PV and VW followed the children at the Neuropediatrics clinic of the same hospital. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Bookshelf (2014) 34:757. In the human genome, there are 46 chromosomes. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Endovascular therapy is a minimally-invasive procedure in which a long, thin tube called a catheter is passed into the blood vessel to repair or strengthen the blood vessel. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. 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). Neurology. All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. It is passed through families in a autosomal dominant fashion. Some individuals do not have any observable symptoms (asymptomatic); others can develop severe, even life-threatening complications. She, then, developed seizures which were controlled by valproic acid. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Most individuals diagnosed with a COL4A1-related disorder have an affected parent. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. 2011 Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P, How are genetic conditions treated or managed? These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. cuts under the microscope. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Cavalin M, Mine M, Philbert M, et al. ACS Omega. Plaisier E, Ronco P. COL4A1-Related Disorders. BMC Med Genet. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. Interestingly, COL4A1 and COL4A2 mutations appear to lead to generally similar outcomes although COL4A2 mutations occur less frequently. small vessel disease: a systematic review. doi: 10.1055/s-0031-1275343, 24. What are the different ways a genetic condition can be inherited? Firstly, it segregates within the family with the phenotype. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. Fax: 203-263-9938, Washington, DC Office Clipboard, Search History, and several other advanced features are temporarily unavailable. (2015) 17:40524. Understanding what it has taken to get her to this point, though, is close to unimaginable. 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: 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). While there are other explanations, parental mosaicism should be considered. 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). Would you like email updates of new search results? Facebook: https://www.facebook.com/Col4A1Foundation Please Note In her first six years of life, Zeeva spent hundreds of nights in the hospital, had 13 operations and countless procedures, (from eye surgeries to Achilles heel, a shunt placed in her brain, and spine surgery). The COL4A1 and COL4A2 genes were screened in proband IV-6. COL4A1 Syndrome CADASIL Bull Acad Natl Med. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. Am J Med Genet A. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 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. my mom suggested we call Boston Childrens Hospital. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Individuals with HANAC syndrome also experience a variety of eye problems. doi: 10.1212/01.WNL.0000123113.46672.68, 25. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Suite 310 (2002) 112:198202. 2012;322:25-30. https://www.ncbi.nlm.nih.gov/pubmed/22868088, Shah S, Ellard S, Kneen R, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 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). Individuals with COL4A1/A2-related disorders have characteristic patterns of brain disease when viewed under advanced imaging techniques. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Danbury, CT 06810 No use, distribution or reproduction is permitted which does not comply with these terms. What is the prognosis of a genetic condition? The size and location of cerebral cavities contributes to clinical variability. Front Aging Neurosci. People with HANAC syndrome develop kidney disease (nephropathy). Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Suite 500 Mutations in the COL4A1 gene cause HANAC syndrome. 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. Various muscles can be affected and muscle strength can become weakened. Researchers are still trying to determine whether there are any specific genotype-phenotype correlations in COL4A1/A2-related disorders. People listened to us and to Zeeva in a very different and proactive way. Some affected individuals may develop weakness or paralysis of one side of the body (hemiparesis or hemiplegia) and have seizures. Resource(s) for Medical Professionals and Scientists on This Disease: We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. At least six affected families have been described in the scientific literature. The information on this site should not be used as a substitute for professional medical care or advice. Front. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. The retina was collected and immunolabeled with an anti-collagen IV antibody, for reconstruction of the entire vascular network (Fig. 55 Kenosia Avenue 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. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. (1982) 40:5679. 1779 Massachusetts Avenue This blood vessel abnormality can cause episodes of bleeding within the eyes following any minor trauma to the eyes, leading to temporary vision loss. (2015) 84:91826. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Recent findings: See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. 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.ejpn.2009.04.010, 27. 2010;17(13):1317-24. doi: 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. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. (2008) 23:17. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. (No doctor had ever taken a call on their lunch break to speak with me). Standardized (15) familiar pedigree is showed in Figure 1. official website and that any information you provide is encrypted Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Here we report a family in which three siblings presented severe hypermetropia and porencephaly. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 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. J Neurol Sci. Danbury, CT 06810 If we dont have a program for you now, please continue to check back with us. PS and NL: followed III-3 at the Erasme Neurology outpatients clinic. Other eye problems experienced by people with COL4A1-related brain small-vessel disease include clouding of the lens of the eye (cataract) and the presence of arteries that twist and turn abnormally within the light-sensitive tissue at the back of the eye (arterial retinal tortuosity). Dr. Madsen suggested Zeeva have an operation called a NCI CPTC Antibody Characterization Program. IV-5Brain MRI revealing porencephalic cyst of frontal horn of lateral right ventricle (C). The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 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. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. Changing lives of those with rare disease. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. National Library of Medicine However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Please note that NORD provides this information for the benefit of the rare disease community. . Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. 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). In cases where the mutation is inherited, the carrier parent is often clinically unaffected. 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. