Shah S, Ellard S, Kneen R, Lim M, Osborne N, Rankin J, et al. U.S. Department of Health and Human Services, Brain small-vessel disease with hemorrhage. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. Yet, as for all COL4A1 mutations, no specific treatment is currently available, and, due to the variable penetrance, adapted follow-up is challenging. The two genes that code for these proteins are tightly linked on chromosome 13 and dominant COL4A1 and COL4A2 gene mutations cause a highly variable, multisystem disorder. Arch Ophthalmol. Sci Rep. 2016;6:18602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728690/, Rannikmae K, Davies G, Thomson PA, et al. (2017) 5758:2944. Firstly, it segregates within the family with the phenotype. Phone: 617-249-7300, Danbury, CT office Phone: 203-263-9938 Research in mice with Col4a1 mutations suggests that the position of the mutation is very important. Other phenotypes include intracranial aneurysms, porencephaly, infantile hemiparesis, muscle cramps, optic nerve dysgenesis and secondary glaucoma. 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. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. 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. She had seizures every day, couldnt gain weight, sleep right, or generally enjoy her life. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. doi: 10.1212/WNL.0000000000001309, 8. The blood vessels as well as thin sheet-like structures called basement membranes that separate and support cells are weakened and more susceptible to breakage. Curr Med Chem. Neurology. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. People with HANAC syndrome develop kidney disease (nephropathy). The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in . doi: 10.1212/WNL.0b013e3181eee440, 28. The variant was found in IV-3 and IV-5 and not in asymptomatic relatives (III-4, IV-1, IV-4). IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. II-2 had a limp since childhood attributed to forceps delivery. These aneurysms have the potential to burst, causing bleeding within the brain (hemorrhagic stroke). The COL4A1 gene has 52 exons and most of the pathogenic variants are distributed across exons 10 to 47 in the triple-helix domain. To use the sharing features on this page, please enable JavaScript. MedlinePlus also links to health information from non-government Web sites. Quincy, MA 02169 10.1161/STROKEAHA.110.581918. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. N Engl J Med. The proportion of cases caused by a de novopathogenic variant is estimated to be at least 27%. percent confident in Dr. Madsen and the epilepsy team. In addition to porencephaly there can be other forms of damage to the brain present at birth. She also showed severe hypermetropia. Other causes of porencephaly were ruled out [maternal alloimmunization, trauma, peri-natal cerebral ischemia (normal Apgar scores at birth), and negative TORCH complex tests]. Please enable it to take advantage of the complete set of features! The site is secure. (2020). Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations. In people with HANAC syndrome, angiopathy affects several parts of the body. For example, networks of COL4A1 and COL4A2 are present in the basement membranes of blood vessels. COL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. 1900 Crown Colony Drive With genetic disorders, the type of mutation, or its location in the gene can sometimes be associated with varying outcomes. Neurology. The latest research shows that insufficient COL4A1/A2 in basement membranes damages different tissues in very different ways. Understanding what it has taken to get her to this point, though, is close to unimaginable. We recently described hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome in 3 families with closely localized COL4A1 mutations. Copyright 2023 by Gould Syndrome Foundation -, https://rarediseases.org/rare-diseases/col4a1-a2-related-disorders/. Our experience with Boston Childrens was very different from the other places we had been for epilepsy and neurology treatment. The management of COL4A1/A2-related disorders may require the coordinated efforts of a team of specialists. The effects of the disorder range from subtle or mild to severe, depending on associated brain abnormalities. Recent findings: 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. Surgery or endovascular therapy can be used to treat intracranial hemorrhage. (1987) 8:4216. PMC Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Zagaglia Selch C, Nisevic JR, et al. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. 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. The first time he came to meet us, Zeeva threw a sock at him. MeSH Thats not to say Zeeva hasnt had to work hard since the surgery. 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. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. In addition to providing strength and support to tissues, basement membranes provide instructional cues to cells. What are the different ways a genetic condition can be inherited? Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Front. Phone: 202-588-5700. Berg's criteria was used for porencephaly (16, 17) and white matter hyperintensities were characterized as in Fazekas et al. 10.2174/092986710790936293. 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. COL4A1/A2-related disorders can also be associated with a variety of abnormalities affecting the front or back of the eyes. doi: 10.1056/NEJMoa1707914, 6. Liu X, Yang Q, Tang L, He J, Tian D, Wang B, Xie L, Li C, Fan D. Front Neurol. Rarely, new mutations in the gene occur in people with no history of the disorder in their family. Genet Med. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. The first reports of human COL4A1 mutations were in patients with autosomal dominant porencephaly and a more recent study found that COL4A1 mutations were found in ~16% of patients with porencephaly. Changing lives of those with rare disease. In the eye, patients may have retinal arteriolar tortuosities and retinal hemorrhages or anterior segment dysgenesis. Muscle cramps can be spontaneous or triggered by exercise. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Stroke is often the first symptom of this condition, typically occurring in mid-adulthood. Am J Med Genet. In the brain, intracerebral hemorrhage is the most frequent phenotype. Children inherit a full complement of chromosomes from each of their parent and so we carry two copies of each gene. Accessibility Lanfranconi S, Markus HS. 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. IV-3 and IV-6 are closely followed by a neuropediatrician (VW). The signs and symptoms can manifest at almost any age from before birth to old age. Treatment While there are other explanations, parental mosaicism should be considered. Our data testing the effects of established mutations on collagen biosynthesis suggest that the intracellular retention of mutant COL4A1 proteins at the expense of their secretion appears to be a common effect of many COL4A1 mutations. 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. Oral expression was reduced and neuropsychological testing revealed language delay with a prominent expression deficit. 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. What does it mean if a disorder seems to run in my family? 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. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Available at: https://www.ncbi.nlm.nih.gov/books/NBK7046/ Accessed January 28, 2019. Neurology. Affected individuals may also experience seizures and migraine headaches accompanied by visual sensations known as auras. ACS Omega. When this enzyme is elevated, it is a sign of muscle damage. Some of these patients have been described as having HANAC syndrome, which is an acronym for hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. Nearly half of these participants were diagnosed with infantile spasms. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M GC. Bone. small vessel disease: a systematic review. 1900 Crown Colony Drive HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. 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. 1779 Massachusetts Avenue 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. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. 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). Exome sequencing in 32 patients with anophthalmia/microphthalmia and developmental eye defects. No microbleeds or cystic cavities were found. Volonghi I, Pezzini A, Del Zotto E, Giossi A, Costa P, Ferrari D, Padovani A. No use, distribution or reproduction is permitted which does not comply with these terms. Rannikme K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al. Epub 2022 Apr 14. 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. doi: Xia XY, Li N, Cao X, Wu QY, Li TF, Zhang C, et al. 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). 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. 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. Yet, five siblings, showing mild phenotype even in the second generation support a Mendelian transmission with variable expressivity and no other mechanism. Fax: 203-263-9938, Washington, DC Office Clinical Testing and Workup Raynaud phenomenon is typically triggered by changes in temperature and usually causes no long term damage. 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. sharing sensitive information, make sure youre on a federal 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. Zeeva is one of fewer than 150 people in the world with a rare disease called Gould Syndrome or COL4A1/A2. Would you like email updates of new search results? As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. Systemic work-up including renal function, CK levels, urinary sediment test, and renal ultrasound proved unremarkable. What is the prognosis of a genetic condition? J Neurol Sci. Fax: 203-263-9938, Washington, DC Office The COL4A1 and COL4A2 genes were screened in proband IV-6. Some individuals with COL4A1-related brain small-vessel disease do not have any signs or symptoms of the condition. 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. (2017) 377:111931. 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/. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. This is called genotype-phenotype correlation. Changing lives of those with rare disease. A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly. Stroke. Doctors and researchers to bring research and medical therapeutic options to those affected. Exon mutations of the COL4A1 genes are responsible for a broad spectrum of cerebral, ocular, and systemic manifestations. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. ClinVar; [VCV000389182.3]. If either parent also carries the mutation, it is considered inherited. doi: 10.1111/cge.12543. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. Bennett RL, French KS, Resta RG, Doyle DL. 2009 Dec 1;73(22):1873-82. doi: 10.1212/WNL.0b013e3181c3fd12. 