However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Col4a1 mutation generates vascular abnormalities correlated with The risk is the same for males and females. Progressive cerebral atrophies in three children with COL4A1 mutations. Danbury, CT 06810 Collagen alpha-1(IV) chain (COL4A1) is a protein that in humans is encoded by the COL4A1 gene on chromosome 13. Contact a health care provider if you have questions about your health. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. 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 It is passed through families in a autosomal dominant fashion. 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). The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 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. Probands' father had severe hypermetropia and bilateral cataracts. COL4A1/A2-related disorders are believed to affect females and males in equal numbers. (2008) 17:42433. (2014) 11:3612. 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). In most cases, an affected person has one parent with the condition. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. In the brain, intracerebral hemorrhage is the most frequent phenotype. Dev Med Child Neurol. When an individual tests positive for a mutation but does not manifest the effects, it is referred to as having incomplete or reduced penetrance. An official website of the United States government. IV-6 was born at 35 weeks after a pregnancy marked by gestational diabetes. MedlinePlus also links to health information from non-government Web sites. 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). Purpose of review: Firstly, it segregates within the family with the phenotype. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. 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. NCI CPTC Antibody Characterization Program. doi: 10.1212/WNL.0000000000000837, 20. 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. mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. This group rarely survives beyond 2 years. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. The https:// ensures that you are connecting to the These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. 2022 Sep;269(9):5153-5156. doi: 10.1007/s00415-022-11111-0. Suite 310 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. Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. 10.1161/STROKEAHA.110.581918. my mom suggested we call Boston Childrens Hospital. View CNBC interview with NORDs Peter Saltonstall and Boston Childrens Dr. Olaf Bodamer emphasizing the importance of investment in rare diseases. 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. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Arch Neurol. Arch Ophthalmol. 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). When we didnt feel we had any options left for treatment, These exceptions are nuanced and should be discussed with a genetic counselor. 4 Both . He underwent at birth neurosonography for axial hypotonia that revealed ventricular asymmetry and right frontotemporal dilatation (Figure 3). III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. 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). 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). In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. One patient (IV-3) was treated for spasticity and seizures with valproic acid. Therapies are based on the specific symptoms in each individual. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. Fax: 203-263-9938, Washington, DC Office The first time he came to meet us, Zeeva threw a sock at him. 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. CADASIL is an acronym that stands for: (C)erebral relating to the brain (A)utosomal (D)ominant a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder (A)rteriopathy disease of the arteries (blood vessels that carry blood away from the heart) (S)ubcortical relating to specific areas of the brain supplied by deep small arteries (I)nfarcts tissue loss in the brain caused by lack of blood flow to the brain, which occurs when circulation through the small arteries is severely reduced or interrupted (L)eukoencephalopathy lesions in the brain white matter caused by the disease and observed on MRI. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. The cells of the retina trigger nerve impulses that run from the optic nerve to the brain to form sight. Summary: 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. Phone: 203-263-9938 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. This variant highlights that the COL4A1 mutation should be sought in cases of familial ophthalmologic pathologies associated with congenital porencephaly or early onset leukoencephalopathy. 2009 Jun 25 [updated 2016 Jul 7]. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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. 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. It is ubiquitously expressed in many tissues and cell types. COL4A1 is a subunit of the type IV collagen and plays a role in angiogenesis. doi: 10.1212/WNL.0b013e3181eee440, 28. doi: 10.1038/gim.2015.30, 21. This condition causes mutations in genes that produce a specific type of collagen. What does it mean to have a COL4A1 - Little Braveheart | Facebook 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, . Clipboard, Search History, and several other advanced features are temporarily unavailable. A diagnosis can be confirmed through molecular genetic testing. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. People listened to us and to Zeeva in a very different and proactive way. 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. Still other individuals may not develop any symptoms until well into adulthood. 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. Neurol. Am J Neuroradiol. Collagen, type IV, alpha 1 - Wikipedia Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. In most people, small vessel disease in the brain does not cause symptoms. January 31, 2019 A diagnosis of COL4A1/A2-related disorders is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques. NORD is a registered 501(c)(3) charity organization. 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. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. PMC 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. 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. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Hum Mol Genet. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. government site. This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. doi: 10.1016/j.matbio.2016.10.003, 23. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Neurology. Changing lives of those with rare disease. 2012;54:569-574. https://www.ncbi.nlm.nih.gov/pubmed/22574627, Lanfranconi S, Markus HS. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. J Neurol Sci. (18) and Staals et al. One year later, right hemiparesis became clinically evident with a lack of right voluntary hand prehension in association with right hemineglect. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome doi: 10.1002/ajmg.10452, 18. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. As a result, the skin around the affected area may turn white or blue for a brief period of time and the area may tingle or throb. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Resource(s) for Medical Professionals and Scientists on This Disease: 2013;73:48-57. https://www.ncbi.nlm.nih.gov/pubmed/23225343, Kuo DS, Labelle-Dumais C, Gould DB. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. NORD is a registered 501(c)(3) charity organization. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. Before All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 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. 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). HANAC syndrome is caused by genetic changes in the COL4A1 gene. The number of genes implicated in epilepsy has grown rapidly in the past decade. 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. If either parent also carries the mutation, it is considered inherited. When these ropes are secreted, they assemble into net-like structures outside the cells. Stroke is a leading cause of death and serious long-term disability in developed nations. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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. Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. 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. To better define pathology caused by Col4a1 mutations, we characterized myopathy in two different Col4a1 mutant mouse strainsCol4a1 ex41 and Col4a1 G394V.We selected these strains from an allelic series of Col4a1 mutant mice because they showed the most severe myopathy according to NPN quantification in quadriceps while having different effects on [1(IV)] 2 2(IV) secretion.