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Doctors and researchers to bring research and medical therapeutic options to those affected. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. In some people, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. 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. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. To use the sharing features on this page, please enable JavaScript. (2018) 91:e207888. Neurol. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Stroke. Epub 2016 Apr 24. (2008) 17:42433. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. In people with HANAC syndrome, the vasculature and other tissues within the kidneys, brain, muscles, eyes, and throughout the body weaken. Neurology. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. This is called genotype-phenotype correlation. 2010 Aug;41(8):e513-8. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). The COL4A1 stroke syndrome. The https:// ensures that you are connecting to the Subsequently, it has been recognized that autosomal dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular disease, whose onset occurs from fetal life onward and whose severity may range from small-vessel disease to fatal intraparenchymal hemorrhage.,, While epilepsy is known to be a clinical feature of porencephaly, the (2010). sharing sensitive information, make sure youre on a federal COL4A1/A2-related disorders are dominant genetic disorders. 1900 Crown Colony Drive The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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.) 4 Both . 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. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Bethesda, MD 20894, Web Policies COL4A1 codes for extracellular matrix proteins that form heterotrimers that are major components of nearly all organ basal membranes. 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. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and review of the literature. What does it mean if a disorder seems to run in my family? (19). Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Quincy, MA 02169 Zeevas brain to treat a cyst in her brain caused by porencephaly. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. Eur J Paediatr Neurol. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). This group rarely survives beyond 2 years. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. 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. https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. 2009 Jun 25 [updated 2016 Jul 7]. 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). doi: 10.1002/ana.23736, 4. Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. They are typically 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 . Epub 2022 Apr 14. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Disclaimer. The site is secure. eCollection 2021. Still other individuals may not develop any symptoms until well into adulthood. The .gov means its official. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. (2009) 73:187382. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. 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). eCollection 2022 Nov 8. Lanfranconi S, Markus HS. doi: 10.1111/cge.12543. We therefore began our analysis of mutant Col4a1 G498V mice by examining the retinal vascular network at three and nine months of age. Washington, DC 20036 The inheritance pattern is autosomal dominant (14) and age-dependent with almost 100% penetrance. If either parent also carries the mutation, it is considered inherited. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. 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). 2009 Jun 25 [Updated 2016 Jul 7]. How can gene variants affect health and development? Gould Syndrome - COL4A1 - COL4A2 genes - Gould Syndrome Foundation Gould Syndrome Foundation 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. Dev Med Child Neurol. 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). How are genetic conditions treated or managed? https://www.ncbi.nlm.nih.gov/pubmed/26610912. Washington, DC 20036 The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. N Engl J Med. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. 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. Some individuals develop cysts on the kidney. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. COL4A1 mutations as a monogenic cause of cerebral One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. 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. (2020). Clinically, COL4A1 mutations are responsible for different overlapping phenotypes including porencephaly (24), brain small vessel disease (2, 57) with or without ocular anomalies, HANAC (13) (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome, ophthalmological abnormalities (912), and non-syndromic autosomal dominant congenital cataracts (10). Affected individuals may have no observable symptoms or only isolated migraines with aura. 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. (2017) 377:111931. 2009;73:1873-1882. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881859/, Mao, M, Alavi MV, Labelle-Dumais, C, Gould DB. (2010) 14:1827. doi: 10.1056/NEJMoa1707914, 6. 11:827. doi: 10.3389/fneur.2020.00827. 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. 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. Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Matrix Biol. 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. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Migraines can occur with or without aura. doi: 10.1212/WNL.0b013e3181eee440, 28. Mutations in the gene have been linked to diseases of the brain, muscle, kidney, eye, and cardiovascular system. Mice with Col4a1 and Col4a2 gene mutations have pathology in many organs and the presence and severity of pathology in a given organ appears to depend on the location of the mutation, genetic context, and environmental interactions. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Neurol. Similar blood vessel weakness and breakage occurs in the eyes of some affected individuals. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. ClinVar; [VCV000389182.3]. Clin Neurol Neurosurg. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. 2017;57-58:29-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328961/, Sondergaard CB, Nielsen JE, Hansen CK, Christensen H. Hereditary cerebral small vessel disease and stroke. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Neurology. National Institute of Neurological Disorders and Stroke. doi: 10.1001/archophthalmol.2010.42, 10. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. Jeanne M, Gould DB. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. 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). Gould Syndrome is an ultra rare genetic, multi-system disorder. Deml B, Reis LM, Maheshwari M, Griffis C, Bick D, Semina E. Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. 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. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. 2010 January 31, 2019 doi: 10.1056/NEJMoa071906, 14. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. COL4A1/COL4A2 gene mutations description, symptoms and the sub-diagnosis. What is the prognosis of a genetic condition? 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. Depending on the cell type that acquires the mutation and when the mutation arises, the individual may have many or few cells with the mutation.