Am J Med Genet A. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. doi: 10.1038/gim.2015.30, 21. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Hereditary cerebral small vessel diseases: a review. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. In the human genome, there are 46 chromosomes. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. Neuropediatrics. Epub 2016 Apr 24. In most people, small vessel disease in the brain does not cause symptoms. Phone: 203-263-9938 (2011) 42:13. FOIA COL4A1 and COL4A2 are on Chr. 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. Science. There are notable differences in the specific signs and symptoms (clinical heterogeneity), and different organs are affected to different degrees between patients even among members of a family who carry the same gene mutation. Six alpha chains of type IV. When this enzyme is elevated, it is a sign of muscle damage. doi: 10.1056/NEJMoa053727, 7. Unauthorized use of these marks is strictly prohibited. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. 30. The first time he came to meet us, Zeeva threw a sock at him. We are a registered 501(c)3 Nonprofit dedicated to providing hope and help to children and adults with Gould Syndrome; affecting COL4A1 and COL4A2 genes. 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: Standardized (15) familiar pedigree is showed in Figure 1. Therapies are based on the specific symptoms in each individual. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Childhood presentation of COL4A1 mutations. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. When these ropes are secreted, they assemble into net-like structures outside the cells. Autosomal Dominant Brain Small Vessel Disease. In the back of the eye, affected individuals have also twisting or distortion (tortuosity) of arteries in the retina (bilateral retinal arterial tortuosity) as part of the syndrome or as an isolated finding. Purpose of review: Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. doi: 10.1111/cge.12543. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. Gould Syndrome is a rare, genetic, multi-system disorder. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. The reference sequences were NM_001845.4 (NP_001836.2) for COL4A1 and NM_001846.2 (NP_001837.2) for COL4A2. (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). The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. Bull Acad Natl Med. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Not only did Dr. Madsen, help heal Zeevas brain, but he was instrumental in supporting us as we founded the Gould Syndrome Foundation, a 501(c)(3) non-profit that promotes education, advocacy, and medical advancements in Gould Syndrome, COL4A1/COL4A2 diseases. Shah S, Kumar Y, McLean B, Churchill A, Stoodley N, Rankin J, et al. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. 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. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. doi: 10.1056/NEJMoa071906, 14. Neurol. 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. Ophthalmological features associated with COL4A1 mutations. This condition causes mutations in genes that produce a specific type of collagen. In the brain, intracerebral hemorrhage is the most frequent phenotype. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Unable to load your collection due to an error, Unable to load your delegates due to an error. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. 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. doi: 10.1055/s-0031-1275343, 24. Probands' father had severe hypermetropia and bilateral cataracts. mutations: a novel genetic multisystem disease. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. Neurology. An official website of the United States government. (No doctor had ever taken a call on their lunch break to speak with me). Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. The COL4A1 and COL4A2 genes were screened in proband IV-6. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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. 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. Internet. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Dr. Madsen suggested Zeeva have an operation called a People listened to us and to Zeeva in a very different and proactive way. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. National Institute of Neurological Disorders and Stroke. Lecordier S, Manrique-Castano D, El Moghrabi Y, ElAli A. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. (18) and Staals et al. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. 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. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. What are the different ways a genetic condition can be inherited? Molecular analysis was performed on a gDNA level by means of PCR amplification of all the coding exons and the flanking intron region. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. 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. (1982) 40:5679. Last updated: doi: 10.1038/gim.2014.210, 3. eCollection 2022 Nov 8. Am J Neuroradiol. Please enable it to take advantage of the complete set of features! Eur J Med Genet. 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. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. When we didnt feel we had any options left for treatment, Gould Syndrome is an ultra rare genetic, multi-system disorder. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. It affects mainly young adults, children and more typically neonates. Teaching families how to advocate for their loved ones and access medical information. Ann Neurol. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). NORD is a registered 501(c)(3) charity organization. (2017) 5758:2944. Since fewer than 100 families have been reported, the exact prevalence of COL4A1-related disorders is not well-established. 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. Full ophthalmological evaluations including slit lamp and fundoscopy were realized and disclosed for bilateral hypermetropia in IV-3 [15 dioptre (D)], IV-6 (8.5 D), IV-5 (10 D), and III-3 (7 D). 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. 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). Individuals with this condition are at increased risk of having more than one stroke in their lifetime. 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. ACS Omega. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. can also contribute. Mutated patients develop a diffuse small vessel disease of the brain as shown by a diffuse leukoencephalopathy on MRI. 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. doi: 10.2214/ajr.149.2.351, 19. Suite 500 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. We believe that the variant p.Gly743Val is likely pathogenic for several reasons. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Childhood presentation of COL4A1 mutations. Lanfranconi S, Markus HS. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. The severity of the condition varies greatly among affected individuals. 