progressive metabolic disorders that affect the brain, spinal cord and often the peripheral nerves. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome The .gov means its official. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Gould Syndrome is an ultra rare genetic, multi-system disorder. Collagen type IV alpha 1 (COL4A1) silence hampers the invasion, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cells through blocking Hedgehog signaling pathway. ACS Omega. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies, https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, https://www.ncbi.nlm.nih.gov/pubmed/28254515, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, https://www.nature.com/articles/gim2014210, https://www.ncbi.nlm.nih.gov/pubmed/23225343, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, https://www.ncbi.nlm.nih.gov/pubmed/22868088, https://www.ncbi.nlm.nih.gov/pubmed/22574627, https://www.ncbi.nlm.nih.gov/pubmed/20558831, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, https://www.ncbi.nlm.nih.gov/pubmed/26610912, https://www.ncbi.nlm.nih.gov/books/NBK7046/, https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet, https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/, https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/, https://rarediseases.org/patient-assistance-programs/caregiver-respite/, Learn more about Patient Assistance Programs >, Arginine: Glycine Amidinotransferase Deficiency, https://rarediseases.org/non-member-patient/epilepsy-foundation/, Gould Syndrome Foundation (COL4a1/COL4A2), https://rarediseases.org/non-member-patient/gould-syndrome-foundation-col4a1-col4a2/, https://rarediseases.org/non-member-patient/national-kidney-foundation/, https://rarediseases.org/non-member-patient/nih-national-eye-institute/, NIH/National Institute of Neurological Disorders and Stroke, Aromatic L-Amino Acid Decarboxylase Deficiency, https://rarediseases.org/non-member-patient/nih-national-institute-of-neurological-disorders-and-stroke/, https://rarediseases.org/non-member-patient/the-arc/, Learn more about Patient Organization & Membership >, HANAC: hereditary angiopathy, nephropathy and cramps syndrome (OMIM #611773), POREN1: autosomal dominant type 1 porencephaly; porencephaly with infantile hemiplegia (OMIM #175780, RATOR: retinal arterial tortuosity (OMIM #180000), BSVD: brain small vessel disease with or without ocular anomalies (OMIM #607595), ICH: susceptibility to intracerebral hemorrhage (OMIM #614519). Matrix Biol. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. 128:4839. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. No microbleeds or cystic cavities were found. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability.