doi: 10.1212/WNL.0000000000006567, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Neurology. 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. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJMG, Barkhof F, Rizzu P, Van der Schoor SRD, et al. 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. What does it mean if a disorder seems to run in my family? 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 page is currently unavailable. (2014) 11:3612. Services that may be beneficial for some affected individuals include medical, social, and/or vocational services such as special remedial education. Zagaglia Selch C, Nisevic JR, et al. The human phenotypes are extremely variable between patients and between families, with disease onset as early as in the fetal period. HANAC syndrome is characterized by angiopathy, which is a disorder of the blood vessels. Suite 310 The size and location of cerebral cavities contributes to clinical variability. Illumina's Sequencing by Synthesis (SBS) technology (MiSeq Personal Sequencer, Illumina) analyzed the generated amplicons. (2007) 357:268795. Lenses corrected for hypermetropia. PMC COL4A1 mutations cause progressive retinal neovascular defects and retinopathy. Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, et al. cutting tissue called the corpus callosum, then make some additional delicate Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, IV-3 and IV-6 are closely followed by a neuropediatrician (VW). Please note that NORD provides this information for the benefit of the rare disease community. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, Hernandez-Hernandez L, et al. Genet Med. This condition causes mutations in genes that produce a specific type of collagen. The COL4A1 gene provides instructions for making one component of a protein called type IV collagen. Early intervention is important in ensuring that children with reach their highest potential. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of a group of conditions called the COL4A1 -related disorders. Lanfranconi S, Markus HS. National Institute of Neurological Disorders and Stroke. This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. 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. When these ropes are secreted, they assemble into net-like structures outside the cells. COL4A1 mutations as a monogenic cause of cerebral Zenteno JC, Cresp J, Buentello-Volante B, Buil JA, Bassaganyas F, Vela-Segarra JI, et al. Neurology. 2014 Mar;261(3):500-3. doi: 10.1007/s00415-013-7224-4. Email: [emailprotected], Some current clinical trials also are posted on the following page on the NORD website: (2014) 83:122834. BMC Med Genet. 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. Molecular analysis in the father disclosed a heterozygous variant c.2228G>T (p.Gly743Val) in exon 30 of the COL4A1 gene that segregated with the phenotype. 2010;17(13):1317-24. doi: 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. COL4A1 Syndrome CADASIL The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Type IV collagen molecules attach to each other to form complex protein networks. The disorder causes many symptoms, not the least of which are strokes and epilepsy. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Muscle cramps can be spontaneous or triggered by exercise. (2005) 308:116771. Hereditary cerebral small vessel diseases: a review. 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. came with risks and was the hardest decision we had ever faced, yet we felt 100 Stroke. Dr. Madsen suggested Zeeva have an operation called a ACS Omega. However, it is also very likely that basement membrane defects also contribute to abnormal signaling and function of cells that form blood vessels in the brain and elsewhere. This analysis represents a subanalysis of the 35 out of 60 children <=18 years of age who reported a history of seizures. Treatment trials will be critical to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COL4A1/A2-related disorders. As the name suggests, mutations in the COL4A1 gene cause COL4A1-related brain small vessel disease. ), A variety of rare genetic disorders may have symptoms similar to those found in COL4A1/A2-related disorders. Summary. In people with COL4A1-related brain small-vessel disease, the vasculature in the brain weakens, which can lead to blood vessel breakage and stroke. 2022 Mar 24;3:100140. doi: 10.1016/j.cccb.2022.100140. However, in rare pathologies with few cases, we may have missed undescribed or subclinical manifestations. 2009 Jun 25 [updated 2016 Jul 7]. 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. 1900 Crown Colony Drive A dashed arrow indicates secondary atrophy in the left cerebral peduncle. Feb;24(1):63-8. doi: 10.1097/WCO.0b013e32834232c6. Therapies are based on the specific symptoms in each individual. The COL4A2 test was negative. 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. Gould Syndrome is diagnosed following a genetic test revealing a mutation in COL4A1 or COL4A2. 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. However, there are exceptions that depend on precisely when and where the mutation arose. Congenital Cephalic Disorders Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. 2022 May 27;13:827165. doi: 10.3389/fneur.2022.827165. Ten months later, the left hemiparesis was observed with a lack of voluntary prehension on his left side without spasticity. Individuals with HANAC syndrome also experience a variety of eye problems. This site needs JavaScript to work properly. (2009) 73:187382. Front Aging Neurosci. 2022 Oct 26;7(44):39680-39689. doi: 10.1021/acsomega.2c03360. COL4A1 is an essential component for basal membrane stability. Aneurysms are bulges or enlargements of a blood vessel caused by weakening of the wall of the blood vessel. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. 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. Other eye problems associated with HANAC syndrome include a clouding of the lens of the eye (cataract) and an abnormality called Axenfeld-Rieger anomaly. This report highlights both the broad spectrum of COL4A1 mutations and the yield of testing the COL4A1 gene in familial ophthalmological and brain disorders. How are genetic conditions treated or managed? *Correspondence: Pasquale Scoppettuolo, Pasquale.scoppettuolo@gmail.com, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3, Creative Commons Attribution License (CC BY). Rarely, new mutations in the gene occur in people with no history of the disorder in their family. No patient had cramps, cardiac symptoms, or abnormalities or Raynaud phenomenon. Would you like email updates of new search results? Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) 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). percent confident in Dr. Madsen and the epilepsy team. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cephalic-Disorders-Fact-Sheet Accessed January 28, 2019. National Taiwan University Hospital, Taiwan, Kaohsiung Chang Gung Memorial Hospital, Taiwan, Carrera de Medicina, Universidad Cientfica del Sur, Peru, Federal University of Rio Grande do Sul, Brazil. Affected infants and children can exhibit delays in reaching developmental milestones and varying degrees of intellectual disability. http://www.centerwatch.com/, For information about clinical trials conducted in Europe, contact: 2009 Jun 25 [Updated 2016 Jul 7]. (D) III- 3Brain MRI showed small asymptomatic lesions in white matter. Gould Syndrome Foundation (COL4a1/COL4A2) seeks to educate the community on the rare disease COL4A1 and it's subcategorical diagnosis'. This group rarely survives beyond 2 years. In the front of the eye, patients can have abnormally small eyes (microphthalmia), cataracts (cloudy lenses), and anterior segment dysgenesis (Axenfeld-Rieger). doi: 10.1002/ajmg.10452, 18. Cavalin M, Mine M, Philbert M, et al. Zeevas brain to treat a cyst in her brain caused by porencephaly. The conditions in this group have a range of signs and symptoms that involve fragile blood vessels. Available online at: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000389182.3 (accessed March 20, 2020). 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. MedlinePlus links to health information from the National Institutes of Health and other federal government agencies. TTY: (866) 411-1010 Slavotinek AM, Garcia ST, Chandratillake G, Bardakjian T, Ullah E, Wu D, et al. COL4A1 -related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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). The expressivity of the disease is highly variable with high intra- and inter-familial variability (2). IV-5 had microcephaly without motor deficits, a language delay, a mental retardation (IQ of 62) that required adapted schooling, and severe hypermetropia. 30. After the COL4A1 mutation was found, systemic manifestations of COL4A1 mutations were investigated. 2011 Role of COL4A1 in small-vessel disease and hemorrhagic stroke. 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. 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. doi: 10.1056/NEJMoa1707914, 6. GeneReviews. 2017 Jan;66:100-103. doi: 10.1016/j.pediatrneurol.2016.04.010. The variability and severity of symptoms is significant and how COL4A1/A2-related disorders will potentially affect an individual can be unique. 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.) 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. 1779 Massachusetts Avenue Each child of an individual with a COL4A1-related disorder has a 50% chance of inheriting the pathogenic variant. What does it mean if a disorder seems to run in my family? Jeanne M, Gould DB. doi: 10.1126/science.1109418, 5. She, then, developed seizures which were controlled by valproic acid. 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). Basement membranes without these networks are unstable, leading to weakening of the tissues that they surround. Thats not to say Zeeva hasnt had to work hard since the surgery. doi: 10.1055/s-0031-1275343, 24. 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). COL4A1-related brain small-vessel disease is characterized by weakening of the blood vessels in the brain. (2013) 73:4857. To date, over 50 pathogenic or likely pathogenic variants have been described in the COL4A1 gene, most of them missense (2). Together, these studies suggest that certain unknown variants of COL4A1 and COL4A2 might contribute to chronic vascular dysfunction. It affects mainly young adults, children and more typically neonates. Bennett RL, French KS, Resta RG, Doyle DL. 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. At 2 years old, IV-6 presented obvious left hemiparesis but could move without help. Epub 2014 Jan 5. Gunda B, Mine M, Kovcs T, Hornyk C, Bereczki D, Vrallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. J Neurol. People with HANAC syndrome develop kidney disease (nephropathy). In addition the whole spectrum of the phenotype is not yet known and there are many asymptomatic patients. By continuing to use this website, you agree to the Terms of Service & Privacy Policy. Comparison of Clinical, Radiographic, and Histological Features in COL4A1 Syndrome Compared With Other Single Gene Disorders Causing SVD. Plaisier E, Chen Z, Gekeler F, Benhassine S, Dahan K, Marro B, Alamowitch S, Paques M, Ronco P. Am J Med Genet A. In cases where the mutation is inherited, the carrier parent is often clinically unaffected. COL4A1 disorder is probably largely underestimated because of its multisystem and variable phenotype. The limitations include the limited number of tested members (only two generations) due to a large family spread over Europe and not fully accessible. Type IV collagen molecules attach to each other to form complex protein networks. 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. Antiinflammatory therapy with canakinumab for atherosclerotic disease. https://nord1dev.wpengine.com/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/, For information about clinical trials sponsored by private sources, contact: Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. 2017;155:45-57. https://www.ncbi.nlm.nih.gov/pubmed/28254515, Alavi MV, Mao M, Pawlikowski BT, et al. CADASIL patients can experience progressive memory loss, deterioration of intellectual abilities and loss of balance with a progressive worsening of these symptoms, but symptoms are usually less severe and occur later in life. Aura refers to additional neurological symptoms that occur with, or sometimes before, the development of the migraine headache. Axenfeld-Rieger anomaly and cataract can cause impaired vision. 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. Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. 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. Zeeva woke up after a ten-hour procedure, opened her eyes, and it felt like we were seeing her for the first time. Stroke. Gould Syndrome is an ultra rare genetic, multi-system disorder. (For more information on this disorder, choose cadasil as your search term in the Rare Disease Database. Childhood presentation of COL4A1 mutations. Drugs that prevent irregular heartbeats (anti-arrhythmic medications) are used to treat supraventricular arrythmia. NORD is a registered 501(c)(3) charity organization. His bedside manner was incredible. Pathology. Aguglia U, Gambardella A, Breedveld GJ, Oliveri RL, Le Piane E, Messina D, et al. Neuropediatrics. Suite 310 doi: 10.1212/WNL.0000000000000837, 20. 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 The COL4A1 gene mutations that cause HANAC syndrome result in the production of a protein that disrupts the structure of type IV collagen. These protein networks are the main components of basement membranes, which are thin sheet-like structures that separate and support cells in many tissues. doi: 10.1007/s00417-014-2800-6, 12. functional hemispherectomy. Urine analysis to test for blood or excess protein can be used to evaluate renal function and identify if the kidneys might be affected. January 31, 2019 If the mutation arises after fertilization, then some cells will carry the mutation and others will not this is called mosaicism. (1982) 40:5679. (2010) 14:1827. Teaching families how to advocate for their loved ones and access medical information. COL4A1-related brain small-vessel disease is part of a group of conditions called the COL4A1-related disorders. Supporting children in their development to reduce handicaps and combining their follow-up with parent counseling could be considered as an ideal approach. 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. 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. Progressive cerebral atrophies in three children with COL4A1 mutations. In addition to porencephaly there can be other forms of damage to the brain present at birth. 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). (2006) 43:4905. 1779 Massachusetts Avenue There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. III-3 was asymptomatic but for severe hypermetropia and bilateral cataracts. 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. The severity of the condition varies greatly among affected individuals. What is the prognosis of a genetic condition? Bethesda, MD 20894, Web Policies Ronco P. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. 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.