doi: 10.1001/archophthalmol.2010.42, 10. Quincy, MA 02169 He also wanted to remove a shunt that was implanted in The first time he came to meet us, Zeeva threw a sock at him. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. 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. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Bookshelf The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Muscle cramps experienced by most people with HANAC syndrome typically begin in early childhood. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. National Center for Biotechnology Information. Bone. J Neurol Sci. doi: 10.1056/NEJMoa071906, 14. Am J Med Genet. official website and that any information you provide is encrypted Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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). Bennett RL, French KS, Resta RG, Doyle DL. 2018;61:765-772. The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Years published: 2019. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. This page is currently unavailable. (2002) 112:198202. Aicardi-Goutieres syndrome - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 mutations are responsible for a wide range of abnormalities affecting mainly the brain and the retinal vasculature, the anterior and posterior ocular structures and the renal glomerules. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. came with risks and was the hardest decision we had ever faced, yet we felt 100 In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). Cysts can also form in one or both kidneys, and the cysts may grow larger over time. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. (2008) 23:17. All authors contributed to the article and approved the submitted version. Berg R, Aleck A, Kaplan A. Familial porencephaly. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. J Perinatol. Genet Med. (1987) 8:4216. 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). The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. Further refinement of COL4A1 and COL4A2 related cortical malformations. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: For instance, retinal arteriolar tortuosity relates to mutations in the amino-terminal one-third of the protein while mutations causing cataracts and ocular morphologic alterations are more likely to occur, closer to the carboxy terminus (22), like the variant we report. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. The retina is the light-sensitive membrane that lines the inside of the eyes. Neurology. Phone: 617-249-7300, Danbury, CT office Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. The severity of the condition varies greatly among affected individuals. He would separate the two halves of her brain by To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). https://www.ncbi.nlm.nih.gov/pubmed/26610912. People with COL4A1-related brain small vessel disease 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). The information on this site should not be used as a substitute for professional medical care or advice. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, At least six affected families have been described in the scientific literature. Stay Informed With NORDs Email Newsletter, Launching Registries & Natural History Studies. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. After a normal neonatal period, those affected develop a rapidly progressive course involving irritability, hyperaesthesia, visual and hearing loss, severe cognitive and motor deterioration, and seizures. 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). However, in people with HANAC syndrome, these aneurysms typically do not burst. FOIA This site needs JavaScript to work properly. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. 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. eCollection 2022. NORD is a registered 501(c)(3) charity organization. Neurology. Am J Med Genet A. doi: 10.1212/01.WNL.0000123113.46672.68, 25. (2010) 75:7479. Suite 500 cuts under the microscope. She was struggling to advance both cognitively and physically because of uncontrolled epilepsy. Advanced imaging techniques can include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). In addition to the effects of a clear COL4A1 or COL4A2 mutation, large genetic studies reported associations for COL4A1/A2 with intracranial aneurysms, myocardial infarction, arterial calcification, arterial stiffness, deep intracerebral hemorrhages, lacunar ischemic stroke, reduced white matter volume and vascular leukoencephalopathy. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. government site. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. 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. Gould Syndrome is an ultra rare genetic, multi-system disorder. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. ClinVar; [VCV000389182.3]. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. If we dont have a program for you now, please continue to check back with us. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Lanfranconi S, Markus HS. IV-3 had a left hemisphere porencephalic cyst and the lack of evidence of a left corticospinal tract on tractography (Figures 3E,F), IV-5 had a porencephalic cyst on the right lateral ventricle (Figure 3C), and III-3 had leukoencephalopathy (Figure 3D). 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. MedlinePlus also links to health information from non-government Web sites. Arterial retinal tortuosity can cause episodes of bleeding within the eye following any minor trauma to the eye, leading to temporary vision loss. It is passed through families in a autosomal dominant fashion. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). In people with HANAC syndrome, angiopathy affects several parts of the body. (2014) 11:3612. What does it mean if a disorder seems to run in my family? Ultrasound in utero from IV-6 (A). View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. and transmitted securely. Gould Syndrome is often characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. Neurol. INTERNET Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. In the human genome, there are 46 chromosomes. The site is secure. Autosomal Dominant Familial Porencephaly Type I. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. The timeline for the clinical examination and ancillary tests performed is illustrated in Figure 2. (2006) 43:4905. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Accessibility Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. 1779 Massachusetts Avenue Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. These exceptions are nuanced and should be discussed with a genetic counselor. 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. 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). functional hemispherectomy. In the brain, intracerebral hemorrhage is the most frequent phenotype. This is not specific to COL4A1/A2-related disorders, and is a sign of many different types of muscle disease. 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.) 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%). COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Neurology. 1900 Crown Colony Drive (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. 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. 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). This group rarely survives beyond 2 years. 10.1161/STROKEAHA.110.581918. Dev Med Child Neurol. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. 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. When we didnt feel we had any options left for treatment, Rouaud T, Labauge P, Lasserve ET, Mine M, Coustans M, Deburghgraeve V, et al. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. The COL4A1 and COL4A2 genes were screened in proband IV-6. There are no standardized treatment protocols or guidelines for affected individuals. HANAC syndrome is caused by genetic changes in the COL4A1 gene. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. 55 Kenosia Avenue Ann Neurol. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Science. (2015) 17:84353. Therapies are based on the specific symptoms in each individual. (2012) 54:56974. (2006) 354:148996. Neurology. In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. doi: 10.1056/NEJMoa1707914, 6. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes or factors influencing the disorder make it challenging to develop a complete picture of associated symptoms and prognosis. Abnormal retinal arteries are prone to rupture causing bleeding associated with temporary loss of vision or even retinal detachments that can cause permanent vision loss. Recent findings: The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. 128:4839. Acute or chronic IOP elevation can lead to glaucoma where the increased pressure damages the optic nerve causing progressive and irreversible vision loss.