This condition causes mutations in genes that produce a specific type of collagen. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. We described the phenotype associated to a likely pathogenic variant of the COL4A1 gene (c.2228G>T, p.Gly743Val) responsible for severe hypermetropia and familial porencephaly. doi: 10.1212/WNL.0000000000001309, 8. This is called genotype-phenotype correlation. In most cases, an affected person has one parent with the condition. Combinations of the in silico tool MutationTaster (21) and the Alamut software (ALAMUT package, http://www.interactivebiosoftware.com, France) predicted the variant to be pathogenic as it likely alters the protein structure/function due to a detrimental effect on 112 heterotrimers formation and type IV collagen stability. This variant p.Gly743Val combines hypermetropia in all heterozygotic patients and highly penetrant antenatal porencephaly (associated with motor and intellectual deficits). Stroke. 10.2174/092986710790936293. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. Neurology. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. One patient (IV-3) was treated for spasticity and seizures with valproic acid. (2012) 54:56974. 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: 10.1212/WNL.0000000000000837, 20. Fax: 203-263-9938, Washington, DC Office 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). Autosomal Dominant Familial Porencephaly Type I. Years published: 2019. Clinical case reports suggest a syndrome with characteristic core findings; however, much about the disorder is not fully understood. 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. The signs and symptoms can manifest at almost any age from before birth to old age. Resource(s) for Medical Professionals and Scientists on This Disease: (2017) 5758:2944. Quincy, MA 02169 All patients suffering from HANAC syndrome display retinal arteriolar tortuosity and occasional retinal hemorrhages. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Careers. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. Neurology. The surgery National Library of Medicine Eur J Paediatr Neurol. Copyright 2023 by Gould Syndrome Foundation -. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. By continuing to use this website, you agree to the Terms of Service & Privacy Policy, A Podcast For The Rare Disease Community, Policy Statements & Letters to Policymakers. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. 2010;17(13):1317-24. doi: The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. (2010) 75:7479. NORD strives to open new assistance programs as funding allows. Received: 06 January 2020; Accepted: 01 July 2020; Published: 11 September 2020. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. This review dsecribes the clinical spectrum of a newly identified disorder related to COL4A1 gene mutations. 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. It is important to discuss these concepts with a genetic counselor and understand their implications. The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. There are no standardized treatment protocols or guidelines for affected individuals. Copyright 2023 NORD National Organization for Rare Disorders, Inc. All rights reserved. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. 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. Mosaic individuals are likely less severely affected, or even asymptomatic, because they have many cells that secrete COL4A1 normally and that can compensate for those cells that cannot. Berg R, Aleck A, Kaplan A. Familial porencephaly. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) Federal government websites often end in .gov or .mil. What does it mean if a disorder seems to run in my family? (2006) 354:148996. Neurology. Neurology. Recent findings: MeSH doi: 10.1111/cge.12543. A similar term, variable expressivity, describes when affected individuals have widely varying signs and symptoms. Prenatal clinical manifestations in individuals with COL4A1/2 variants. Additionally, consultation with a genetic counselor is strongly recommended for affected individuals and their families and psychosocial support for the entire family is essential. Seattle, WA: University of Washington, Seattle; 1993-. Dr. Joseph Madsen was as wonderful in person as he had been on the phone. Mosaicism can contribute to both reduced penetrance or variable expressivity but other factors do as well. cutting tissue called the corpus callosum, then make some additional delicate The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). 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. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. 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 . Fax: 203-263-9938, Washington, DC Office A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. 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. Before Arch Ophthalmol. 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. Dev Med Child Neurol. More info about Gould Syndrome is available at https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. (2015) 17:84353. The degree of mosaicism is highly variable ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation and depends on the stage during development that the mutation occurred. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Schwarz JM, Cooper DN, Schuelke M, Seelow D. Mutationtaster2: Mutation prediction for the deep-sequencing age. Matrix Biol. Gould Syndrome is often characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology); however, many other aspects of the syndrome including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities continue to emerge and the full spectrum is still uncharacterized. The information on this site should not be used as a substitute for professional medical care or advice. 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. (2014) 83:122834. The size and location of cerebral cavities contributes to clinical variability. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. eCollection 2022. It is passed through families in a autosomal dominant fashion. Some of the patient advocacy organizations listed in the Resources section below provide support and information to affected individuals and their families. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. ACS Omega. . 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). This condition causes mutations in genes that produce a specific type of collagen. Front Aging Neurosci. Fazekas F, Chawluk JB, Alavi A. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. COL4A1/A2-related disorders are rare, genetic, multi-system disorders. Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain. Curr Opin Neurol. 2007 Aug;62(2):177-84. doi: 10.1002/ana.21191. Disease Overview. IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Gould Syndrome is an ultra rare genetic, multi-system disorder. 2010 Oct;152A(10):2550-5. doi: 10.1002/ajmg.a.33659. (1982) 40:5679. 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). Suggestive evidence for linkage to chromosome 13qter for autosomal dominant type 1 porencephaly. 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. Type IV collagen molecules attach to each other to form complex protein networks. 11:827. doi: 10.3389/fneur.2020.00827. Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. PMC This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. 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). This raises questions about what tests Liliane has a lot to be grateful for this holiday season. Graefe's Arch Clin Exp Ophthalmol. Novel heterozygous COL4A2 variant c.2572A>G, p.(I858V) mimicking Sneddon's and Divry van Bogaert Syndrome. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. COL4A1/A2-related disorders are caused by dominant mutations in the COL4A1 or COL4A2 genes. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. 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. 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 Bone. MedlinePlus also links to health information from non-government Web sites. seizure activity. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1-related disorders. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. Painful muscle cramps can occur and can develop before three years of age. Molecular genetic testing can detect variations in the COL4A1 and COL4A2 genes that cause these disorders, but is available only as a diagnostic service at specialized laboratories. The retina is the light-sensitive membrane that lines the inside of the eyes. IV-3 was diagnosed with ventriculomegaly in utero. 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). The site is secure. The networks formed by the COL4A1 and COL4A2 proteins are called basement membranes and are present in every organ of the body. doi: No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Treatment https://www.ncbi.nlm.nih.gov/pubmed/26610912. Please note that NORD provides this information for the benefit of the rare disease community. It affects mainly young adults, children and more typically neonates. This can occur if the carrier is a mosaic which means that some cells carry the mutation while other cells do not. (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). COL4A1 and COL4A2 are on Chr. Over 100 families have been identified with these disorders in the medical literature and many more cases are known that are not in the published literature. It looks like nothing was found at this location. percent confident in Dr. Madsen and the epilepsy team. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. 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. The strengths of our study are the extensive systemic work-up, the 5-year neurological follow-up, and the pluridisciplinary approach. (2015) 84:91826. 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 COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. As a result, type IV collagen molecules cannot attach to each other to form the protein networks in basement membranes. Genet Med. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. 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. 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/. Type IV collagen is an important component of basement membranes in many tissues, especially blood vessels 1-6. The COL4A1 stroke syndrome. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Suite 310 doi: 10.1038/nmeth.2890, 22. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. Fragile or damaged blood vessels or basement membranes in the kidneys can lead to blood in the urine (hematuria). Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. 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).