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. See our, COL4A1-related brain small-vessel disease, URL of this page: https://medlineplus.gov/genetics/condition/col4a1-related-brain-small-vessel-disease/. Collagen type IV alpha 1 (COL4A1) and 2 (COL4A2) are extracellular matrix proteins that together constitute a major component of nearly all basement membranes. 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. (2013) 73:4857. 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). The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. can also contribute. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. IV-3 was diagnosed with ventriculomegaly in utero. Paques M, Ronco P. Novel COL4A1 mutations associated with HANAC syndrome: a role Stroke is a leading cause of death and serious long-term disability in developed nations. PV and VW followed the children at the Neuropediatrics clinic of the same hospital. 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. doi: 10.1136/jmg.2005.035584, 15. 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. Washington, DC 20036 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. (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). Neurology. (2015) 88:46873. Some people with COL4A1-related brain small-vessel disease have an eye abnormality called Axenfeld-Rieger anomaly. 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. Bethesda, MD 20894, Web Policies Copyright 2020 Scoppettuolo, Ligot, Wermenbol, Van Bogaert and Naeije. Gould DB, Phalan FC, Breedveld GJ, Van Mil SE, Smith RS, Schimenti JC, et al. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459649/, Federico A, Di Donato I, Bianchi S, et al. Individuals with this condition are at increased risk of having more than one stroke in their lifetime. This condition causes mutations in genes that produce a specific type of collagen. It is possible that insufficient collagen in the basement membrane predisposes blood vessels in the brain to leak or rupture. III-3 was informed of the genetic diagnosis and is now regularly followed and screened for cataracts and brain aneurysms. INTERNET Purpose of review: 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). and transmitted securely. IV-3 goes to a normal school, but special schooling is required for IV-6. Please note that NORD provides this information for the benefit of the rare disease community. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms. Some may only develop specific symptoms such as isolated migraines or strokes in childhood or adulthood. (2010). Because the collagen is found throughout the body, COL4A1/A2 affects many organ systems, including the brain, kidneys, eyes, and muscles. 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). For asymptomatic patients, cerebral and vessel imaging for aneurysm screening and ophthalmologic follow-up are indicated (2). When these ropes are secreted, they assemble into net-like structures outside the cells. Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. 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). Porencephaly refers to the formation of fluid-filled cysts or cavities within of the brain. (2004) 62:16135. 8600 Rockville Pike The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Contact a health care provider if you have questions about your health. 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). 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. Suite 310 Cephalic Disorders Fact Sheet. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. Last updated: For example, the position of the mutation along the length of the protein can influence the severity of cerebrovascular disease and mutations in functional subdomains can influence the likelihood of tissue-specific involvement (for example, muscle). 2009 Jun 25 [updated 2016 Jul 7]. The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. doi: 10.2214/ajr.149.2.351, 19. Bookshelf Congenital Cephalic Disorders The extents to which intracellular and/or extracellular insults contribute to pathology remain an open question. Years published: 2019. The heterozygous variant c.2228G>T [NM_001845.4(COL4A1):c.2228G>T (p.Gly743Val)] was identified in exon 30 of the COL4A1 gene. 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 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. Abnormal blood vessels in the brain are a major consequence of COL4A1 and COL4A2 gene mutations. Autosomal Dominant Familial Porencephaly Type I. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Disease Overview. eCollection 2022 Nov 8. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. These exceptions are nuanced and should be discussed with a genetic counselor. 2010;41:e513-518. Image showed ventricular asymmetry and brain MRI confirmed right frontotemporal dilatation (B). COL4A1/A2-related disorders are dominant genetic disorders. 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. doi: 10.1056/NEJMoa053727, 7. Neurology. He was confident this would reduce or stop the eCollection 2022. 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). Quincy, MA 02169 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. 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. Symptoms of the following disorders can be similar to those of COL4A1/A2-related disorders. 2015;84:918-926. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667/, Meuwissen ME, Halley DJ, Smit LS, et al. 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.
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