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 (24), hemorrhage (2, 57) and aneurysms (8)], ophthalmological (912) (retinal artery tortuosity, Axenfeld Rieger anomalies, cataracts, and severe hypermetropia), renal (13) (renal cysts, and microscopic hematuria), and systemic (13) findings (cramps with a high creatine kinase level [CK], Raynaud's phenomenon, and arrhythmias). Phone: 202-588-5700. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Stroke. came with risks and was the hardest decision we had ever faced, yet we felt 100 Accessibility for the triple helical CB3[IV] domain. This site needs JavaScript to work properly. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. doi: 10.1016/j.matbio.2016.10.003, 23. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. 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. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Contact a health care provider if you have questions about your health. This can lead to problems 1) if too much of the misfolded protein accumulates within cells, 2) if not enough of the protein exits the cells to form networks, and 3) occasionally, the presence of the mutant proteins outside the cells can interfere with the structure of the network. Phone: 617-249-7300, Danbury, CT office 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/. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 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. She, then, developed seizures which were controlled by valproic acid. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Pathology. 1. Berg R, Aleck A, Kaplan A. Familial porencephaly. HANAC syndrome is a rare condition, although the exact prevalence is unknown. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. Cerebral small vessel disease with hemorrhage is likely milder continuum from porencephaly and exhibits many of the same symptoms (with the exception of the brain cavities). The p.Gly743Val variant is a conservative substitution that occurs in a position highly conserved across species (SIFT analysis: DeleteriousScore 0, median: 4.22, highly conserved nucleotide and amino acid, up to Tetraodon considering 11 species) and affects a crucial and abundant residue within the triple-helix-forming collagenous domain of the protein, which consist of long stretches of Gly-X-Y repeats. NORD strives to open new assistance programs as funding allows. Autosomal Dominant Familial Porencephaly Type I. 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. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 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. For example, if the mutation arises during the formation of the sperm or the egg, then all of the cells that make up the child will carry the mutation. 2021 Sep 10;13:727590. doi: 10.3389/fnagi.2021.727590. Background: COL4A1 mutations cause familial porencephaly, infantile hemiplegia, cerebral small vessel disease (CSVD), and hemorrhagic stroke. 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. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. Mutations in COL4A1 or COL4A2 cause Gould Syndrome and, because these two proteins are found in almost all tissues; nearly any organ can be affected. doi: 10.1001/archneur.1983.04050080067013, 17. Careers. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. (2014) 15:16. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. Federal government websites often end in .gov or .mil. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Matrix Biol. (2007) 357:268795. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. 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. doi: 10.1007/s10897-008-9169-9, 16. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. Neurology. The information on this site should not be used as a substitute for professional medical care or advice. Doctors and researchers to bring research and medical therapeutic options to those affected. Fax: 203-263-9938, Washington, DC Office This group rarely survives beyond 2 years. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. Given the variable expressivity of these mutations, COL4A1/A2-related disorders are likely under diagnosed and the exact number of people who have these disorders is unknown. 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, . 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). 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 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). Please note that NORD provides this information for the benefit of the rare disease community. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: Going from having seizures every day for six years to having no seizures is nothing short of a miracle. Type IV collagen molecules attach to each other to form complex protein networks. 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). Genetic counseling will be proposed when IV-3 and IV-6 intend to start a family as there is a 50% risk of mutation transmission to the next generation and potential obstetrical complications. What is the prognosis of a genetic condition? Muscle cramps can be spontaneous or triggered by exercise. Additional features 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. Please note that NORD provides this information for the benefit of the rare disease community. Genet Med. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. 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. (2002) 112:198202. 2009 Jun 25 [Updated 2016 Jul 7]. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 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. The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. 2011 Various muscles can be affected and muscle strength can become weakened. (2005) 308:116771. HHS Vulnerability Disclosure, Help U.S. Department of Health and Human Services, Autosomal dominant familial hematuria, retinal arteriolar tortuosity, contractures, Hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome. How are genetic conditions treated or managed? HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. The .gov means its official. It is ubiquitously expressed in many tissues and cell types. doi: 10.1212/WNL.0b013e3181c3fd12, 9. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. Facebook: https://www.facebook.com/Col4A1Foundation Please Note Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. seizure activity. Patients must rely on the personal and individualized medical advice of their qualified health care professionals before seeking any information related to their particular diagnosis, cure or treatment of a condition or disorder. 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). mutations: a novel genetic multisystem disease. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. doi: 10.1126/science.1109418, 5. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. Years published: 2019. It is important to discuss these concepts with a genetic counselor and understand their implications. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. (2004) 62:16135. This is called genotype-phenotype correlation. Firstly, it segregates within the family with the phenotype. doi: 10.1111/cge.12379, 13. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected.