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. In the brain, intracerebral hemorrhage is the most frequent phenotype. But she is learning to read, enjoys swimming, horseback riding, and is a glass jewelry and pottery artist. doi: 10.1038/nmeth.2890, 22. COL4A1 and COL4A2 are on Chr. While muscle cramps may begin in childhood, many of the other symptoms do not appear until later in life. Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 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). 1779 Massachusetts Avenue The variant was confirmed by bidirectional fluorescence DNA sequencing (Sanger method). III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. 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). Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Front Aging Neurosci. However, in people with HANAC syndrome, these aneurysms typically do not burst. 1900 Crown Colony Drive 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). The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. 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. 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. 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, . Epub 2010 Jun 17. Many patients with COL4A1 and COL4A2 mutations have additional signs and symptoms that do not include the cerebral vasculature. Quincy, MA 02169 Epub 2016 Apr 24. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors. 2012;21:R97-R110. The https:// ensures that you are connecting to the Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. Unauthorized use of these marks is strictly prohibited. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Cataracts, which are a clouding of the lenses of the eyes, are often present from birth (congenital) and may be one of the first identifiable signs of the syndrome. (2009) 73:187382. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. II-2 had a limp since childhood attributed to forceps delivery. doi: 10.1212/WNL.0000000000001309, 8. However, these findings can be observed independently or in combinations, in many patients with COL4A1 and COL4A2 mutations. Neurology. Curr Opin Neurol. For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). This condition causes mutations in genes that produce a specific type of collagen. The ultimate goal of IAMRARE is to unite patients and research communities in the improvement of care and drug development. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. NORD is a registered 501(c)(3) charity organization. Neurology. Born at term after a 39-week pregnancy, IV-3 had an unremarkable first clinical evaluation at 3 months. Science. Affected individuals have kidney disease (nephropathy) causing blood in the urine (hematuria) that can either be seen by the naked eye (gross hematuria) or only visible when tested (microscopic hematuria). Neuropediatrics. Lanfranconi S, Markus HS. Phone: 203-263-9938 doi: 10.1001/archophthalmol.2010.42, 10. COL4A1 collagen type IV alpha 1 chain [ (human)] - National Center for At least 50 individuals with this condition have been described in the scientific literature. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). 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. Arch Ophthalmol. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. Neurology. doi: 10.1038/gim.2015.30, 21. These genes are the blueprints for two proteins that wind together like a long rope inside cells. 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. J Perinatol. cutting tissue called the corpus callosum, then make some additional delicate 10.1161/STROKEAHA.110.581918. Genet Med. Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. While there are other explanations, parental mosaicism should be considered. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Secondly, the p.Gly743Val variant is a missense mutation that shares features with other missense pathogenic mutations that occur in the COL4A1 gene exon 30: congenital porencephaly, epilepsy, and neuropsychological anomalies in p.Gly749Ser (23, 24), ophthalmologic defects and neuropsychological deficits in absence of systemic signs in variant p.Gly755Arg (2527), and antenatal fetal intracerebral hemorrhage, ocular anomalies associated to cerebral leukoencephalopathy in variant p.Gly773Arg (12, 28, 29). Copyright 2023 by Gould Syndrome Foundation -. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. 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). What does it mean to have a COL4A1 - Little Braveheart | Facebook 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/. Painful muscle cramps can occur and can develop before three years of age. N Engl J Med. (2017) 5758:2944. (2015) 17:40524. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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). In the human genome, there are 46 chromosomes. Am J Med Genet. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome Genet Med. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. PMC Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 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). If either parent also carries the mutation, it is considered inherited. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. J Genet Couns. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). Neurology. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. Am J Med Genet A. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Comparisons may be useful for a differential diagnosis: CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. 2015;17:843-853. https://www.nature.com/articles/gim2014210, Yoneda Y, Haginoya K, Kato M, et al. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. To use the sharing features on this page, please enable JavaScript. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. Still other individuals may not develop any symptoms until well into adulthood. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. Changing lives of those with rare disease. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. (2005) 308:116771. 2018;91:e2078-e2088. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. 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. No ophthalmological surgery was planned on annual control for any member, but only positive lens correction prescribed. Disease Overview. 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. FOIA https://www.clinicaltrialsregister.eu/, JOURNAL ARTICLES NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. 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. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The signs and symptoms can manifest at almost any age from before birth to old age. NCI CPTC Antibody Characterization Program. 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. Type IV collagen molecules attach to each other to form complex protein networks. small vessel disease: a systematic review. (2010) 14:1827. (No doctor had ever taken a call on their lunch break to speak with me). 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. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. The COL4A1 and COL4A2 genes were screened in proband IV-6. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Role of COL4A1 in small-vessel disease and hemorrhagic stroke. 2008 May;192(5):971-84; discussion 984-6. Stroke. When our 8-year-old daughter, Zeeva, giggles and runs in her walker to the swing set, its like watching pure childhood joy. Orignac I, Dousset V, Lacombe D, Orgogozo JM, Arveiler B, Goizet C. COL4A1 doi: 10.1126/science.1109418, 5. Ophthalmological features associated with COL4A1 mutations. Glaucoma is initially treated with topical medications and, if medical therapy is unsuccessful, surgery. She has regular physical, speech, and occupational therapy. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: September 2003. Interpretation of variant significance was done according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines (20). His bedside manner was incredible. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. It is not uncommon for an unaffected parent to have a severely affected child. Contact a health care provider if you have questions about your health. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Col4a1 mutation generates vascular abnormalities correlated with COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. COL4A1 encodes type IV collagen 1 chain, a crucial component of nearly all basement membrane including vasculature, renal glomerule and ocular structures. How can gene variants affect health and development? Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. There is in addition a specific phenotype called HANAC with constant nephropathy, muscle cramps and frequent intracranial aneurysms. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. Until just this year, her 16-year-old daughter Emily, who #1 Ranked Childrens Hospital by U. S. News & World Report. When a mutation occurs in one of these genes, the rope does not wind up properly and it stays inside the cell. 4 Both . In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.). Practical approach to the diagnosis of adult-onset - BMJ Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission. Orphanet: HANAC syndrome 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. Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. 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. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. 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. Fax: 203-263-9938, Washington, DC Office Powered by NORD, the IAMRARE Registry Platform is driving transformative change in the study of rare disease. This group rarely survives beyond 2 years. Disclaimer. Front. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. Arch Neurol. Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. Neurol. Genet Med. The first time he came to meet us, Zeeva threw a sock at him. HANAC syndrome is a rare condition, although the exact prevalence is unknown. These types of correlations can be difficult to detect in patients because of the broad genetic variability in humans. Please note that NORD provides this information for the benefit of the rare disease community. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, Calvas P,

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